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					                                            PHARMACOLOGY

Explain the concept of drug action with respect to:
receptor theory
enzyme interactions
physico-chemical interactions

Drug action can be distinguished into three categories:

          Receptors
          Enzymatic interactions
          Physic-chemical interactions



Receptor occupation theory

          After studying quantitative aspects of drug action, Clark (1937) propounded a theory of drug
           action based on occupation of receptors by specific drugs and that the pace of the cellular
           function can be altered by interaction of these receptors with the drugs
          Interaction between drug (D) and receptor (R) is governed by law of mass action and the
           effect (E) to be a direct function of drug receptor complex
                             D + R  DR  E



           Postulates of the theory:
                o The intensity of response is proportional to the fraction of receptors occupied by
                    the drug and maximal response occurs when all the receptors are occupied
                o Drugs exert an “all or none” action on each receptor i.e. either the receptor is fully
                    activated or not at all, there is no partial activation
                o A drug and its receptor have complementary structural features and stand in rigid
                    ‘lock and key’ relationship


           Modifications by ariens and Stephenson in 1950:
              o All receptors need not be occupied for maximal response; for full agonists there
                   often was a large receptor reserve
              o Affinity: ability of the drug to combine with the receptor
              o Intrinsic activity (efficacy ): ability of the drug to activate the receptor consequent
                   to receptor occupation
              o It should be possible to submaximally activate a receptor and ‘all or none’ action is
                   not necessary
              o Theoretical quantity (S) was interposed denoting strength of stimulus imparted to
                   the cell by the activation of the receptor

                     SCAN EQUATIONS FROM PG 37
          Depending upon the agonist, DR could generate a stronger or weaker S, probably as a
           function of the conformational change brought about by the agonist in the receptor
       Partial agonists because they submaximally stimulate a receptor, should be capable of
        bringing about intermediate degrees of conformational change in the receptor. Further a
        drug could induce changes in the receptor which may make it either more or less favourably
        aligned to combine with the drug. Thus the receptor can not be considered to have rigid
        conformation
    The two properties of affinity and intrinsic activity are independently variable, accordingly:
            o Agonists-have both affinity and maximal intrinsic activity (IA=1) eg adrenaline,
                 histamine, morphine
            o Competitive antagonists: have affinity but no intrinsic activity (IA=0) eg propanolol,
                 atropine, chlorpheniramine, naloxone
            o Partial agonists: have affinity and submaximal intrinsic activity (IA between 0 to1) eg
                 nalorphine
            o Inverse agonists: have affinity but intrinsic activity with a minus sign (IA between 0
                 to – 1) eg: DMCM
Types of receptor – drug interactions: (usually co-exist)

       Ionic
       Hydrogen bonding
       Hydrophobic
       Van der Waals
       Covalent (usually leads to prolonged action)



ENZYMATIC INTERACTION:

Almost all biological reactions are carried out under catalytic influence of enzymes

Drugs increase or decrease the rate of enzymatically mediated reaction

Enzymatic interaction:

       Stimulation
       Inhibition
            o Non-specific inhibition
            o Specific inhibition
                     Competitive
                            Equilibrium type
                            Non-equilibrium type
                     Non-competitive

STIMULATION

Enzymatic activity can be increased by drugs by way of :

       Stimulation – wherein the affinity of the enzyme for it substrate increases and hence the
        rate constant (Km) of the reaction decreases. Eg – arenaline stimulates adenylyl cyclase,
        pyridoxine acts as a co-factor and increases decarboxylase activity
       Induction - synthesis of more enzyme protein eg many drugs induce microsomal enzymes,
        methicillin induce penicillinase in some bacteria
INHIBITION

      Non-specific inhibition – drugs alter the tertiary structure of the enzyme protein and thus
       inhibit it. Eg heavy metal salts, strong acids and alkalies, alcohol, formaldehyde, phenol
      Specific inhibition – inhibition of particular enzyme
           o Competitive inhibition
                      Equilibrium type competitive inhibition:
                              The drug competes with normal substrate or co-enzyme so that
                                  new equilibrium is achieved in the presence of drugs
                              ↑Km but Vmax remains unchanged – i.e. higher substrate conc. Is
                                  required to achieve ½ maximal reaction velocity, but if the substrate
                                  conc. Is sufficiently increased, it can displace the drug and same
                                  maximal velocity can be achieved
                              Examples- physostigmine and neostigmine compete with
                                  acetylcholine for cholinesterase; sulfonamides compete with PABA
                                  for bacterial folate synthesis. Example of drug competing with
                                  coenzyme – warfarin competes with vitamin K which acts as a
                                  coenzyme for enzymes synthesizing clotting factors
                      Non-equilibrium type competitive inhibition –
                              Drugs react with the same catalytic site of the enzyme but either
                                  form strong co-valent bonds or have such high affinity for the
                                  enzyme that the normal substrate is not able to displace the drug
                              ↑Km and ↓Vmax
                              Examples: organophosphates react covalently with the esteric site
                                  of the enzyme cholinesterase, methotrexate affinity for
                                  dihydrofolate reductase
           o Non-competitive inhibition:
                      The drug reacts with the adjacent site and not with the catalytic site, but
                         alters the enzyme in such a way that it loses its catalytic property
                      Km is unchanged, Vmax is reduced
                      Examples – acetazolamide inhibition of carbonic anhydrase, Digoxin
                         inhibition of Na-K atpase, Aspirin & indomethacin inhibition of
                         cyclooxygenase, theophyline inhibition of phosphodiesterase
PHYSICO-CHEMICAL INTERACTION

Physical action:

       A physical property of the drug is responsible for its action
       Examples:
            o Mass of drug- bulk laxatives
            o Adsorptive property – charcoal
            o Osmotic activity – Mannitol
            o Radio-activity – 131I
            o Radioopacity – contrast medium

Chemical action

       The drug reacts extracellularly according to simple chemical equations:
       Examples
            o   Antacids neutralize gastric HCL
            o   Acidfying (NH4CL) and alkalinizing (NaHCO3) agents react with buffers in plasma and
                alter pH of urine
            o   Oxidizing agents (KMnO4, I2) are germicidal and inactivate ingested alkaloids
            o   Chelating agents (Cal. Disod. Edentate, BAL, penicillamine) sequester toxic metals.



To explain receptor activity with regard to:
ionic fluxes
second messengers and G proteins
nucleic acid synthesis
evidence for the presence of receptors
regulation of receptor number and activity
structural relationships

Two functions of a receptor:

       ligand binding - ligand-binding domain
       message propagation - effector domain
            o Directly effect on its cellular target - effector protein(s)
            o Conveyed by intermediary cellular signaling molecules called transducers.



The mechanism of translation of receptor activation into functional response can be grouped into 4
major categories:

       G-protein coupled receptors
       Receptors with intrinsic ion channel
       Enzymatic receptors
       Receptors regulating gene expression



Receptors with intrinsic ion channels:

       ligand-gated ion channels or receptor operated channels
       Convey their signals by altering the cell's membrane potential or ionic composition.
       Example - nicotinic cholinergic receptor, the -aminobutyric acid A (GABAA) receptor
       Agonists directly operate ion channels without the intervention of any coupling protein or
        second messenger hence the response is fastest



Second messengers and G proteins

G protein coupled receptors:
       Large family of cell membrane receptors which are linked to the effector
        (enzyme/channel/carrier protein) through one or more GTP activated proteins (G proteins)
        for response effectuation
       The molecule has 7 alpha helical membrane spanning hydrophobic amino acid segments
        which run into 3 extra cellular and 3 intracellular loops
       The agonist binding site is located somewhere between the helices on the extracellular
        surface while another recognition site formed by cytosolic segments binds the coupling G
        protein
       G protein float in the membrane with their exposed domain lying in the cytosol and are
        heterotrimeric in composition (α,β & γ subunit)
       In the inactive state GDP is exposed to their exposed domain ; activation through the
        receptor leads to the displacement of GDP by GTP
       The active alpha subunit carrying GTP dissociates from other 2 subunits to either activate or
        inhibit the effector
       The alpha subunit has GTPase activity: the bound GTP is slowly hydrolyzed to GDP: the α
        subunit then dissociates from the effector to rejoin the other subunits
       There are three major effector pathways through which G coupled receptors function:
             o Adenyl cyclase : CAMP pathway
             o Phospholipase C: IP3-DAG pathway
             o Channel regulation



Adenyl cyclase: CAMP pathway – activation of AC results in intracellular accumulation of second
messenger cAMP which functions almost exclusively through cAMP-dependent protein kinase (PKA).
The PKA phosphorylates and alters the function of many enzymes, ion channels, carriers and
structural proteins to manifest as increased contractility / impulse generation relaxation,
glycogenolysis, lipolysis etc the reverse occurs when the AC is inhibited by the inhibitory Gi protein

 SCAN diagram from pg 41
Phospholipase C: IP3-DAG pathway: activation of phospholipase C hydrolyses the membrane
phospholipid, phosphatidylinositol-4,5-bisphosphate IP3 + DAG. IP3 binds to receptors on Ca2+
release channels in the Ca2+ stores of the endoplasmic reticulum, triggering the release of Ca2+. Ca2+
inturn can – (i) bind to & regulate ion channels (e.g., large conductance Ca2+-activated K+ channels),
(ii) bind to calmodulin, and the resulting Ca2+-calmodulin complex then can bind ion channels (e.g.,
small conductance Ca2+-activated K+ channels) or to intracellular enzymes such as Ca2+-calmodulin-
dependent protein kinases (e.g., CaMKII, MLCK, and phosphorylase kinase). DAG binds (i)protein
kinase C (PKC)  promotes association with the cell membrane and lowering its requirement for
activation by Ca2+ (ii) other proteins that participate in non-kinase-mediated regulation of processes
such as neurotransmitter release.

SCAN diagram from pg 42
Transcription Factors.
Receptors for steroid hormones, thyroid hormone, vitamin D, and the retinoids are soluble DNA-
binding proteins that regulate the transcription of specific genes

These receptors act as dimerssome as homodimers and some as heterodimers

Thr receptors have three regions:

      Ligand binding domain: near carboxy terminus  binds hormones
      DNA binding domain: mediates binding to specific sites on the genome to activate or inhibit
       transcription of the nearby gene. These regulatory sites in DNA are likewise receptor-
       specific: the sequence of a "glucocorticoid-response element," with only slight variation, is
       associated with each glucocorticoid-response gene
      amino-terminal region: provides the activation function (AF) domain essential for
       transcriptional regulation.




Evidence for drug action through receptors



      Many drugs exhibit structural and stereospecificity and he3nce cells may have some
       mechanism to recognize a particular chemical configuration and three dimensional
       structure.
           o Example of structural specificity – iso-propyl substitution on the ethylamine side
               chains of sympathetic drugs produces compounds with marked cardiac and
               bronchial activity
           o Example for stereo specificity – levo noradrenaline is 10 times more potent than
               dextro noradrenaline


      Competitve antagonism is seen between specific agonist and antagonist. Langley in 1878
       observed the antagonism between pilocarpine and atropine and proposed that they reacted
       with the same receptive substance on cell
      It was calculated by clark that adrenaline and acetylcholine produce their maximal effect on
       frog’s heart by occupying only 1/6000th of the cardiac cell surface – thus special regions of
       reactivity to such drugs must be present on the cell




Receptor regulation:



      Receptor exist in dynamic state; their density and efficacy is subject to regulation by the
       level of ongoing activity and other physiopathological influences
      Super-sensitization: In tonically active systems, prolonged deprivation of the agonist results
       in supersensitivity of the receptor as well as the effector system to the agonist
           o  Example – clonidine and opioid withdrawal
           o  Mechanism involved: (1) unmasking of receptors (2) proliferation of receptors (3)
              accentuation of signal amplification by the transducer
      De-sensitization: continued intense receptor stimulation causes de-sensitization
           o Example – asthma patients treated continuously with beta agonists
           o Mechanisms involved:
                   1. Masking or internalization of receptor: develops quickly wears off quickly
                   2. Decreased synthesis/ increased destruction of the receptor: develops over
                       week or months and recedes slowly
           o Heterologous desensitization - response to all agonists which act through different
              receptors but produce the same overt effect is decreased by exposure to any one of
              these agonists
           o Homologous desensitization – desensitization is limited to agonists of the receptor
              being repeatedly activated



Second messenger system:
Secondary messenger system is a method of cellular signaling whereby a diffusable signaling
molecule is rapidly produced/secreted, which can then go on to activate effector proteins within the
cell to exert a cellular response.

Types of secondary messenger molecules

There are three basic types of secondary messenger molecules:
    Hydrophobic molecules: water-insoluble molecules, like diacylglycerol, and
        phosphatidylinositols, which are membrane-associated and diffuse from the plasma
        membrane into the intermembrane space where they can reach and regulate membrane-
        associated effector proteins
    Hydrophilic molecules: water-soluble molecules, like cAMP, cGMP, IP3, and Ca2+, that are
        located within the cytosol
    Gases: nitric oxide (NO) and carbon monoxide (CO), which can diffuse both through cytosol
        and across cellular membranes.

These intracellular messengers have some properties in common:
    They can be synthesized/released and broken down again in specific reactions by enzymes
        or ion channels.
    Some (like Ca2+) can be stored in special organelles and quickly released when needed.
    Their production/release and destruction can be localized, enabling the cell to limit space
        and time of signal activity.

Common mechanisms of secondary messenger systems
To define and explain dose-effect relationships of drugs with reference to:
graded and quantal response
therapeutic index
potency and efficacy
competitive and non-competitive antagonists
partial agonists, mixed agonist-antagonists and inverse agonists

GRADED DOSE-RESPONSE RELATIONS
Figure depicts graded dose-response curves that relate dose of four different drugs to the
magnitude of a particular therapeutic effect




Potency
Drugs A and B are more potent than drugs C and D

Curves A&B are more left shifted than C&D i.e same efficacy is reached with lower dose



Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of
that drug's maximal effect.
Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part
on the efficiency with which drug-receptor interaction is coupled to response.



The clinical effectiveness of a drug depends not on its potency (EC50), but on its maximal efficacy
and its ability to reach the relevant receptors. This ability can depend on its route of
administration, absorption, distribution through the body, and clearance from the blood or site of
action.



For therapeutic purposes, the potency of a drug should be stated in dosage units, usually in terms
of a particular therapeutic end point (eg, 50 mg for mild sedation, 1 mcg/kg/min for an increase in
heart rate of 25 beats/min). Relative potency, the ratio of equi-effective doses (0.2, 10, etc), may
be used in comparing one drug with another.


Maximal Efficacy
This parameter reflects the limit of the dose-response relation on the response axis.



Drugs A, C, and D in Figure have equal maximal efficacy, while all have greater maximal efficacy
than drug B.

It may be determined by the drug's mode of interactions with receptors or by characteristics of the
receptor-effector system involved.

practical efficacy of a drug for achieving a therapeutic end point (eg, increased cardiac
contractility) may be limited by the drug's propensity to cause a toxic effect (eg, fatal cardiac
arrhythmia) even if the drug could otherwise produce a greater therapeutic effect.


Disadvantages of graded dose response relationship:
     such curves may be impossible to construct if the pharmacologic response is an either-or
          (quantal) event, such as prevention of convulsions, arrhythmia, or death.
         the clinical relevance of a quantitative dose-response relationship in a single patient, no
          matter how precisely defined, may be limited in application to other patients, owing to the
          great potential variability among patients in severity of disease and responsiveness to
          drugs.

QUANTAL DOSE-EFFECT CURVES
         Quantal effect is an an either-or (quantal) event
         Example of quantal effect – relief of headache, increase in heart rate of 20 beats/min,
          death of an experimental animal
         Dose of drug required to produce a specified magnitude of effect in a large number of
          individual patients is determined
         The cumulative frequency distribution of responders versus the log dose is plotted
         For most drugs, the doses required to produce a specified quantal effect in individuals are
          lognormally distributed and hence a frequency distribution of such responses plotted
          against the log of the dose produces a gaussian normal curve of variation
       The resulting cumulative frequency distribution from summation of responses constitutes a
        quantal dose-effect curve (or dose-percent curve) of the proportion or percentage of
        individuals who exhibit the effect plotted as a function of log dose




       The quantal dose-effect curve is often characterized by stating:
            o   median effective dose (ED50), the dose at which 50% of individuals exhibit the
                specified quantal effect. The ED50 can be used to compare potencies and
                selectivity of a drug for different quantal effects
            o   median toxic dose (TD50) the dose required to produce a particular toxic effect
                in 50% of animals
            o   median lethal dose (LD50) the dose required to produce death in 50% of
                animals
       Therapeutic index is a measure of margin of safety of a drug and is a ratio of LD50 to
        ED50 or median lethal dose to median effective dose
       Both curves provide information regarding the potency and selectivity of drugs; the
        graded dose-response curve indicates the maximal efficacy of a drug, and the quantal
        dose-effect curve indicates the potential variability of responsiveness among individuals.


Competitive antagonist                               Non competitive antagonist
Antagonist binds with the same receptor as the       Binds to another site of receptor
agonist
Antagonist resembles chemically with the             Does not resemble
agonist
Parallel rightward shift of the agonist DRC          Flattening of agonist DRC
The same maximal response can be attained by         Maximal response is suppressed
increasing the dose of agonist
The antagonist apparently reduces affinity of        The antagonist apparently reduces intrinsic
agonist or appears to have inactivated a certain     activity of the agonist or appears to have
number of agonist molecules                         inactivated a certain number of receptors
Intensity of response depends on concentration      Response depends only on the concentration of
of both agonist and antagonist                      antagonist
Examples: Ach-atropine, morphine- naloxone          Diazepam-bicuculline


A mixed agonist-antagonist is a drug or receptor ligand that possesses pharmacological properties
similar to both AGONISTS and ANTAGONISTS for certain RECEPTOR sites. Well-known mixed agonist-
antagonists are drugs that interact with OPIOID (morphine-like) receptors. Pentazocine, nalbuphine,
butorphanol, and BUPRENORPHINE are all mixed agonist-antagonists for opioid receptors. These
drugs bind to the μ (mu) opioid receptor to compete with other substances (e.g., MORPHINE) for this
binding site; they either block the binding of other drugs to the μ receptor (i.e., competitive
antagonists) or produce a much smaller effect than that of "full" agonists (i.e., they are only partial
agonists). Therefore, these drugs block the effects of high doses of morphine-like drugs at μ opioid
receptors, while producing partial agonist effects at κ (kappa) and/or δ (delta) opioid receptors.

Describe efficacy and potency with reference to dose-response curves

(See above answer)

Explain the Law of Mass Action and describe affinity and dissociation constants

When a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the
concentration of the drug and the concentration of the receptor.




D = drug
R = receptor,
DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation.
KD = Dissociation Constant
KA = Association Constant

In general, the drug-receptor interaction is characterized first by binding of drug to receptor and
second by generation of a response in a biological system. The first function is governed by the
chemical property of affinity, ruled by the chemical forces that cause the drug to associate reversibly
with the receptor
At any given time, the concentration of agonist-receptor complex [DR] is equal to the product of
k1[D][R] minus the product k2[DR]. At equilibrium, k1[D][R]=k2[DR]. The equilibrium dissociation
constant (KD) is then described by ratio of the off-rate and the on-rate (k2/k1).




The affinity constant is the reciprocal of the equilibrium dissociation constant.
A high affinity means a small KD.
The affinity of a drug is influenced most often by changes in its off-rate (k2) rather than its on-rate
(k1).

Fractional occupancy (f) of receptors by agonist:




This can be expressed in terms of KA (or KD) and [D]:




Thus, when [D]=KD , a drug will occupy 50% of the receptors present. From this analysis, it is possible
to relate a drug's potency in a particular receptor system to its KD . Potent drugs are those which
elicit a response by binding to a critical number of a particular receptor type at low concentrations
(high affinity) compared with other drugs acting on the same system and having lower affinity and
thus requiring more drug to bind to the same number of receptors.


Describe the mechanisms of adverse drug effects

Adverse drug reaction has been defined as ‘any noxious change which is suspected to be due to a
drug, occurs at doses normally used in man, requires treatment or decrease in dose or indicates
caution in the use of the same drug

Mechanisms of adverse effects are:
   1. Side effects: these are unwanted but often unavoidable pharmacodynamic effects that occur
      at therapeutic doses
          a. Side effect may be based on the same action as the therapeutic effect eg atropine
              used in pre-anaesthetic medication for its anti-secretory effects causes dryness of
              mouth
          b. Side effect may be based on a different facet of action eg promethazine produces
              sedation which is unrelated to its anti-allergic action
          c. An effect may be therapeutic in one context but side effect in another context eg
              codeine used as cough suppressant causes constipation
   2. Secondary effects: indirect consequences of a primary action of drug eg suppression of
      bacterial flora by tetracyclines paves the way of superinfections
3. Toxic effects: result of excessive pharmacological action of the drug due to overdosage of
   prolonged usage. The overdose may be absolute (accidental, suicidal, homicidal) or relative
   (eg usual dose of gentamycin in presence of renal failure). The effects are predicatble and
   dose related
       a. May result from functional alteration eg high dose of atropine causes alteration
       b. Drug induced tissue damage eg hepatic necrosis from paracetamol overdose
       c. Extension of therapeutic effect – coma by barbiturates
4. Intolerance: appearance of characteristic toxic effects at therapeutic doses in certain
   individuals eg few doses of carbamazepine may cause ataxia
5. Idiosyncracy: genetically determined abnormal reactivity to a chemical eg barbiturates cause
   excitation
6. Drug allergy: it is immunologically mediated reaction producing stereotype symptoms which
   are unrelated to pharmacodynamic profile of the drug and are largely independent of the
   dosage. The drug or its metabolite act as antigen or more commonly hapten. Mechanisms
   and types of allergic reaction:
   HUMORAL:
       a. Type I (anaphylactic) reactions: reaginic antibodies (IgE) are produced and fixed to
            the mast cells. On exposure to the drug the Ag:Ab reactions take place on the
            surface of the mast cells releasing mediators like histamine 5HT, leukotrienes etc
            resulting in urticaria, itching, angioedema, asthma, rhinitis, and anaphylactic shock.
       b. Type II (cytolytic) reactions: drug + specific component of the tissue act as Ag. The
            resulting Ab bind to the target cells. On reexposure, Ag:Ab reactions take place on
            the surface of these cells, complement is activated and cytolysis occurs. Eg
            thrombocytopenia, agranulocytosis, aplastic anaemia etc
       c. Type III (retarded arthus) reactions: these are mediated by circulating antibodies.
            Ag:Ab complexes bind Ag and precipitate on the vascular endothelium giving rise to
            destructive inflammatory response. Manifestations :rashes, serum sickness,
            polyarteritis nodosa, stevens jhonsons syndrome.
   CELLULAR
       d. Type IV (delayed hypersensitivity) reactions: these are mediated through production
            of sensitized T lymphocytes carrying receptors for the Ag. On contact with the Ag
            these T cells produce lymphokines which attract granulocytes and generate an
            inflammatory response. Eg contact dermatitis, rash, fever etc
7. Photosensitivity: cutaneous reactions from drug induced sensitivity of the skin to the UV
   radiation
       a. Photo-toxic: drug or its metabolite accumulate in the skin, absorb light and
            undergoes a photochemical reaction followed by a photobiochemical reaction
            resulting in local tissue damage i.e. erythema, edema, blistering followed by
            hyperpigmentation and desquamation. The shorter wavelengths are responsible
            (290-320 nm UV-B) eg fluroquinolones
       b. Photoallergic: drug or its metabolite induced cell mediated inflammatory response
            which on exposure to light of longer wavelength (320-400nm UVA) produces
            papulous, eczematous contact dermatitis like picture.
8. Drug dependence: state in which use of drug for personal satisfaction is accorded a higher
   priority than other basic needs often in the face of known health risks.
       a. Psychological dependence
       b. Physical dependence
       c. Drug abuse
       d. Drug addiction
       e. Drug habituation
9. Drug withdrawal reaction: eg acute adrenal insufficiency
    10. Teratogenecity: capacity of the drug to cause fetal abnormalities when administered to the
        pregnant mother eg thalidomide –phocomelia. The type of malformation depends on the
        drug as well as stage of exposure to the teratogen
    11. Carcinogenetiy and mutagenicity: usually oxidation of the drug results in the production of
        reactive intermediates which affect genes and may cause structural changes in the
        chromosomes




Describe the physiological effects and principles of management of drug overdose




To explain the concept of pharmacokinetic modeling of single and multiple
compartment models and define:
half-life
clearance
zero and first order kinetics
volume of distribution
bio-availability
area under the plasma concentration time curve
extraction ratio

Half life
The half-life (t1/2) is the time it takes for the plasma concentration or the amount of drug in the body
to be reduced by 50%.

Clearance
     Theoretical proportionality constant relating rate of drug removal to plasma concentration.

       Represents volume of blood or plasma from which a drug is removed in unit time.

       Is the sum of different ways of drug elimination by various organs in the body.

       CL=CL renal + CL hepatic + CL others
       MEASUREMENT OF CLEARANCE:
           -       Single dose: Cl = Dose/AUC
           -       Infusion: Cl = Infusion Rate/CSS
                   where CSS is steady state concentration

Zero order kinetics:
Constant amount of drug is eliminated per unit time, i.e. rate of elimination remains constant
irrespective of drug conc. Eg ethanol. Clearance decreases with increasing concentration
Elimination ofsome drugs reach saturation over the therapeutic range and hence the kinetics of
elimination change from first order to zero order eg phenytoin, warfarin, theophylline

First order kinetics:
Constant fraction (F for first order , f for fraction )of drug is eliminated per unit time, i.e. rate of
elimination is directly proportional to the drug conc. Clearance remains constant


Volume of distribution:
The volume that would accommodate all the drug in the body, if the conc. Throughout was the same
as in the plasma

Vd=dose administered IV/plasma conc.

Factors governing Vd:
     Lipid:water partition co-efficient of the drug
     pKa value of the drug
     Degree of plasma protein binding
     Affinity for different tissues
     Fat:lean body mass ratio
     Diseases like CHF, uremia, cirrhosis

Bioavailability
It is the measure of fraction of administered dose of a drug that reaches systemic circulation in the
unchanged form

Area under the plasma concentration time curve

Area under the plasma concentration curve over time is a measure of bioavailability and drug
exposure

Extraction ratio

extraction ratio of the drug is the fraction of the amount of drug in the plasma extracted by the
organ and is given by
Extraction ratio = (Arterial conc. – venous conc.)/Arterial conc.

Single and multi compartment models:

The central volume of distribution (V1) describes an apparent volume in a model that assumes that some tissues behave the
same as plasma. Volume of distribution at steady-state (Vssd ) describes the apparent volume into which a drug will disperse
during a prolonged infusion; it is the sum of all the compartment volumes in the model describing a drug‟s kinetic behaviour
(V1, V2 and V3 in the three-compartment model shown in Fig. 1). Movement of drug between different compartments
(distribution/redistribution) is determined by the concentration gradient between compartments and the inter-compartmental
clearance. Clearance attributable to excretion describes removal of drug from the body. Rate of elimination from one
compartment to another is the product of concentration in the compartment from which drug is being eliminated, and inter-
compartmental clearance. Rate of excretion is the product of central compartment concentration and clearance.


Modelling is a mathematical tool used to predict the way in which plasma concentration varies over time. Each drug requires
its own model as it is fitted to observed drug behaviour.

One compartment model
The drug appears to distribute instantaneously after IV administration of a single
dose. If the mechanisms for drug elimination are not saturated a semi-log plot of
plasma concentration versus time will be linear and drug elimination is first order.




the decline of plasma concentration with time for a drug introduced into this central
compartment:




where k is the rate constant for elimination that reflects the fraction of drug removed from the
compartment per unit of time. This rate constant is inversely related to the half-life of the drug (k =
0.693/t1/2).
Physiologically,
the central volume = the initial dilution volume into which the drug is mixed.

This reflects
1.the volume of the heart, great vessels, and the venous volume of the upper arm.
2. reflects any uptake into the pulmonary parenchyma prior to the blood reaching the
arterial circulation.
3. For drugs directly metabolized in the plasma, V1 also reflects the metabolism of
the drug en route from the venous cannula to the arterial sampling catheter, which
appears pharmacokinetically as dilution of the drug into a larger space.


Constant rate infusion
When an i.v. infusion is started at a constant rate of „f‟ mg/min in a simple one-compartment model, Concentration (C)
increases, initially quickly, but then more slowly, as the rate of excretion is initially slow but increases with increasing
plasma concentration in a negative exponential fashion. Equilibrium is reached when input = output. The input rate is f mg/
min and output is the rate of excretion, giving f = CL*C mg/min. Thus the concentration at equilibrium is determined by the
ratio of the infusion rate to the clearance of the drug (C = f /CL mg/ml). The plasma concentration will remain unchanged as
long as the infusion rate is held constant.

Bolus-primed continuous infusion
If an infusion is started at the rate needed to achieve the required plasma concentration it would take about three time
constants (or five half-lives) to reach that concentration. Instead, a bolus dose of drug is given and the infusion started at our
calculated rate. The size of the bolus dose should be enough to fill the volume of distribution. For the simple one-
compartment model this would be Ce/V, where Ce is the required equilibrium concentration.

Stopping the infusion
Decline in plasma concentration for this simple model will follow a simple single exponential curve. The time constant will
be that for excretion.
In this simple model, the handling of drug by the body can be described as a single exponential process, and, independent of
the duration of infusion, it will always take the same time for the plasma concentration to halve.
Two compartment pharmacokinetic model, with two volumes, (central and
peripheral) and two clearances (central, and intercompartmental)




Distribution clearance

Distribution clearance is the transfer of drug between the blood or plasma and the
peripheral tissues. It is a function of tissue blood flow, and permeability of the
capillary walls to the drug.

For a drug which is avidly taken up in peripheral tissues, such as propofol (a
lipophilic anesthetic drug), the sum of the metabolic clearance and the distribution
clearance approaches cardiac output.

For drugs which are metabolized directly in the plasma, such as remifentanil (an
opioid whose ester linkage is cleaved by circulating esterases), the sum of metabolic
and distribution clearance can exceed cardiac output.

Peripheral volumes of distribution

The distribution volume is the volume which relates the plasma drug concentration to
the total amount of drug in the body.
 If you could know the total amount of drug in the body, Xtotal drug, and you knew the
concentration of drug in the plasma, Cplasma,
 then you could derive a volume term relating these:
                   X total drug
        C plasma =
                   V total body
After all body tissues have equilibrated with the plasma. This situation is called
steady state, and at steady state Vtotal body becomes Vdss, the volume of distribution at
steady state. Vdss is the algebraic sum of the peripheral volumes and the central
volumes estimated by compartmental modeling

TWO COMPARTMENT MODEL

         -     Biphasic decline
               a)     Initial rapid distribution followed by
               b)     Elimination phase
-        Biexponential relationship given by equation

Cp = Ae-t + Be-t

Where A & B are intercepts on the ordinate
-    Assumes a central compartment into which drug is administered and also
     eliminated
-    Peripheral compartment.




Multi-compartment models
In practice, either a two- or threecompartment model is required explain the pharmacokinetic behaviour of many drugs
A three compartment model.
V1 = volume of central compartment
V2 and V3 = volume of peripheral compartments
(sizes of these vary from drug to drug and are influenced by physichochemical properties of the drug such as lipid solubility &
and patient factors e.g. tissue binding)
k10 = The rate constant for elimination from plasma - represents excretion
k12 and k13 = rate constants for distribution to compartments 2 and 3, respectively
k21 and k31 = rate constants for redistribution from compartments 2 and 3 to central compartment
Clearances: attributable to excretion (V1 * k10) and inter-compartmental clearances between compartments 1 and 2 (V1 * k12 = V2
* k21) and 1 and 3 (V1 * k13 = V3 *k31). A drug may only enter and leave the model through the central compartment.


The central compartment models the changes in plasma concentration of the drug in question
The other compartments represent regions of the body that can temporarily remove drug from, and later release drug back
into, the plasma.
Drugs that are permanently charged have low volumes of distribution and are often described using a two compartment
model (e.g. pancuronium).
Drugs that are highly lipid soluble, such as fentanyl and propofol, have a very large peripheral volume of distribution (V3)
compared with their central compartment volume (V1).

As shown in diagram, intercompartmental clearance between central and third compartment is given by V1* k13 = V3 * k31
Hence as per this formula, If V1 is much smaller than V3 it implies that rapid distribution is associated with slow
redistribution; however, slower distribution is associated with rapid redistribution.

Fixed infusion rate
In this model, starting a fixed rate infusion will cause plasma concentrations to increase rapidly at first, but three processes
will remove drug from plasma: distribution to compartments 2 and 3; and excretion.
Initially, distribution may contribute more to removal of drug from plasma than will excretion
The direction and speed of drug movement will depend on the concentration gradients between the plasma and peripheral
compartments and the inter-compartmental clearances.
As the infusion continues, movement of drug into the second compartment slows as the concentration within that
compartment increases, but distribution to the third compartment continues. Plasma concentrations continue to increase, but
more slowly, as the concentrations in the two compartments approach that of plasma.
Excretion will contribute to elimination throughout, but becomes increasingly important as plasma concentration increases.
Eventually, steady-state will be reached when there is no inter-compartmental movement of the drug. Input to the central
compartment from infusion balances output from excretion and the concentration of drug is the same in each compartment.
For drugs with very large Vss d and slow distribution it may take many hours before equilibrium is reached with a fixed
infusion rate.

Context-sensitive half-time
On stopping an infusion, three possible processes contribute to a decline in plasma concentration: distribution to the second
and third compartments, and excretion.
The relative contributions of these to the initial decline in plasma concentration vary according to the duration of the
infusion. The longer the infusion, the lower the concentration gradients between plasma (central compartment) and
compartments 2 and 3, so the lower the contribution of distribution to elimination.
After a very short infusion, plasma concentration will fall to half the initial concentration in a very short time, due to the
combined effects of distribution and excretion.
If the infusion runs to equilibrium, there is no contribution from distribution and elimination occurs only by excretion, which
is opposed by re-distribution from peripheral compartments.
Thus, the longest time for plasma concentrations to halve will occur following equilibrium when, with some drugs such as
fentanyl , it may come close to terminal elimination half-life.
For infusions of intermediate duration, the time for the plasma concentration to halve will be between these two extreme
values.
This „halving time‟ is known as the context-sensitive halftime where the „context‟ is the duration of the infusion.
The extent of the variation in context-sensitive half-time for a given drug depends on the relative magnitude of clearance
attributable to excretion compared with inter-compartmental clearance.
The time to reach maximum context-sensitive half-time depends largely on Vssd and rate constant for re-distribution  it
is shortest for drugs with a low Vss d and low rate constant for redistribution (e.g. remifentanil) and longest for large Vss
d and high rate constant for redistribution (e.g. fentanyl).


Propofol has a context-sensitive half-time that varies between 3 min for a very short infusion to about 18 min after a 12-h
infusion. This relatively small variation in context-sensitive half-time, despite a large V3, occurs because excretion is rapid
compared with redistribution.
For weak acids and bases, the degree of ionization influences pharmacokinetics. The lower pKa of alfentanil (6.4) compared
with fentanyl (8.5) means that the concentration of the un-ionized, diffusible form of alfentanil is 100 times greater than that
of fentanyl. This accounts for its rapid onset-time and short t1/2 keo. For modelling purposes, alfentanil has a smaller central
compartment volume, a very much lower Vssd and a lower clearance than fentanyl. As a result of these differences, fentanyl
has a shorter context-sensitive half-time than alfentanil for short infusions (<2 h). However, alfentanil reaches its maximum
context-sensitive half-time after just 90 min, so has a very much shorter context sensitive half-time than fentanyl after very
long infusions. Fentanyl becomes a very long acting drug if given at high infusion rates for many hours because it has a large
V3 and redistribution is rapid (in contrast with propofol); thus plasma concentrations are maintained despite rapid excretion.
Remifentanil has a relatively constant context-sensitive half-time. This is because clearance attributable to excretion (ester
hydrolysis) is very high and Vssd is much smaller than for other opioids. Thiopental is less commonly given by continuous
infusion but may be used for burst-suppression of the EEG when it is given for many hours or even days at high dosage. It
takes an extremely long time for the effects to wear-off and there are several reasons for this. The metabolism of thiopental is
normally a first-order process; however, once plasma concentrations exceed a certain value, the enzyme system becomes
saturated and metabolism becomes a zero-order process (i.e. rate of elimination becomes constant rather than dependent
upon plasma concentration). Thus, the usual pharmacokinetic models are inappropriate after prolonged infusion. It should
also be remembered that thiopental is metabolized to pentobarbital, which is also a sedative and excreted slowly. Thus, the
clinical effects reflect not only plasma concentration of thiopental but also that of its major metabolite. To summarize:

Context sensitive T ½ independent of duration of infusion
Eg. remifentanil
T ½ ~ 2-5 min

moderately influenced by duration eg. alfentanil, propofol, midazolam.
Eg. T ½ propofol = 12 to 38 min after 8 hours.

Marked prolongation T ½ by duration of infusion
Eg. fentanyl from 24 min to 280 min, when infusion duration increase from 1 to 8 hr.




Describe absorption and factors that will influence it with reference to clinically
utilised sites of administration

Absorption is the movement of the drug from its site of administration into the circulation.
Ficks law of diffusion = solubility * Surface area* ΔConc. / thickness

General factors affecting absorptions are:
    Aqueous solubility – drugs given in solid phase must dissolve in the aqueous biophase before
       they are absorbed. For poorly water soluble drugs rate of dissolution governs rate of
       absorption. The drug given as watery solution is absorbed faster than when the same is
       given in solid form or as a oily solution
      Concentration – passive transport depends on conc. Gradient, drug given as concentrated
       solution is absorbed faster than from dilute solution
      Area of absorbing surface – larger it is faster is the absorbtion
      Vascularity of the absorbing surface – blood circulation removes the drug from the site of
       absorption and maintains conc gradient across the membrane. Increased blood flow
       increases drug absorption
      Route of administration – each route has its own peculiarities.

ROUTE        ABSORPTION                    SPECIAL UTILITY             LIMITATIONS AND
             PATTERN                                                   PRECAUTIONS
Intravenous  Absorption                    Valuable for emergency Increased risk of adverse
             circumvented                  use                         effects
             Potentially immediate         Permits titration of dosage Must inject solutions
             effects                                                   slowly as a rule
             Suitable for large            Usually required for high- Not suitable for oily
             volumes and for               molecular-weight protein solutions or poorly
             irritating substances,        and peptide drugs           soluble substances
             or complex mixtures,
             when diluted
Subcutaneous Prompt, from aqueous     Suitable for some poorly       Not suitable for large
             solution                 soluble suspensions and        volumes
               rate of absorption     for instillation of slow-
               following subcutaneous release implants
               injection of a drug often
               is sufficiently constant
               and slow to provide a
               sustained effect
              Slow and sustained,                                    Possible pain or necrosis
              from repository                                        from irritating substances
              preparations
Intramuscular Prompt, from aqueous Suitable for moderate             Precluded during
              solution             volumes, oily vehicles,           anticoagulant therapy
                                   and some irritating
                                   substances
              Slow and sustained,  Appropriate for self-            May interfere with
              from repository      administration (e.g.,            interpretation of certain
              preparations         insulin)                         diagnostic tests (e.g.,
                                                                    creatine kinase)
Oral ingestion Variable, depends on        Most convenient and      Requires patient
               many factors                economical; usually more compliance
                                           safe
                      surface area                                 Bioavailability potentially
                      blood flow                                   erratic and incomplete -
                      the physical                                  limited absorption of some
                       state of the drug                             drugs because of their
                       (solution,                                    physical characteristics (e.g.,
                       suspension, or                                water solubility), emesis as
                          solid dosage                                    a result of irritation to the
                          form)                                           GI mucosa, destruction of
                         water solubility                                some drugs by digestive
                         drug's                                          enzymes or low gastric pH,
                          concentration                                   irregularities in absorption
                         Absorption is                                   or propulsion in the
                          favored when                                    presence of food or other
                          the drug is in                                  drugs, and the need for
                          the nonionized                                  cooperation on the part of
                          and more                                        the patient. In addition,
                          lipophilic form.                                drugs in the GI tract may be
                         ↑ gastric                                       metabolized by the enzymes
                          emptying  ↑                                    of the intestinal flora,
                          rate of drug                                    mucosa, or liver before they
                          absorption                                      gain access to the general
                                                                          circulation.




Sublingual Administration.
     protects the drug from rapid hepatic first-pass metabolism
Transdermal Absorption.
     Absorption depends on the surface area over which applied
     Lipid solubility
     increased cutaneous blood flow also enhance absorption
     hydrated skin is more permeable than dry skin

Rectal Administration.
    50% of the drug that is absorbed from the rectum will bypass the liver
    irregular and incomplete

Intrathecal
     to overcome the blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier
     injected directly into the spinal subarachnoid space.
     Brain tumors also may be treated by direct intraventricular drug administration.

Pulmonary Absorption.
    gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium
      and mucous membranes of the respiratory tract.
    Access to the circulation is rapid by this route because the lung's surface area is large.
    avoidance of hepatic first-pass loss
    in the case of pulmonary disease, local application of the drug at the desired site of action.

Topical Application.
Mucous Membranes. Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx,
oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects. Occasionally,
as in the application of synthetic antidiuretic hormone to the nasal mucosa, systemic absorption is
the goal. Absorption through mucous membranes occurs readily.

Eye.
Topically applied ophthalmic drugs are used primarily for their local effects
Systemic absorption that results from drainage through the nasolacrimal canal is usually
undesirable..

Describe factors influencing the distribution of drugs (e.g. protein binding, lipid
solubility, pH, pKa) and their alteration in physiological and pathological
disturbance

Factors governing rate of drug distribution

    1. Membrane Permeability
    2. Blood Perfusion


Factors governing extent of drug distribution:

    1.   Lipid:water partition co-efficient of the drug
    2.   pKa value of the drug
    3.   Degree of plasma protein binding
    4.   Affinity for different tissues
    5.   Fat:lean body mass ratio
    6.   Diseases like CHF, uremia, cirrhosis
    7.   Differences in regional blood flow


Following absorption or systemic administration into the bloodstream, a drug distributes into
interstitial and intracellular fluids. Cardiac output, regional blood flow, capillary permeability, and
tissue volume determine the rate of delivery and potential amount of drug distributed into tissues.

Rapid 1st phase: Initially, liver, kidney, brain, and other well-perfused organs receive most of the drug
Initially, liver, kidney, brain, and other well-perfused organs receive most of the drug

Slower 2nd phase: Delivery to muscle, most viscera, skin, and fat is slower. May require minutes to
several hours before the concentration of drug in tissue is in equilibrium with that in blood. The
second phase also involves a far larger fraction of body mass than does the initial phase and
generally accounts for most of the extravascularly distributed drug.



Lipid solubility and transmembrane pH gradients are important determinants of uptake for drugs
that are either weak acids or bases.

The more important determinant of blood-tissue partitioning is the relative binding of drug to
plasma proteins and tissue macromolecules.


Degree of ionization

This is really important with regard to local anaesthetics. The essential fact to know is that highly
ionized drugs cannnot cross lipid membranes (basically they can't go anywhere) and unionised drugs
can cross freely. Morphine is highly ionised, fentanyl is the opposite. Consequently the latter has a
faster onset of action. The degree of ionisation depends on the pKa of the drug and the pH of the
local environment. The pKa is the the pH at which the drug is 50% ionised. Most drugs are either
weak acids or weak bases. Acids are most highly ionised at a high pH (i.e. in an alkaline
environment). Bases are most highly ionised in an acidic environment (low pH). For a weak acid, the
more acidic the environment, the less ionised the drug, and the more easily it crosses lipid
membranes. If you take this acid, at pKa it is 50% ionised, if you add 2 pH points to this (more
alkaline), it becomes 90% ionised, if you reduce the pH (more acidic) by two units, it becomes 10%
ionised. Weak bases have the opposite effect.

Local anaesthetics are weak bases: the closer the pKa of the local anaesthetic to the local tissue pH,
the more unionised the drug is. That is why lignocaine(pKa 7.7) has a faster onset of action than
bupivicaine (pKa 8.3). If the local tissues are alkalinised (e.g. by adding bicarbonate to the local
anaesthetic), then the tisssue pH is brought closer to the pKa, and the onset of action is hastened.




Plasma Proteins.

       Albumin is a major carrier for acidic drugs; 1-acid glycoprotein binds basic drugs. Drugs
        binding to albumin – barbiturates, benzodiazepine, phenytoin, penicillin, warfarin. Drugs
        binding to α1 acid glycoprotein – β blockers, methadone, prazocin, lignocaine
       The binding is usually reversible exceptions - covalent binding of reactive drugs such as
        alkylating agents
       The fraction of total drug in plasma that is bound is determined by:
            o drug concentration
            o the affinity of binding sites for the drug
            o the number of binding sites
       Mass-action relationships determine the unbound and bound concentrations –
            o At low conc. of drug (less than the plasma protein binding dissociation constant), the
                 fraction bound is a function of the concentration of binding sites and the
                 dissociation constant.
            o At high drug concentrations (greater than the dissociation constant), the fraction
                 bound is a function of the number of binding sites and the drug concentration.
       Therefore, plasma binding is a nonlinear, saturable process.
       Disease-related factors. For example, hypoalbuminemia secondary to severe liver disease or
        the nephrotic syndrome results in reduced binding and an increase in the unbound fraction.
        Also, conditions resulting in the acute-phase reaction response (e.g., cancer, arthritis,
        myocardial infarction, and Crohn's disease) lead to elevated levels of 1-acid glycoprotein
        and enhanced binding of basic drugs.
       Because of nonselective binding, drugs with similar physicochemical characteristics can
        compete with each other and with endogenous substances for these binding sites, resulting
        in noticeable displacement of one drug by another. For example, displacement of
        unconjugated bilirubin from binding to albumin by the sulfonamides and other organic
        anions is known to increase the risk of bilirubin encephalopathy in the newborn.
       For narrow-therapeutic-index drugs, a transient change in unbound concentrations
        occurring immediately following the dose of a competing drug could be of concern, such as
        with the anticoagulant warfarin.
       Slight changes in binding of tightly bound drugs can be significant – 99 to 98% leads to
        double the free concentrations – increased activity – increased elimination e.g.
        phenylbutazone displacing tolbutamide
       Binding of a drug to plasma proteins limits its concentration in tissues and at its site of action
       Binding of a drug to plasma protein also limits the drug's glomerular filtration because this
        process does not immediately change the concentration of free drug in the plasma (water is
        also filtered).
       Drug transport and metabolism also are limited by binding to plasma proteins


Tissue Binding.

       Many drugs accumulate in tissues at higher concentrations than those in the extracellular
        fluids and blood. For example, during long-term administration of the antimalarial agent
        quinacrine, the concentration of drug in the liver may be several thousand fold higher than
        that in the blood. Other eg skeletal mucle and heart – digoxine, kidney – digoxine,
        chloroquine, brain – acetazolamide, adipose tissue – thiopentone
       Such accumulation may be a result of active transport or, more commonly, binding.
       Tissue binding of drugs usually occurs with cellular constituents such as proteins,
        phospholipids, or nuclear proteins and generally is reversible.
       Serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached
        through the circulation.


Fat As a Reservoir.

       Many lipid-soluble drugs are stored by physical solution in the neutral fat.
       For example, as much as 70% of the highly lipid-soluble barbiturate thiopental may be
        present in body fat 3 hours after administration.
       Fat is a rather stable reservoir because it has a relatively low blood flow.


Redistribution.

Redistribution is a factor in terminating drug effect primarily when a highly lipid-soluble drug that
acts on the brain or cardiovascular system is administered rapidly by intravenous injection or by
inhalation. A good example of this is the use of the intravenous anesthetic thiopental, a highly lipid-
soluble drug.


Central Nervous System and Cerebrospinal Fluid
The lipid solubility of the nonionized and unbound species of a drug is therefore an important
determinant of its uptake by the brain; the more lipophilic a drug is, the more likely it is to cross the
blood-brain barrier.

Another important factor in the functional blood-brain barrier involves membrane transporters that
are efflux carriers present in the brain capillary endothelial cell and capable of removing a large
number of chemically diverse drugs from the cell.

Placental Transfer of Drugs.

Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are
important general determinants in drug transfer across the placenta. The fetal plasma is slightly
more acidic than that of the mother (pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs
occurs. As in the brain, P-gp and other export transporters are present in the placenta and function
to limit fetal exposure to potentially toxic agents.

Describe the mechanisms of drug clearance and how physiological and
pathological disturbance may affect these

Clearance is defined as the theoretical volume of the plasma from which the drug is completely
removed in unit time

Value of clearance for a particular drug usually is constant over the range of concentrations
encountered clinically because systems for elimination of drugs usually are not saturated, and thus
the absolute rate of elimination of the drug is essentially a linear function of its concentration in
plasma - first-order kinetics

If elimination mechanisms get saturated, kinetics approach zero order and clearance (CL) will vary
with the concentration of drug, often according to the equation

CL=Vm/(Km+C)

Km = concentration at which half the maximal rate of elimination is reached

m = maximal rate of elimination

At the simplest level, clearance of a drug is its rate of elimination by all routes normalized to the
concentration of drug C in some biological fluid where measurement can be made:

CL=rate of elimination/C

Thus, when clearance is constant, the rate of drug elimination is directly proportional to drug
concentration.


Clearance of drug by several organs is additive. Division of the rate of elimination by each organ by a
concentration of drug (e.g., plasma concentration) will yield the respective clearance by that organ.
Added together, these separate clearances will equal systemic clearance:
CLrenal + CLhepatic + CLothers = CL

Systemic clearance may be determined at steady state by using the following equation:

Dosing rate = Cl*Css

CL is clearance of drug

Css is the steady-state concentration of drug

For a single dose of a drug with complete bioavailability and first-order kinetics of elimination,
systemic clearance may be determined by

CL= dose/AUC

where AUC is the total area under the curve that describes the measured concentration of drug in
the systemic circulation as a function of time (from zero to infinity).


A further definition of clearance is useful for understanding the effects of pathological and
physiological variables on drug elimination, particularly with respect to an individual organ. The rate
of presentation of drug to the organ is the product of blood flow (Q) and the arterial drug
concentration (CA), and the rate of exit of drug from the organ is the product of blood flow and the
venous drug concentration (CV). The difference between these rates at steady state is the rate of
drug elimination by that organ:




E = extraction ratio

Calculations of a drug's extraction ratio are useful for modeling the effects of disease of a given
metabolizing organ on clearance and in the design of ideal therapeutic properties of drugs in
development.

Hepatic Clearance

Flow limited clearance - For drugs which are very efficiently removed from blood by the liver, the
extraction ratio is >0.7 and clearance is limited to hepatic blood flow and not by intrahepatic
processes. eg diltiazem, lidocaine, morphine, and propranolol)

intrinsic clearance of liver – intrinsic capacity of the liver to eliminate a drug in the absence of
limitations imposed by blood flow.

 In biochemical terms and under first-order conditions, intrinsic clearance is a measure of the ratio of
the Michaelis-Menten kinetic parameters for the eliminating process (i.e.,m/Km) and thus reflects
the maximum metabolic or transport capability of the clearing organ.
Capacity limited clearance - When the drug-metabolizing capacity is small in comparison with the
rate of drug presentation, clearance will be proportional to the unbound fraction of drug in blood
and the drug's intrinsic clearance.

Hence, For a drug with a high extraction ratio, clearance is limited by blood flow, and changes in
intrinsic clearance owing to enzyme induction or hepatic disease should have little effect. Similarly,
for drugs with high extraction ratios, changes in protein binding owing to disease or competitive
binding interactions by other drugs should have little effect on clearance. By contrast, changes in
intrinsic clearance and protein binding will affect the clearance of drugs with low intrinsic clearances
such as warfarin, and thus extraction ratios, but changes in blood flow will have little effect.

Renal Clearance

Renal clearance of a drug results in its appearance in the urine.

In considering the impact of renal disease on the clearance of a drug, complications that relate to
filtration, active secretion by the kidney tubule, and reabsorption from it must be considered along
with blood flow.

Renal blood flow is inversely correlated with age, as is creatinine clearance, which can be predicted
from age and weight:



        Men:

                                                     (140 - age ) x weight( kg )
        Creatinine Clearance ( ml / min ) =
                                                  72 x serum creatinine ( mg %)

        Women: 85% of the above



The rate of filtration of a drug depends on the volume of fluid that is filtered in the glomerulus and
the unbound concentration of drug in plasma because drug bound to protein is not filtered.

The rate of secretion of drug by the kidney will depend on the drug's intrinsic clearance by the
transporters involved in active secretion as affected by the drug's binding to plasma proteins, the
degree of saturation of these transporters, and the rate of delivery of the drug to the secretory site.

In addition, processes involved in drug reabsorption from the tubular fluid must be considered. The
influences of changes in protein binding and blood flow and in the number of functional nephrons
are analogous to the examples for hepatic elimination.

When renal clearance > 0.7 total clearance, drug accumulation may occur in renal disease.
When renal clearance < 0.3 total clearance, renal disease has little effect.

Describe the mechanisms of drug metabolism. To describe Phase 1 and Phase 2
reactions, hepatic extraction ratio and its significance, first pass effect, enzyme
induction and inhibition

Metabolism of the drug leads to
    Inactivation – eg morphine, propanolol
    Active metabolite from an active drug eg – diazepam  desmethyl diazepam
    Activation of pro-drug eg enalapril  enelaprilat, prednisone  prednisolone, α methyl
      deopa  α methyl norepinephrine
Metabolism reactions:
    Non-synthetic/Phase I
    Synthetic/conjugation/Phase II


                          Metabolism                                     Excretion
Drug ----------------- Phase I ---metabolite ----------------------------------
Drug ---------------- Phase I -- Phase II -- metabolite---------------------
Drug --------------- Phase II -metabolite ------------------------------------

Non synthetic/Phase I reactions
   1. Oxidation
           a. Most important reaction
           b. Addition of O2/ -ve charged radical or removal of hydrogen / +vely charged radical
           c. Various oxidation reactions : hydroxylation, oxygenation at CNS atoms, N or O
               dealkylation, oxidative deamination etc
           d. Mostly carried out by group of monooxygenases in the liver which in the final step
               involve a cytochrome P450 reductase & O2
           e. Eg barbiturates, phenothiazines, paracetamol, steroids, phenytoin, benzos
   2. Reduction
           a. Involves cytochrome P450 enzymes working in opposite direction
           b. Eg halothane
   3. Hydrolysis
           a. Clevage of drug molecule by taking up a molecule of water
           b. Ester + H20 ---esterase- acid + alcohol
           c. Hydrolysis occur in liver, intestines, plasma and other tissues
   4. Cyclization
           a. Formation of ring structure
           b. Eg – proguanil
   5. Decyclyzation
           a. Opening of the ring
           b. Eg – barbiturate, phenytoin

Synthetic / phase II reaction
     Involves conjugation of the drug or its phase I metabolite with an endogenous substrate,
        generally derived from carbohydrate or amino acid to form a polar highly ionized organic
        acid which is easily excreted in urine / bile
     Have high energy requirements

     1. Glucoronide conjugation
            a. Most important synthetic reaction
            b. Compounds with hydroxyl or carboxyl acid group are easily conjugated with
               glucoronic acid eg aspirin, phenacetin, morphine
            c. Drug glucoronides excreted in bile can be hydrolyzed by bacteria in the gut
    2. Acetylation
           a. Compounds having amino or hydrazine residues are conjugated with the help of
               acetyl coenzyme A eg sulfonamides, hydralazine
           b. Genetic influence – fast and slow acetylators
    3. Methylation
           a. Amines and phenols can be methylated
           b. Methionine and cysteine act as methyl donors
           c. Eg adrenaline
    4. Sulphate conjugation
           a. Phenolic compounds and steroids sulfated by sulfokinases
    5. Glycine conjugation
           a. Salicylates and other drugs having carboxylic acid group
    6. Glutathione conjugation
           a. Forming mercaptupurate
           b. Eg paracetamol intermediate metabolite viz NPQI

Non-specific enzymes:
     Microsomal
            o Located in the smooth ER, primarily in liver also in kidney, intestine and lung
            o Eg CYP 450
            o Catalyse most of the oxidation, reduction, hydrolysis
            o Inducible by drugs
     Non-microsomal
            o Present in cytoplasm and mitochonidria of hepatic cells as well as in other tissues
                including plasma
            o Some oxidation reduction mainly hydrolysis and all conjugation reactions except
                glucoronidation
            o Not inducible and common genetic polymorphism
Hoffman elimination – refers to inactivation of the drug in the body fluids by spontaneous molecular
rearrangements without the agency of any enzyme eg atracurium

Explain and apply concepts related to intravenous bolus and infusion kinetics. To
describe the concepts of effect-site and effect-site equilibration time and their
clinical applications. To describe the concept of context sensitive half time and its
clinical applications

covered above
Calculate loading and maintenance dosage regimens

Design and Optimization of Dosage Regimens
The intensity of a drug's effect is related to its concentration above a minimum effective
concentration, whereas the duration of this effect reflects the length of time the drug level is above
this value.

Therapeutic window exists reflecting a concentration range that provides efficacy without
unacceptable toxicity.

In general, the lower limit of the therapeutic range appears to be approximately equal to the drug
concentration that produces about half the greatest possible therapeutic effect, and the upper limit
of the therapeutic range is such that no more than 5% to 10% of patients will experience a toxic
effect.


For many drugs, however, the effects are difficult to measure (or the drug is given for prophylaxis),
toxicity and lack of efficacy are both potential dangers, or the therapeutic index is narrow. In these
circumstances, doses must be titrated carefully, and drug dosage is limited by toxicity rather than
efficacy. Thus, the therapeutic goal is to maintain steady-state drug levels within the therapeutic
window.


MAINTENANCE DOSE

       In most clinical situations, drugs are administered in a series of repetitive doses or as a
        continuous infusion to maintain a steady-state concentration of drug within the therapeutic
        window. Calculation of the appropriate maintenance dosage is a primary goal.
       To maintain the chosen steady-state, the rate of drug administration is adjusted such that
        the rate of input equals the rate of loss. Hence,
             o Dosing rate = target Cp * CL/F
             o CL = clearance, F = bioavailability term, value varies between 0 and 1
       If the clinician chooses the desired concentration of drug in plasma and knows the clearance
        and bioavailability for that drug in a particular patient, the appropriate dose and dosing
        interval can be calculated.

        Example. Oral digoxin is to be used as a maintenance dose to gradually "digitalize" a 69-kg
        patient with congestive heart failure. A steady-state plasma concentration of 1.5 ng/ml is
        selected. Based on the fact that the patient's creatinine clearance (CLCr) is 100 ml/min,
        digoxin's clearance is estimated. Oral bioavailability of digoxin is 70% (F = 0.7). Hence using
        above equation dose rate of 0.34mg/24 hr is achieved

       Dosing Interval for Intermittent Dosage.

            o   Marked fluctuations in drug concentrations between doses are not desirable.
            o   Assuming absorption and distribution to be instantaneous, fluctuations in drug
                concentrations between doses would be governed entirely by the drug's elimination
                half-life. If the dosing interval T were chosen to be equal to the half-life, then the
                total fluctuation would be twofold; this is often a tolerable variation.
            o   Maximal dose strategy in drugs with large therapeutic index: The dosing interval
                can be much longer than the elimination half-life (for convenience). The half-life of
                amoxicillin is about 2 hours, but dosing every 2 hours would be impractical. Instead,
                amoxicillin often is given in large doses every 8 or 12 hours.
            o   For drugs with narrow therapeutic range: Maximal and minimal concentrations that
                will occur for a particular dosing interval is estimated.
            o   Estimation of minimal steady state conc. : Css,min may be reasonably determined by:
                      Where k equals 0.693 divided by the clinically relevant plasma half-life and T
                       is the dosing interval. The term exp(-kT) is, in fact, the fraction of the last
                       dose (corrected for bioavailability) that remains in the body at the end of a
                       dosing interval.
                    -KT = 0.693T/t1/2
           o   Estimation of maximal steady state conc. : Css,max - For drugs that follow
               multiexponential kinetics and are administered orally, estimation involves a
               complicated set of exponential constants for distribution and absorption. If these
               terms are ignored for multiple oral dosing, the conc. Can calculated as:




                      Because of the approximation, the predicted maximal concentration from
                       will be greater than that actually observed.


LOADING DOSE

   o   The loading dose is one or a series of doses that may be given at the onset of therapy with
       the aim of achieving the target concentration rapidly.
   o   A loading dose may be desirable if the time required to attain steady state by the
       administration of drug at a constant rate (four elimination half-lives) is long relative to the
       temporal demands of the condition being treated.
   o   The appropriate magnitude for the loading dose is

       Loading dose = target Cp *Vss/F



   o   Disadvantages - First, the particularly sensitive individual may be exposed abruptly to a toxic
       concentration of a drug. Moreover, if the drug involved has a long half-life, it will take a long
       time for the concentration to fall if the level achieved is excessive. Loading doses tend to be
       large, and they are often given parenterally and rapidly; this can be particularly dangerous if
       toxic effects occur as a result of actions of the drug at sites that are in rapid equilibrium with
       plasma. This occurs because the loading dose calculated on the basis of Vss subsequent to
       drug distribution is at first constrained within the initial and smaller "central" volume of
       distribution. It is therefore usually advisable to divide the loading dose into a number of
       smaller fractional doses that are administered over a period of time. Alternatively, the
       loading dose should be administered as a continuous intravenous infusion over a period of
       time.
Describe the pharmacokinetics of drugs administered in the epidural and subarachnoid
space

Some random important points – however more information is
required
epidurally administered opioids must traverse the dura and arachnoid mater, diffuse through the CSF,
traverse the pia mater to reach the surface of the spinal cord, diffuse
through the white mater and then the gray mater to reach dorsal horn opioid receptors.

it is an opioid’s physicochemical properties that largely determine its bioavailability in the spinal cord
dorsal horn and thus its suitability for spinal administration.

Spinal Drug Distribution
All drugs placed in the epidural space are subject to multiple potential fates. Which of these fates will
be met by a particular drug is largely dependant on its physicochemical properties
     o exit the intervertebral foramina to reach the paraspinous muscle space
     o diffuse into epidural fat
     o diffuse into ligaments that border the epidural space
     o diffuse across the spinal meninges

Lipid solubility – the amount of opioid sequestered in the epidural fat after epidural administration is
entirely dependant on the drug’s octanol: buffer distribution coefficient

Both mean residence time (MRT) and terminal elimination half-life are closely related to lipid solubility.

lipid soluble opioids spend a relatively large amount of time in the epidural space.

mechanisms involved in the movement of drugs from epidural space:
   o diffusion through the spinal meninges (most proven mechanism)
   o preferential diffusion through the spinal nerve root cuff
   o uptake by radicular arteries traversing the epidural space with subsequent distribution to the
      spinal cord.

the cellular arachnoid mater is the principal meningeal barrier to diffusion accounting for 95% of the
resistance to meningeal permeability

lipid solubility is the principal determinant of an individual drug’s meningeal permeability coefficient.

The relationship between meningeal permeability and lipid solubility is biphasic.

drugs of intermediate lipid solubility (e.g., alfentanil, lidocaine, bupivacaine) are all more permeable
than morphine, fentanyl and sufentanil.

Drug “sequestered” in the epidural fat is not bioavailable to traverse the arachnoid mater.

The dura mater is an important site of drug clearance. The human dura mater is a highly vascular
structure with a rich network of arterioles/capillaries running along its border with the arachnoid mater.

In effect, drugs diffusing through the dura mater must traverse this “vascular barrier” without being
cleared via the capillary network if they are to reach the underlying arachnoid mater.

Because lipid soluble molecules traverse capillaries more readily than do more hydrophilic molecules,
one can assume that lipid soluble opioids may be cleared by this mechanism more readily than less
lipid soluble opioids.

arachnoid mater is also a metabolic barrier. For example, the meninges contain multiple enzyme
systems that are potentially capable of drug metabolism (e.g., cytochrome P450, glucuronysl
transferase). In fact, acetylcholinesterase activity in the spinal meninges is equal to that in the
spinal cord.

Once drugs traverse the arachnoid mater to reach the CSF, their residence time in CSF is dependant
on their relative aqueous solubility, which explains the clinical observation that morphine undergoes
greater rostral spread than do more hydrophobic drugs.

An important difference between epidurally and intrathecally administered opioids is that a significant
amount of an intrathecally administered drug is “lost” by diffusion into the epidural space. In fact,
diffusion into the epidural space is a major route of elimination for many drugs administered
intrathecally

Diffusion through brain tissue - increasing lipid solubility actually decreases the ability of an opioid to
diffuse into the spinal cord and increases the likelihood that the drug will preferentially end up in the
white mater instead of the gray matter.

Bioavailability in the extracellular fluid space is critical because it is the drug in this environment that is
able to reach opioid receptors.

increasing lipid solubility decreases the spinal cord bioavailability of spinally administered drugs.

Drug Baricity and Patient Position. The baricity of the local anesthetic injected will determine the
direction of migration within the dural sac. Hyperbaric solutions will tend to settle in the dependent
portions of the sac, while hypobaric solutions will tend to migrate in the opposite direction. Isobaric
solutions usually will stay in the vicinity where they were injected, diffusing slowly in all directions.
Consideration of the patient position during and after the performance of the block and the choice
of a local anesthetic of the appropriate baricity is crucial for a successful block during some surgical
procedures.



The duration of action of epidurally administered local anesthetics frequently is prolonged, and
systemic toxicity decreased, by addition of epinephrine. Addition of epinephrine also makes
inadvertent intravascular injection easier to detect and modifies the effect of sympathetic blockade
during epidural anesthesia.

For each anesthetic agent, a relationship exists between the volume of local anesthetic injected
epidurally and the segmental level of anesthesia achieved. The amount needed decreases with
increasing age and also decreases during pregnancy and in children.

The concentration of local anesthetic used determines the type of nerve fibers blocked. The highest
concentrations are used when sympathetic, somatic sensory, and somatic motor blockade are
required. Intermediate concentrations allow somatic sensory anesthesia without muscle relaxation.
Low concentrations will block only preganglionic sympathetic fibers.



Explain clinical drug monitoring with regard to peak and trough concentrations,
minimum therapeutic concentration and toxicity

therapeutic drug monitoring refers to individualization of dosage by maintaining plasma or
blood drug conc. Within a target range.
Characteristics of drug which make therapeutic drug monitoring useful:
Marked pharmacokinetic variability
Therapeutic and adverse effects related to the drug conc.
Narrow therapeutic index
Defined therapeutic conc. Range
Desired therapeutic effect difficult to monitor

Drug monitoring is used in two major situation:
Drug used prophylactically to maintain the absence of a condition such as a seizure
To avoid seious toxicity as with the aminoglycosides

2 major important principles in using therapeutic ranges
Most drug responses are graded responses and are continuous through out the conc. Range
Individual patients will have individual therapeutic range – this is the residual
pharmacodynamic variability

Timing of samples – the least variable point in the dosing interval is the pre dose or trough
conc. For the drugs with short half lives in relation to the dosing interval, samples should be
collected pre-dose. For drugs with long t1/2 eg phenytoin and amiodarone samples
collected at any point in the dosing interval can be satisfactory

It is best to wait for steady state to be reached before taking samples except drugs with very
long T1/2 and toxicity eg amiodarone
Two important factors which influence interpretation of results:
-        protein binding: total drug is measured, however it is the unbound fraction that
         produces effect. unbound fraction can change with disease state/displacement by
         another drug
-        Active metabolite: metabolite which may not be measured can contribute to the
         therapeutic response

The major use of measured concentrations of drugs (at steady state) is to refine the estimate of CL/F
for the patient being treated
CL/F= dosing rate / Css (measured)

CL/F can be substituted in the following equation to deduce new dosing rate
Dosing rate = target Cp * (CL/F)

If a drug follows first-order kinetics, the average, minimum, and maximum concentrations at steady
state are linearly related to dose and dosing rate. Therefore, the ratio between the measured and
desired concentrations can be used to adjust the dose, consistent with available dosage sizes:




Define tachyphylaxis, tolerance, addiction, dependence and idiosyncrasy
Tachyphylaxis:

Diminished effect to the same concentration of the drug, following continued or subsequent
exposure to the drug

Tolerance
Requirment of higher dose of drug to produce a given response.

Addiction
It is a pattern of compulsive drug use characterized by over whelming involvement with the
use of the drug

Dependence
State in which use of drug for personal satisfaction is accorded a higher priority than other basic
needs often in the face of known health risks

Idiosyncrasy
Genetically determined abnormal reactivity to a chemical eg barbiturates cause excitation


Describe mechanisms of tolerance

Requirement of higher dose of drug to produce a given response

Drug tolerance may be:
    Natural- the species / individual is inherently less sensitive to the drug eg rabbits are
       tolerant to atropine
    Acquired – uninterrupted presence of the drug in the body favours development of
       tolerance. Eg tolerance develops to the sedative and euphoric actions of morphine
       but not to its constipating and miotic actions
    Cross tolerance – development of tolerance to pharmacologically related drugs eg
       alcoholics are relatively tolerant to barbiturates and and general anaesthetics. Closer
       the two drugs are, the more complete is the cross tolerance
Mechanisms: incompletely understood.
    Pharmacokinetic / drug disposition tolerance – the effective concentration of the
       drug at the active site is decreased, mostly by enhancement of drug elimination on
       chronic use eg. barbiturates
    Pharmacodynamic/cellular tolerance – drug action is lessened; cells of the target
       organ become less responsive eg. morphine, barbiturates, nitrates. This may be due
       to down regulation of the receptors, weakening of the response effectuation or
       other compensatory homeostatic mechanisms

Understand genetic variability

Pharmacogenetics is the study of the genetic basis for variation in drug response.
PHARMACOGENETICS
Genetically determined variability in drug response.

Genetic Terms :

1.    Autosome :         Chromosomes other than sex chromosomes.

2.    Phenotype :        Outward manifestation of genetic trait.

3.    Genotype :         Characterised of genetic pair.

4.    Homozygous :        Presence of 2 identical complementary genes.

5.    Heterozygous :      Presence of 2 different complementary genes.


Potential consequences of Polymorphic drug metabolism

1.    Extended pharmacological effect
2.    Adverse drug reactions
3.    Lack of prodrug activation
4.    Increased effective dose
5.    Metabolism by alternative deleterious pathways
6.    Drug interaction


Examples of Pharmacogenetics

a)    Anaesthetic Drugs
      Porphyria
      Butyryl cholinesterase (pseudocholinesterase)
      Malignant hyperpyrexia

b)    Other Drugs
      Debrisoquine / sparteine hydroxylase (CYP2 D6)
      G6 P dehydrogenase
      Alcohol dehydrogenase
      N-Acetyl transferase
      Glucuronyl transferase
ACUTE HEPATIC PORPHYRIA

3 Syndromes :      Acute intermittent Porphyria
                   Variegate Porphyria
                   Hereditary Porphyria

Porphyria precipitated by drugs that induce -aminolaevulinic acid (ALA)
synthetase leading to excessive production of porphyria (ALA,
porphobilinogen).

Effects :          Abdominal crisis
                   Neurotoxicity – demyelination of nerves - esp intercostal
                   nerves. Resulting in sensory changes and motor paralysis

Inducers :         Barbiturates, phenytoin, alcohol, some benzodiazepines,
                   cephalosporins, sulphonylureas, oral contraceptives, some
                   steroids.


BUTYRYL CHOLINESTESTERASE (PSEUDOCHOLINESTERASE)
DEFICIENCY

1.    Abnormal gene that leads to deficiencies of active normal form of plasma
      cholinesterase.
2.    Atypical / abnormal pseudocholinesterase has greatly reduced affinity for
      succinyl choline.
3.    Several variants of atypical cholinesterase and all genetically arise from a
      single locus on chromosome 3.
4.    Detected and diagnosed by inhibition of cholinesterase by 10-5 mol/L
      concentration of dibuchaine on benzoyl choline (substrate).
      Normal 80% inhibition
      Atypical 20% inhibition (homozygote)
               60% inhibition (heterozygote)

      Other variants :

      Fluoride Resistance (different allele on same gene)
      Silent Gene = No activity & extremely sensitive to suxamethonium

CHOLINESTERASE VARIANTS
Variant            Frequency            Activity            Sux Sensitivity
Usual (U)          0.98                 Normal              Normal
Atypical (dibucaine) 0.02               Decrease by 76%    Homozygote
                                                           = 2hr paralysis

Fluoride             0.003              Decreased by 60%   F/F ~ / 1-2 hr
                                                           Paralysis

Silent               0.0003             No activity        S/S 3-4 hr. paralysis




Second Locus Variants
C5 and Cynthiana variants – determined by genes located on a second locus –
resistant to suxamethonium

MALIGNANT HYPERPYREXIA
Increased temperature with muscle contraction and rigidity associated with
excessive Ca++ release in muscle associated with suxamethonium and volatile
anaesthetic agents.

Incidence : 1 : 35,000

Genetic disorder of RYANODINE receptor in sarcoplasmic reticulum.

Triggers. Suxamethonium
          All volatile anaesthetic agents catecholamines

In vitro test : Halothane + Caffeine used

May be also associated with increased influx of extracellular calcium via L –
Type channels and calcium antagonists (eg. diltiazem) may be protective.


? Halothane Hepatitis
Lymphocyte epoxide activity reduced in patients with halothane hepatitis and
twins

CYTOCHROME P450 POLYMORPHISM

1.       Most drugs metabolised by CYP2D6 (25%) AND CYP3A4 (51%)
2.       CYP 3A4 ( by grapefruit juice ) lovastatin, cyclosporin, saquinivir
         (HIV protease inhibitor)
3.       CYP 2D6 (Debrisoquine hydroxylase)
         (1) Inactive 6% Caucasians
                    1% Orientals
           Also inhibited by Quinidine

     (2)   Ultra-rapid metaboliser 20% Ethiopian
                                      7% Spanish
     (3)   Substrates
           i)     Analgesics : Codeine, dextromethorphan
           ii)    Psychiatric drugs
                  Amitriptylines & tricyclics
                  SSRI
                  Haloperidol
                  Mianserin

           iii)   Cardiovascular Drugs
                  Alprenolol, amiodarone, mexiletine, flecanide.


ACETYLATION POLYMORPHISM

1.   Fast + Slow Acetylators
2.   Slow acetylators in 50-60% Caucasions
                             5% Japanese
3. Substrate : Isoniazid, Procainamide, Sulphonamide, hydralazine,
                    Nitrazepam.
     Eg. hydralazine         slow acetylators   Lupus phenomenon.

G6 P Dehydrogenase deficiency

1.   Delayed regeneration of NADPH which protects erythrocytes from
     oxidative injury by drugs.
2.   Haemolysis with anti-malarials, NSAIDS; Sulphonamides.
3.   Develop haemolytic anaemia & jaundice on exposure to above drugs.
Describe alterations to drug response due to physiological change with special
reference to neonates, the elderly and pregnancy

Preganacy:
Drugs given during pregnancy can affect the fetus. There are marked physiological changes during
pregnancy especially in the third trimester which can alter drug disposition:
    1. GI motility is reduced  delayed absorption of orally administered drug
    2. Plasma and extracellular fluid volume expands – volume of drug distribution may increase
    3. While plasma albumin level falls, that of α1 acid glycoprotein increases – the unbound
        fraction of acidic drugs increases but that of basic drug decreases
    4. Renal blood flow increases markedly – polar drugs will be eliminated faster
    5. Hepatic microsomal enzymes undergo induction – many drugs are metabolized faster

Children
Drug disposition in childhood does not vary linearly with either body weight or body surface area,
and there are no reliable, broadly applicable principles or formulas for converting doses of drugs
used in adults to doses that are safe and effective in children.

Variability in pharmacokinetics is greatest at times of physiological change (e.g., the newborn or
premature baby or at puberty) such that dosing adjustment, often aided by therapeutic drug
monitoring for drugs with narrow therapeutic indices, becomes critical for safe, effective
therapeutics.

Most drug-metabolizing enzymes are expressed at low levels at birth, followed by an isozyme-
specific postnatal induction of CYP expression. CYP2E1 and CYP2D6 appear in the first day, followed
within 1 week by CYP3A4 and the CYP2C subfamily. CYP2A1 is not expressed until 1 to 3 months
after birth. Some glucuronidation pathways are decreased in the newborn, and an inability of
newborns to glucuronidate chloramphenicol was responsible for the "gray baby syndrome"
characterized by vomiting, neonatal hypothermia, flaccidity, cyanosis, and cardiovascular collapse

When adjusted for body weight or surface area, hepatic drug metabolism in children after the
neonatal period often exceeds that of adults.

Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly
reduced GFRs (2 to 4 ml/min/1.73 m2) & tubular transport, and prematurity reduces renal function
even further. As a result, neonatal dosing regimens for a number of drugs (e.g., aminoglycosides)
must be reduced to avoid toxic drug accumulation. GFR (corrected for body surface area) increases
progressively to adult levels by 8 to 12 months of age.

Drug pharmacodynamics in children also may differ from those in adults. Antihistamines and
barbiturates that generally sedate adults may cause children to become "hyperactive." The
enhanced sensitivity to the sedating effects of propofol in children has led to the administration of
excessive doses that produced a syndrome of myocardial failure, metabolic acidosis, and multiorgan
failure. Unique features of childhood development also may provide special vulnerabilities to drug
toxicity; for example, tetracyclines can permanently stain developing teeth, and glucocorticoids can
attenuate linear growth of bones.

Blood brain barrier is more permeable – drugs attain higher conc. In CNS (accumulation of
unconjugated bilirubin causes kernicterus)
Drug absorption may also be altered in infants because of lower gastric acidity and slower intestinal
transit
Transdermal absorption is faster as their skin is thin and more permeable

After first year of life, drug metabolism is often faster than the adults eg theophylline, phenytoin,
carbamazepine t1/2 is shorter



The Elderly
Increased inter-individual variability of doses required for a given effect

The reduction in lean body mass, serum albumin, and total-body water, coupled with the increase in
percentage of body fat, alters distribution of drugs in a manner dependent on their lipid solubility
and protein binding. Increased or decreased volume of distribution of lipophilic and hydrophilic
drugs respectively.

The clearance of many drugs is reduced in the elderly. Renal function declines at a variable rate to
about 50% of that in young adults. Hepatic blood flow and drug metabolism also are reduced in the
elderly, but the variability of these changes is great. In general, the activities of hepatic CYPs are
reduced, but conjugation mechanisms are relatively preserved.

Frequently, the elimination half-lives of drugs are increased as a consequence of larger apparent
volumes of distribution of lipid-soluble drugs and/or reductions in the renal or metabolic clearance.

Drugs that depress the CNS produce increased effects at any given plasma concentration.

Slower absorption due to reduced motility and blood flow to the intestines, lower plasma protein
binding due to lower plasma albumin.

More prone to develop adverse effects




Describe alterations to drug response due to pathological disturbance with special
reference to cardiac, respiratory, renal and hepatic disease

Impaired Renal Clearance of Drugs
    Common drugs which are primarily cleared by the kidney- vancomycin, aminoglycoside
       antibiotics, and digoxin.

       When renal clearance of a drug is diminished, the desired pharmacological effect can be
        maintained either by decreasing the dose or lengthening the interval between doses.

       Clearance of the drugs which are primarily cleared unchanged by the kidneys is reduced
        parallel to decrease in creatinine clearance. Creatinine clearance can be used, as estimated
        from serum creatinine by the formula of Cockcroft and Gault:
        The 0.85 multiplier for women accounts for their reduced muscle mass.

       Drug metabolites that may accumulate with impaired renal function may be
        pharmacologically active or toxic. Although meperidine is metabolized extensively and is not
        dependent on renal function for elimination, its metabolite, normeperidine, is cleared by the
        kidney and accumulates when renal function is impaired  high levels in renal failure
        probably account for the central nervous system (CNS) excitation with irritability, twitching,
        and seizures


       Loading dose of the drug is not altered but the maintenance dose should be reduced or
        intervals prolonged

       If the t1/2 of the drug is prolonged the attainment of the steady state plasma conc. With
        maintainance doses is delayed proportionately

       Plasma proteins specially albumin are often low or altered in structure in patients with renal
        disease – binding of the acidic drugs are altered

       The permeability of the blood brain barrier is increased in renal failure – opiates,
        barbiturates, benzodiazepines etc produce more CNS depression

       Pethidine should be avoided as its metabolite nor-pethidine can accumulate on repeated
        dosing and cause seizure.

       The target organ sensitivity may also be increased. Anti-hypertensives produce more
        postural hypotension in patients with renal insufficiency

       Certain drugs worsen the existing clinical condition in renal failure eg tetracycline have an
        anti-anabolic effect and accentuate uremia; NSAIDS and carbenoxolone cause more fluid
        retention

       Thiazide diuretic tend to reduce GFR are ineffective in renal failure and can worsen uremia

       Potassium sparing diuretics can cause severe hyperkalemia

       Phenformin more likely to produce lactic acidosis in renal failure



Impaired Hepatic Clearance of Drugs
Liver disease can influence drug disposition in several ways:
     Bioavailability of drugs having high first pass metabolism is increased due to loss of
         hepatocellular function and portocaval shunting
       Serum albumin is reduced – protein binding of acidic drugs is reduced and more drug is
        present in the free form
       Metabolism and elimination of some drugs (morphine, pentobarbitone, lidocaine,
        propanolol) is decreased and their dose should be reduced.
       Prodrugs needing hepatic metabolism for activation eg prednisone, are less effective and
        should be avoided
       The sensitivity of the brain to the depressant action of morphine and barbiturates is
        markedly increased in cirrhotics – normal doses can produce coma
       Brisk dieresis can produce mental changes in patients with impending hepatic
        encephalopathy because diuretics cause hypokalemic alkalosis which favour conversion of
        NH4+ to NH3 enters brain more easily
       Oral anticoagulants can markedly increase prothrombin time because clotting factors are
        already low
       Fluid retaining action of phenylbutazone and carbenoxolone and lactic acidosis due to
        metformin are accentuated



Altered Drug Binding to Plasma Proteins.
When a drug is highly bound to plasma proteins, its egress from the vascular compartment is limited
largely to the unbound (free) drug. Thus, the therapeutic response should be related to the level of
unbound drug in plasma rather than to the total drug concentration.
Hypoalbuminemia owing to renal insufficiency, hepatic disease, or other causes can reduce the
extent of binding of acidic and neutral drugs; in these conditions, measurement of free drug
provides a more accurate guide to therapy than does analysis of total drug.
Because a small change in the extent of binding produces a large change in the level of free drug,
drugs for which changes in protein binding are particularly important are those that are more than
90% bound to plasma protein. Phenytoin is one such drug, and measurement of unbound phenytoin
is used to guide dosing in patients with renal failure or other conditions that reduce protein binding

Metabolic clearance of such highly bound drugs also is a function of the unbound fraction of drug.
Thus, clearance is increased in those conditions that reduce protein binding; shorter dosing intervals
therefore must be employed to maintain therapeutic plasma levels.

Circulatory Insufficiency Owing to Cardiac Failure or Shock.
In circulatory failure, neuroendocrine compensation can reduce renal and hepatic blood flow
substantially. Accordingly, elimination of many drugs is reduced. Particularly affected are drugs with
high hepatic extraction ratios, such as lidocaine, whose clearance is a function of hepatic blood flow;
in this setting, only half the usual infusion rate of lidocaine is required to achieve therapeutic plasma
levels.

Decreasing drug absorption from git due to mucosal edema and splanchnic vasoconstriction.

Modifying volume of distribution which can increase for some drugs due to expansion of
extracellular fluid volume or decrease for others as a result of decreased tissue perfusion – loading
doses of drugs like lidocaine and procainamide should be lowered

Retarding drug elimination as a result of decreased perfusion and congestion of liver, reduced
glomerular filtration rate and increased tubular reabsorption; doing rate of drugs should be reduced,
as for lignocaine, theophylline
The decompensated heart is more sensitive to digitalis




Classify and describe adverse drug effects

(done above)


Classify and describe mechanisms of drug interaction (also see notes in RAH I)

Drug interaction is a marked alteration in the effects of some drugs resulting from co-administration
with another agent.

Drug interactions may be pharmacokinetic or pharmacodynamic

Pharmacokinetic Interactions
    Diminished Drug Delivery to the Site of Action
          o Impaired gastrointestinal absorption: For example, aluminum ions in certain
              antacids or ferrous ions in oral iron supplements form insoluble chelates of the
              tetracycline antibiotics, thereby preventing their absorption. The antifungal
              ketoconazole is a weak base that is only soluble at acid pH. Drugs that raise gastric
              pH, such as the protein pump inhibitors and histamine H2-receptor antagonists,
              impair the dissolution and absorption of ketoconazole.
          o Hepatic CYPs play a key role in the metabolism of a large number of drugs, and their
              expression can be induced or their activity inhibited by a diverse array of drugs.
              Examples of drugs that induce these enzymes include antibiotics (e.g., rifampin),
              anticonvulsants (e.g., phenobarbital, phenytoin, and carbamazepine), nonnucleoside
              reverse transcriptase inhibitors (e.g., efavirenz and nevirapine), and herbal drugs
              (e.g., St. John's wort). Induction of these enzymes accelerates the metabolism of
              drugs that are their substrates and notably decreases oral bioavailability by
              increasing first-pass metabolism in the liver. The inducing drugs lower the plasma
              levels of drugs that are metabolized predominantly by these enzymes, including
              cyclosporine, tacrolimus, warfarin, verapamil, methadone, dexamethasone,
              methylprednisolone, low-dose oral contraceptives, and the HIV protease inhibitors.
    Increase Drug Delivery to the Site of Action
          o Inhibition of Drug-Metabolizing Enzymes. For drugs whose clearance depends
              primarily on biotransformation, inhibition of a metabolizing enzyme leads to
              reduced clearance, prolonged half-life, and drug accumulation during maintenance
              therapy, sometimes with severe adverse effects. Hepatic CYP3A isozymes catalyze
              the metabolism of many drugs that are subject to significant drug interactions owing
              to inhibition of metabolism. Drugs metabolized predominantly by CYP3A isozymes
              include immunosuppressants (e.g., cyclosporine and tacrolimus), HMG-CoA
              reductase inhibitors (e.g., lovastatin, simvastatin, and atorvastatin), HIV protease
              inhibitors (e.g., indinavir, nelfinavir, saquinavir, amprinavir, and ritonavir), Ca2+
              channel antagonists (e.g., felodipine, nifedipine, nisoldipine, and diltiazem),
              glucocorticoids (e.g., dexamethasone and methylprednisolone), benzodiazepines
              (e.g., alprazolam, midazolam , and triazolam), and lidocaine.

              The inhibition of CYP3A isoforms may vary even among structurally related members
              of a given drug class. For example, the antifungal azoles ketoconazole and
              itraconazole potently inhibit CYP3A enzymes, whereas the related fluconazole
              inhibits minimally except at high doses or in the setting of renal insufficiency.
              Similarly, certain macrolide antibiotics (e.g., erythromycin and clarithromycin)
              potently inhibit CYP3A isoforms, but azithromycin does not. In one instance, the
              inhibition of CYP3A4 activity is turned to therapeutic advantage. The HIV protease
              inhibitor ritonavir inhibits CYP3A4 activity; when administered in combination with
              other protease inhibitors metabolized by this pathway, it increases their half-lives
              and permits less frequent dosing.

              Drug interactions mediated by inhibition of CYP3A can be severe. Examples include
              nephrotoxicity induced by cyclosporine and tacrolimus and severe myopathy and
              rhabdomyolysis resulting from increased levels of HMG-CoA reductase inhibitors.
              Whenever an inhibitor of the CYP3A isoforms is administered, the clinician must be
              cognizant of the potential for serious interactions with drugs metabolized by CYP3A.

            Drug interactions also can result from inhibition of other CYPs. Amiodarone and its
            active metabolite desethylamiodarone promiscuously inhibit several CYPs, including
            CYP2C9, the principal enzyme that eliminates the active S-enantiomer of warfarin.
            Because many patients treated with amiodarone are also receiving warfarin (e.g.,
            subjects with atrial fibrillation), the potential exists for major bleeding
            complications.
          o Inhibition of Drug Transport. The best-studied drug transporter is the P-
            glycoprotein, which initially was defined as a factor that actively transported
            multiple chemotherapeutic drugs out of cancer cells, thereby rendering them
            resistant to drug action. P-glycoprotein is expressed on the luminal aspect of
            intestinal epithelial cells (where it functions to inhibit xenobiotic absorption), on the
            luminal surface of renal tubular cells, and on the canalicular aspect of hepatocytes;
            inhibition of P-glycoprotein-mediated transport at these sites results in increased
            plasma levels of drug at steady state. Digoxin is largely dependent on transport by P-
            glycoprotein for elimination, and drugs that inhibit the transporter can elevate
            plasma digoxin levels to the toxic range. Inhibitors of P-glycoprotein include
            verapamil, diltiazem, amiodarone, quinidine, ketoconazole, itraconazole, and
            erythromycin; as discussed earlier, many of these drugs also inhibit CYP3A4. P-
            glycoprotein on the capillary endothelium that forms the blood-brain barrier exports
            drugs from the brain, and inhibition of P-glycoprotein enhances CNS distribution of
            some of these drugs (e.g., some HIV protease inhibitors).

Pharmacodynamic Interactions
      Synergism: when the action of one drug is facilitated or increased by other
          o Additive synergism: the effect of the two drugs are in the same direction and
              simply add up:
                   Examples: aspirin + paracetamol (as analgesic/anti-pyretic), nitrous
                      oxide + ether (general anaesthetic), ephedrine + theophylline
                      (bronchodilator)
          o Supraadditive syndergism: the effect of combination is greater than the
              individual effects of components:
                    Examples: acetylcholine + physostigmine (inhibition of breakdown),
                     Levodopa+carbidopa/benserazide (inhibition of peripheral
                     metabolism), sulfonamide + trimethoprim (sequential blockade),
                     Captopril + diuretic (tackling two contributory factors)
      Antagonism: One drug decreases or inhibits the action of the another
          o Physical: based on the physical property eg charcoal adsorbs alkaloids and
             can prevent their absorption
          o Chemical: the two drugs react chemically and form inactive product
                  Eg tannins + alkaloids – insoluble alkaloids tannate is formed,
                     chelating agents (BAL, Cal. Disod. Edentate) complex metals (As, Pb)
                  Drugs may react when mixed in the same syringe – thiopentone +
                     succinylcholine, Penicillin G sod + succinylcholine, Heparin +
                     penicillin/tetracycline/hydrocortisone
          o Physiological/functional: the two drugs act on different receptors or have
             different mechanisms but have opposite overt effects on the same
             physiological function i.e. have pharmacological effects in opposite directions
             eg. Histamine and adrenaline on bronchial muscle and BP, glucagon and
             insulin on blood sugar
          o Receptor: competitive and non-competitive antagonism (discussed
             previously)




Explain the mechanisms and significance of pharmacogenetic disorders such as
malignant hyperpyrexia, porphyria, atypical cholinesterase and disturbance of
cytochrome function

Some important pharmacogenetic diseases:
    Atypical pseudocholinesterase: prolonged succinylcholine apnoea
    G6PD deficiency – haemolysis with primaquine and other oxidizing drugs like
      sulphonamides, dapsone, quinine, chloroquinine, nalidixic acid, nitrofurantoin etc
    Acetylator polymorphism: isoniazid neuropathy, procainamide, and hydralazine
      induced lupus in slow acetylators
    Acute intermittent porphyria – precipitated by the barbiturates due to genetic defect in
      the repression of porphyrin synthesis
    CYP2D6 abnormality causes poor metoprolol / debrisoquin metabolizer status
    Malignant hyperthermia after halothane
    Inability to hydroxylate phenytoin – toxicity at usual doses
    Resistance to coumarin anticoagulants due to an abnormal enzyme (that regenerates
      the reduced form vit K) which has low affinity for the coumarins
    Precipitation of an attack of angle closure glaucoma by mydriatics in individuals with
      narrow angle

Malignant hyperthermia mechanism:
In a large proportion (50-70%) of cases, the propensity for malignant hyperthermia is due to
a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum. RYR1
opens in response to increases in intracellular Ca2+ level mediated by L-type calcium
channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle
contraction. RYR1 has two sites believed to be important for reacting to changing
Ca2+ concentrations: the A-site and the I-site. The A-site is a high affinity Ca2+ binding site
that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's
closing. Caffeine, Halothane, and other triggering agents act by drastically increasing the
affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant
proteins. Mg2+ also affect RYR1 activity, causing the protein to close by acting at either the
A- or I-sites. In MH mutant proteins, the affinity for Mg2+ at either one of these sites is
greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a
lowered activation and heightened deactivation threshold. The process of reabsorbing this
excess Ca2+ consumes large amounts of ATP (adenosine triphosphate), and generates the
excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged
by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak"
into the circulation, including potassium, myoglobin, creatine, phosphate and creatine kinase.
The other known causative gene for MH is CACNA1S, which encodes L-type voltage-gated
calcium channel α-subunit. There are two known mutations in this protein, both affecting the
same residue, R1086. This residue is located in the large intracellular loop connecting
domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When
these mutant channels are expressed in HEK 293 (human embryonic kidney) cells, the
resulting channels are five times more sensitive to activation by caffeine (and presumably
halothane) and activate at 5-10mV more hyperpolarized. Furthermore, cells expressing these
channels have an increased basal cytosolic Ca2+ concentration. As these channels interact
with and activate RYR1, these alterations result in a drastic increase of intracellular Ca2+,
and, thereby, muscle excitability.
Other mutations causing MH have been identified, although in most cases the relevant gene
remains to be identified.
Genetics- At least 70 mutations in the ryanodine receptor have been described, which are
transmitted in an autosomal dominant fashion. The gene is located on the long arm of the
nineteenth chromosome (19q13.1). These mutations tend to cluster in one of three domains
within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the
protein, which interacts with L-type calcium channels and Ca2+. MH3 is located in the
transmembrane forming C-terminus. This region is important for allowing Ca2+ passage
through the protein following opening.
Triggered by volatile anesthetic inhalation or intravenous succinylcholine administration,
MHS is a hypermetabolic disorder of skeletal muscle that is often, but not always, associated
with significant increases in body temperature to 43.3°C (110.0°F) or higher. Approximately
1 in 15,000 children and 1 in 50,000 adults are susceptible to MHS. It is intriguing to note the
much higher incidence in children than in adults, perhaps indicating that MHS behaves like a
complex genetic disease. Pharmacogenetic studies of MHS have found numerous
associations with variations in the ryanodine receptor (RYR1) gene, with approximately
50% of cases involving mutations within this gene. In addition, a mutation in the α1 subunit
of the voltage dependent calcium channel has been associated with 1% of North American
MHS cases. However, the true percentage is difficult to determine because at least 23
different RYR1 polymorphisms seem to be associated with MHS. Particularly severe cases of
MHS tend to occur in individuals with central core disease, a muscular disorder also known
to be associated with RYR1 polymorphisms.

   GENE PRODUCT DRUGS                                RESPONSES AFFECTED
   (GENE)
  Drug metabolizers
  CYP2C9            Tolbutamide, warfarin,          Anticoagulant effect of warfarin
                    phenytoin, nonsteroidal         (Aithal et al., 1999; Roden, 2003;
                    antiinflammatories              Weinshilboum, 2003)
  CYP2C19           Mephenytoin, omeprazole,        Peptic ulcer response to omeprazole
                    hexobarbital,                   (Kirchheiner et al., 2001)
                    mephobarbital, propranolol,
                    proguanil, phenytoin
  CYP2D6            β blockers, antidepressants,    Tardive dyskinesia from
                    antipsychotics, codeine,        antipsychotics, narcotic side effects,
                    debrisoquine,                   codeine efficacy, imipramine dose
                    dextromethorphan,               requirement, β blocker effect
                    encainide, flecainide,          (Kirchheiner et al., 2001;
                    fluoxetine, guanoxan, N-        Weinshilboum, 2003)
                    propylajmaline,
                    perhexiline, phenacetin,
                    phenformin, propafenone,
                    sparteine
  CYP3A4/3A5/3A7 Macrolides, cyclosporine,          Efficacy of immunosuppressive effects
                    tacrolimus, Ca2+ channel        of tacrolimus (Evans and Relling,
                    blockers, midazolam,            2004)
                    terfenadine, lidocaine,
                    dapsone, quinidine,
                    triazolam, etoposide,
                    teniposide, lovastatin,
                    alfentanil, tamoxifen,
                    steroids


Atypical cholinesterases
The effectiveness of neuromuscular blockers such as succinylcholine and mivacurium is
strongly associated with genetic factors. Variations in the gene for plasma
butyrylcholinesterase (pseudocholinesterase), the enzyme that hydrolyzes these drugs, have
been correlated with dramatic interindividual differences in the duration of drug-induced
muscular paralysis. Normally, patients completely recover neuromuscular function within 5–
10 min after receiving 1.0 –1.5 mg/kg succinylcholine. However, heterozygous (single allele)
expression of the butyrylcholinesterase Asp70Gly polymorphism results in production of a
less effective form of plasma butyrylcholinesterase. These patients typically take three to
eight times longer to recover neuromuscular function after succinylcholine administration.
Homozygous expression (both alleles) of the butyrylcholinesterase Asp70Gly polymorphism
prolongs the recovery of neuromuscular function even further, resulting in a recovery period
up to 60 times longer than that associated with the normal allele. Allelic variation within the
butyrylcholinesterase gene has also been shown to significantly prolong mivacurium- induced
muscle paralysis.
ACUTE HEPATIC PORPHYRIA

3 Syndromes :      Acute intermittent Porphyria
                   Variegate Porphyria
                   Hereditary Porphyria

Porphyria precipitated by drugs that induce -aminolaevulinic acid (ALA)
synthetase leading to excessive production of porphyria (ALA,
porphobilinogen).

Effects :          Abdominal crisis
                   Neurotoxicity – demyelination of nerves - esp intercostal
                   nerves. Resulting in sensory changes and motor paralysis

Inducers :         Barbiturates, phenytoin, alcohol, some benzodiazepines,
                   cephalosporins, sulphonylureas, oral contraceptives, some
                   steroids.


BUTYRYL CHOLINESTESTERASE (PSEUDOCHOLINESTERASE)
DEFICIENCY

5.    Abnormal gene that leads to deficiencies of active normal form of plasma
      cholinesterase.
6.    Atypical / abnormal pseudocholinesterase has greatly reduced affinity for
      succinyl choline.
7.    Several variants of atypical cholinesterase and all genetically arise from a
      single locus on chromosome 3.
8.    Detected and diagnosed by inhibition of cholinesterase by 10-5 mol/L
      concentration of dibuchaine on benzoyl choline (substrate).
      Normal 80% inhibition
      Atypical 20% inhibition (homozygote)
               60% inhibition (heterozygote)

      Other variants :

      Fluoride Resistance (different allele on same gene)
      Silent Gene = No activity & extremely sensitive to suxamethonium

CHOLINESTERASE VARIANTS
Variant            Frequency            Activity            Sux Sensitivity
Usual (U)          0.98                 Normal              Normal
Atypical (dibucaine) 0.02               Decrease by 76%    Homozygote
                                                           = 2hr paralysis

Fluoride             0.003              Decreased by 60%   F/F ~ / 1-2 hr
                                                           Paralysis

Silent               0.0003             No activity        S/S 3-4 hr. paralysis




Second Locus Variants
C5 and Cynthiana variants – determined by genes located on a second locus –
resistant to suxamethonium

MALIGNANT HYPERPYREXIA
Increased temperature with muscle contraction and rigidity associated with
excessive Ca++ release in muscle associated with suxamethonium and volatile
anaesthetic agents.

Incidence : 1 : 35,000

Genetic disorder of RYANODINE receptor in sarcoplasmic reticulum.

Triggers. Suxamethonium
          All volatile anaesthetic agents catecholamines

In vitro test : Halothane + Caffeine used

May be also associated with increased influx of extracellular calcium via L –
Type channels and calcium antagonists (eg. diltiazem) may be protective.


? Halothane Hepatitis
Lymphocyte epoxide activity reduced in patients with halothane hepatitis and
twins

CYTOCHROME P450 POLYMORPHISM

4.       Most drugs metabolised by CYP2D6 (25%) AND CYP3A4 (51%)
5.       CYP 3A4 ( by grapefruit juice ) lovastatin, cyclosporin, saquinivir
         (HIV protease inhibitor)
6.       CYP 2D6 (Debrisoquine hydroxylase)
         (2) Inactive 6% Caucasians
                        1% Orientals
               Also inhibited by Quinidine

       (2)     Ultra-rapid metaboliser 20% Ethiopian
                                          7% Spanish
       (3)     Substrates
               iv) Analgesics : Codeine, dextromethorphan
               v)     Psychiatric drugs
                      Amitriptylines & tricyclics
                      SSRI
                      Haloperidol
                      Mianserin

               vi)     Cardiovascular Drugs
                       Alprenolol, amiodarone, mexiletine, flecanide.


ACETYLATION POLYMORPHISM

3.   Fast + Slow Acetylators
4.   Slow acetylators in 50-60% Caucasions
                             5% Japanese
3. Substrate : Isoniazid, Procainamide, Sulphonamide, hydralazine,
                    Nitrazepam.
     Eg. hydralazine         slow acetylators   Lupus phenomenon.

G6 P Dehydrogenase deficiency

4.     Delayed regeneration of NADPH which protects erythrocytes from
       oxidative injury by drugs.
5.     Haemolysis with anti-malarials, NSAIDS; Sulphonamides.
6.     Develop haemolytic anaemia & jaundice on exposure to above drugs.



Describe immune mechanisms which may result in reactions to drugs, intravenous
fluids and latex.

Immune mechanisms of adverse effects to drugs have been discussed above

Prevalence in general population with no risk factors  <1%

Prevalence amongst health care workers 7-13.7% in contrast to 0.8% amongst non health care
workers in hospital setting
Immunology:

Raw latex is the sap of the rubber tree – hevea brasiliensis

14 antigenic proteins have been identified in the latex extracts

Cross reactivity with several fruits containing proteins known as class 1 chitinases; most notably
banana, avocado, chestnut and kiwi fruit.

Common routes of exposure- airborne, intravenous, mucosal

Repeated exposure over time increases the incidence of sensitivity

Mechanisms:

The various chemicals added during processing can provoke an irritant dermatitis which is not an
allergic reaction

Some reactions may be due to type IV hypersensitivity contact dermatitis

IgE mediated reactions to the latex protein antigens. The result is mast cell degranulation, with the
release of mediators such as histamine, tryptase, prostaglandins and leukotrienes. The clinical
effects of this type I immediate hypersensitivity reaction range from urticarial skin rashes to full
blown anaphylaxis



Techniques used for investigation of latex allergy:

In-vitro test: radio-allergosorbent test (RAST) involves the reaction of the patient’s serum with an
antigen polymer complex in the presence of [125I] – labelled IgE antibody. This allows quantification
of the amount of antibody present in the patient’s serum. Rate of the false –ve results ~ 25%

In vivo test: skin prick test and intradermal test.

Group of patients at high risk of latex allergy:

       Occupational exposure to latex eg health care workers
       Multiple operations, especially laparotomies
       Repeated bladder catheterization- the prevalence inpatients with spina bifida has been
        reported as 60%
       Atopy or a history of allergy to the foods known to cross react with latex
       History of anaphylaxis with no identified provoking agent
       Women are at higher risk than med – the reason for this is not clear, but may be due to
        increased exposure to rubber, either domestically (e.g. gloves) or medically (e.g. pregnancy,
        barrier contraception)
Define shelf-life and outline factors that may influence drug potency during
Storage


      Generally time taken for potency of drug to be reduced by 10%
      May be more stringent if breakdown products are toxic
      Expiry Date only valid if stored according to manufacturer
      This is important with suxamethonium

    Rate of breakdown affected by
         TEMPERATURE
         pH
         OXYGEN
         LIGHT
         HUMIDITY
         PACKAGING
         GLASS
                 LEACHING OF AGENTS FROM GLASS
                 BREAKAGE
         PLASTIC
                 CONVENIENT
                 “BREATHING” THROUGH PVC
                 BREAKDOWN PRODUCTS



Describe methods of preserving shelf-life of drugs.
ADDITIVES
    Solvent
           WATER
           PROPYLENE GLYCOL
           O/W EMULSIONS
           BENZYL ALCOHOL
    THE IMPORTANCE OF SOLUBILITY
           LARGE AMOUNT/ LOW VOLUME

      ADJUST pH
      ADJUST TONICITY
      PRESERVATIVES
      AGENTS TO RETARD DECOMPOSITION
      SPECIAL ADDITIVES
      CO-SOLVENTS
   •   Preservatives
               Chemical preservatives
               Antimicrobials
   •   Solvents
               Glycols
               Macrogols
               Intralipid
               Non-ionic surfactants
   •   Isotonicity
   •   Buffers

Chemical preservatives:
   • Anti-oxidants
             true anti-oxidants
             combine with free radicals to prevent oxidation
             e.g, thymol in halothane,
             hydroxytoulene, alpha tocopherol
   • Reducing agents
             Ascorbic acid, Na and K salts of sulphurous acids
   • Anti-oxidant synergists
             Citric acid eg in vecuronium, fentanyl
   • Buffers
          • citrate or phosphate used to prevent chemical decomposition and also
             ensure optimum pH eg fentanyl, vecuronium
          • NaOH in propofol

Anti microbials
   • Benzyl alcohol
   • Chlorbutol
   • Chlorocresol
   • Phenol
   • Parabens – parahydroxybenzoic acid esters

Benzyl alcohol
   • In Solu-Medrol (methyl prednisolone), d-tubocurare.
   • Toxicity
       1. Cardiovascular effects – hypotension, myocardial depression, decreased SVR.
       2. Respiratory effects – hyperventilation
       3. CNS – depression and inflammatory changes if introduced directly on peripheral
           nerves

Chlorbutol
   • Antibacterial and antifungal actions
   • In some preparations of atropine and curare
   • Toxicity - Reduce blood pressure ? mechanism
Chlorocresol
   • Antibacterial actions
   • In some preparations of morphine, curare, heparin
   • Toxicity
             Reduce myocardial contractility
             Neural toxicity – not to be used in epidural/spinals
             Allergic reactions seen with s/c heparin

Phenol
   • Antibacterial actions
   • In some preparations of glucagon
   • Toxicity
             Reduce myocardial contractility
             Neural toxicity

Parabens
   • Antibacterial actions, used in multi-use vials of local anaesthetics
   • Toxicity
             Allergic reactions
             Neural toxicity – peripheral nerves.

Sodium metabisulphite
   • Antibacterial actions, used in propofol
   • Antioxidant actions; used in adrenaline
   • Toxicity
             Allergic reactions
             Neural toxicity – peripheral nerves.

Propylene glycol – solvent
   • Used as solvent for lipid soluble agents eg diazepam, phenytoin
   • Toxicity
              CVS – arrhythmias in animals
              Veins – pain and thrombophlebitis

Polyethylene glycol –solvent
    • Used as solvent for lipid soluble agents eg nitrofurantoin, etomidate
    • Toxicity
               Veins – pain and thrombophlebitis
Surfactants
    • Cremophor EL
    • Lecithin phosphatide in propofol
       Used to lower surface tension of lipid particles to form micelles so that small fat
       particles can be suspended in water to from an emulsion

Cremophor EL
   • Polyoxyethylated castor oil – solvent for lipid soluble agents, also reduces surface
      tension
   •   Used in Althesin, Vitamin K, anti-cancer drugs
   •   Toxicity
               High allergic potential – anaphylactic and   anaphylactoid reactions

Intralipid - solubilising agent
    • Used in propofol, diazepam *“diazemuls”+

Isotonicity
    • Glycerol in propofol
    • Mannitol in dantrolene etc

Physical methods for prolonging shelf life
   • Cold temperature
   • Protect from uv light by amber colour ampoules/ vials
   • Exclusion from O2 and CO2
   • Freeze dried preparation eg vecuronium by reducing hydrolysis
   • Retard decomposition by sod carbonate or buffers




Describe the mechanisms of action and potential adverse effects of buffers, antioxidants,
anti-microbial and solubilizing agents added to drugs

(described above)

Outline the variations in generic nomenclature of commonly used drugs (e.g.
epinephrine/adrenaline, lidocaine/lignocaine)




Define isomerism and provide a classification with examples. To describe the
clinical importance of isomerism

Definitions

1. ISOMER :                  Compounds with same molecular formula but different
                             molecular structure.

2. STRUCTURAL OR CONSTITUTIONAL ISOMERS :
                    Compounds with the same numbers of chemical elements which
                    differ in their position and arrangement.

                             Differ structurally in the arrangement of bonds connecting their
                             atoms.
3. STEREOISOMERS :                Molecules with identical groups are arranged differently
                                  spatially i.e. relative arrangement of atoms in space differ.

                                  May be optical – ability to rotate polarised light differently; (+)
                                  or d if polarised light is rotated to right
                                  (-) or l if polarised light is rotated to left.
                                          Note : No structural feature that steers direction of light
                                           rotation.
                                          May differ with different solvents.

DO NOT BE CONFUSED WITH FISHER’S D OR L nomenclature

D - Configuration – relative to (+) glyceraldehyde

L - Configuration - relative to (-) glyceraldehyde.


4. ENANTIOMERS :                  Pairs of stereoisomers that exist in a mirror-image relationship.
                                  Typical example is where the centre of asymmetry is around a
                                  carbon atom, a saturated carbon atom attached to 4 different
                                  substituents.

5. RACEMATE :                     substance containing equal amounts of enantiomers and being
                                  optically neutral.

6. CHIRALITY :                    Compounds that are related to each other as an object by mirror
                                  image & therefore cannot be superimposed – usually has an
                                  asymmetrical carbon atom (but can be nitrogen, sulphur or
                                  phosphorus).

                                  R and S nomenclature is used.
                                  R Configuration : The 4 substituents around the chiral centre
                                  are assigned priorities according to atomic number and atomic
                                  weight.
                                   With smallest atom or group extending from viewer, if the
                                      arrangement of the largest to the smallest groups occur in a
                                      clockwise orientation, then compound is designated R
                                      (Rectus).
                                   If the arrangement of the largest to the smallest groups
                                      occur in an anticlockwise orientation, the compound is
                                      designed S (senester).

                                  STRUCTURAL ISOMERS
                                   Identical empirical formula and basic chemical skeleton.
                                   Differs in position of substituent groups.
                                  Example Enflurane vs Isoflurane.
                                  C3H2F5 O Cl
                                  Isoflurane = CHF2 .O. CHCl. CF3
                                  Enflurane = CHF2 .O. CF2. CHF Cl
                             DYNAMIC ISOMERISM (TAUTOMERS)
                             Changes in chemical structure when equilibrium between 2
                             forms altered (eg. pH changes).

                             Barbiturates (a) Keto form insoluble at neutral pH  (=C=S).
                                           (b) Enol Form – soluble at alkaline pH = C-OH
                                               or = C - SH

                             OPTICAL STEROISOMERS
                             -       mirror image of each other
                             -       rotate polarized light because of molecular asymmetry.
                             Examples :
                              (a) Pharmacodynamic effects.
                                     Atropine : l – isomer 50x more potent.
                                     Morphine : 16 possible isomers only l isomers active.
                                     Thiopentone : S isomer more potent but more rapidly
                                     eliminated.
                                     Etomidate : only R isomer active.
                                     Ketamine : (a) S isomer - potent
                                                   (b) R isomer - side effects +
                             (b)Pharmacokinetic effects
                                     Local anaesthetics:
                                                   S prilocaine - slow metabolism
                                                   S warfarin - more potent but more rapid
                                                   metabolism.

                             GEOMETRIC ISOMERISM
                              Occurs with drugs with C = C double bonds
                              CIS -CIS, trans, cis-trans isomers eg. mivacurium - 3
                               geometric isomers - CIS – atracurium.


Describe the processes by which new drugs are approved for research and clinical
use in Australia, and to outline the phases of human drug trials (phase I-IV)

In Australia therapeutic goods administration (TGA) have overall control of therapeutic
goods via pre-market evaluation and approval of products, licensing of manufacturers and
post market surveillance.

There are two main schemes under which the drug may be trialled:
    Clinical trial exemption (CTX) – rarely used – application for trial submitted to the
       TGA  raises objections  if objections satisfactory met  forwards to human
       research ethics committee (HREC) for approval  trial goes ahead without further
       assessment from TGA.
    Clinical trial notification (CTN) – data submitted to HREC of the institution where the
       trial will be conducted  HREC approval forwarded to the institution and TGA
       notified on the CTN form.
    PHASE ONE
         The new drug is tested in a SMALL GROUP (n= 20-100) to evaluate SAFETY,
           DOSAGE and SIDE EFFECTS
    PHASE TWO
         Given to a larger group to check EFFICACY and incidence of SIDE EFFECTS.
           Months-years

    PHASE THREE
         Larger group confirm EFFICTIVNESS and COMPARE to current treatments.
           Several thousand patients. Trials are randomised and blinded. This stage lasts
           years
    PHASE FOUR
         POST-MARKETING SURVEILLENCE
         LONG TERM EFFECTIVNESS
         SPECIFIC GROUPS (E.G. ELDERLY)


To outline methods which decrease absorption and enhance drug elimination such as
activated charcoal, emetic agents, gastric lavage, haemodialysis, charcoal
haemoperfusion and whole bowel irrigation.


Emesis
Major tools of gastric decontamination in the management of acute poisoning

Routine use is declining

Contraindicated in certain situations:

    1. If the patient has ingested a corrosive poison, such as a strong acid or alkali (e.g., drain
       cleaners), emesis increases the likelihood of gastric perforation and further necrosis of the
       esophagus
    2. If the patient is comatose or in a state of stupor or delirium, emesis may cause aspiration of
       the gastric contents
    3. If the patient has ingested a CNS stimulant, further stimulation associated with vomiting may
       precipitate convulsions
    4. If the patient has ingested a petroleum distillate (e.g., kerosene, gasoline, or petroleum-
       based liquid furniture polish), regurgitated hydrocarbons can be aspirated readily and cause
       chemical pneumonitis. In contrast, emesis should be considered if the ingested solution
       contains potentially dangerous compounds, such as pesticides. In general, the ability of
       various hydrocarbons to produce pneumonitis is inversely proportional to their viscosity: If
       the viscosity is high, as with oils and greases, the risk is limited; if the viscosity is low, as with
       mineral seal oil found in liquid furniture polishes, the risk of aspiration is high.



Methods to stimulate emesis:

Mechanically: by stroking the posterior pharynx


Ipecac:

         The most common household emetic
         Syrup of ipecac is available in 0.5 and 1 fluid ounce containers (approximately 15 and 30 ml)
         Takes 15 to 30 minutes to produce emesis; this compares favorably with the time usually
          required for adequate gastric lavage.
         The oral dose is 15 ml in children from 6 months to 12 years of age and 30 ml in older
          children and adults. Administration of ipecac should be followed by a drink of water. If
          emesis does not occur, ipecac should be removed by gastric lavage. Chronic abuse of ipecac
          for weight reduction can result in cardiomyopathy, ventricular fibrillation, and death.
         Mechanism of action: Ipecac acts as an emetic because of its local irritant effect on the
          enteric tract and its effect on the chemoreceptor trigger zone (CTZ) in the area postrema of
          the medulla.
         Current evidence/ recommendation: In 2004, the American Academy of Clinical Toxicology
          and the European Association of Poisons Control Centers and Clinical Toxicologists issued
          position papers on the use of ipecac syrup in poisonings - concluded that syrup of ipecac
          should not be administered routinely in the management of poisoned patients. Ipecac may
          be indicated when it can be administered to conscious, alert patients within 60 minutes of
          poisoning. Concerns:
           o      Benefits highly variable and diminished rapidly with time
           o      Initial use of ipecac in fact may be counterproductive by reducing the efficacy of
                  other, later, and presumably more effective treatments such as use of activated
                  charcoal, oral antidotes, and whole-bowel irrigation.



Apomorphine

      Stimulates the CTZ and causes emesis
      Usually administered by the subcutaneous route, 6 mg for adults and 0.06 mg/kg for
       children.
      However, this can be an advantage over ipecac in that it can be administered to an
       uncooperative patient and produces vomiting in 3 to 5 minutes.
      Concerns: Because apomorphine is a respiratory depressant, it should not be used if the
       patient has been poisoned by a CNS depressant or if the patient's respiration is slow and
       labored.
      Current status: used rarely as an emetic.



Gastric Lavage.

      Gastric lavage is accomplished by inserting a tube into the stomach and washing the
       stomach with water, normal saline, or one-half normal saline to remove the unabsorbed
       poison.
      The procedure should be performed as soon as possible, but only if vital functions are
       adequate or supportive procedures have been implemented.
      Method: The only equipment needed for gastric lavage is a tube and a large syringe. The
       tube should be as large as possible so that the wash solution, food, and poison (whether in
       the form of a capsule, pill, or liquid) will flow freely, and lavage can be accomplished quickly.
       A 36-French tube or larger should be used in adults and a 24-French tube or larger in
       children. Orogastric lavage is preferred over nasogastric lavage because a larger tube can be
       employed. To prevent aspiration, an endotracheal tube with an inflatable cuff should be
       positioned before lavage is initiated if the patient is comatose, having seizures, or has lost
       the gag reflex. During gastric lavage, the patient should be placed on his or her left side
       because of the anatomical asymmetry of the stomach, with the head hanging face down
       over the edge of the examining table. If possible, the foot of the table should be elevated.
       This technique minimizes chances of aspiration. The contents of the stomach should be
       aspirated with an irrigating syringe and saved for chemical analysis. The stomach then may
       be washed with saline solution. Saline solution is safer than water in young children because
       of the risk of water intoxication, manifested by tonic-clonic seizures and coma. Only small
       volumes (120 to 300 ml) of lavage solution should be instilled into the stomach at one time
       so that the poison is not pushed into the intestine. Lavage is repeated until the returns are
       clear, which usually requires 10 to 12 washings and a total of 1.5 to 4 L of lavage fluid. When
       the lavage is complete, the stomach may be left empty, or an antidote may be instilled
       through the tube. If no specific antidote for the poison is known, an aqueous suspension of
       activated charcoal and a cathartic often is given.
      The contraindications to this procedure generally are the same as for emesis, and there is
       the additional potential complication of mechanical injury to the throat, esophagus, and
       stomach.
      Current status/recommendation: gastric lavage should not be used routinely in the
       management of the poisoned patient but should be reserved for patients who have ingested
       a potentially life-threatening amount of poison and when the procedure can be undertaken
       within 60 minutes of ingestion.



Chemical Adsorption

      Activated charcoal avidly adsorbs drugs and chemicals on the surfaces of the charcoal
       particles, thereby preventing absorption and toxicity.
      Many, but not all, chemicals are adsorbed by charcoal. For example, alcohols, hydrocarbons,
       metals, and corrosives are not well adsorbed by activated charcoal, and charcoal therefore is
       of little value in treating these poisonings.
      The effectiveness of charcoal also depends on the time since the ingestion and on the dose
       of charcoal; one should attempt to achieve a charcoal-drug ratio of at least 10:1.
      Activated charcoal usually is prepared as a mixture of at least 50 g (about 10 heaping
       tablespoons) in a glass of water. The mixture is then administered either orally or via a
       gastric tube. Because most poisons do not appear to desorb from the charcoal if charcoal is
       present in excess, the adsorbed poison need not be removed from the gastrointestinal tract.
       Activated charcoal should not be used simultaneously with ipecac because charcoal can
       adsorb the emetic agent in ipecac and thus reduce the drug's emetic effect. Charcoal also
       may adsorb and decrease the effectiveness of specific antidotes.
      Activated charcoal also can interrupt the entero-hepatic circulation of drugs and enhance
       the net rate of diffusion of the chemical from the body into the gastrointestinal tract. For
       example, serial doses of activated charcoal have been shown to enhance the elimination of
       theophylline and phenobarbital.

      No benefit of treatment with ipecac or lavage plus activated charcoal as compared with
       charcoal alone.
      Current status/recommendation: while experimental and clinical trials demonstrate that
       elimination of some drugs can be enhanced by treatment with activated charcoal in
       volunteer studies, rarely has it been demonstrated to reduce morbidity or mortality in a
       controlled study. The position paper recommends consideration of activated charcoal
       treatment only if a patient has ingested a life-threatening amount of carbamazepine,
       dapsone, phenobarbital, quinine, or theophylline.
      Contraindications: unprotected airway, the presence of intestinal obstruction, or if the
       gastrointestinal tract is not intact or there is decreased peristalsis.
      Universal antidote, which consists of two parts burned toast (not activated charcoal), one
       part tannic acid (strong tea), and one part magnesium oxide. In practice, the universal
       antidote is ineffective.
      Activated charcoal is useful in interrupting the enterohepatic circulation of drugs such as
       tricyclic antidepressants and glutethimide. A nonabsorbable polythiol resin has been used to
       treat poisoning by methylmercury owing to its capacity to bind mercury excreted into the
       bile. Cholestyramine hastens the elimination of cardiac glycosides by a similar mechanism.



Chemical Inactivation

      Antidotes can change the chemical nature of a poison by rendering it less toxic or preventing
       its absorption.
      Formaldehyde poisoning can be treated with ammonia to form hexamethylenetetramine;
       sodium formaldehyde sulfoxylate can convert mercuric ion to the less soluble metallic
       mercury; and sodium bicarbonate converts ferrous iron to ferrous carbonate, which is poorly
       absorbed.
      Chemical inactivation techniques seldom are used today, however, because valuable time
       may be lost, whereas emetics, activated charcoal, and gastric lavage are rapid and effective.
      In the past, neutralization was the usual treatment of poisoning with acids or bases. Vinegar,
       orange juice, or lemon juice has been used often for the patient who has ingested alkali, and
       various antacids often have been advocated for treatment of acid burns. The use of
       neutralizing agents is controversial because they may produce excessive heat. Carbon
       dioxide gas produced from bicarbonates used to treat oral poisoning with acids can cause
       gastric distension and even perforation. The treatment of choice for ingestion of either acids
       or alkalis is dilution with water or milk. Similarly, burns produced by acid or alkali on the skin
       should be treated with copious amounts of water.

Purgation

      The rationale for using an osmotic cathartic is to minimize absorption by hastening the
       passage of the toxicant through the gastrointestinal tract.
      Cathartics generally are considered harmless unless the poison has injured the
       gastrointestinal tract.
      Cathartics are indicated after the ingestion of enteric-coated tablets, when the time after
       ingestion is greater than 1 hour, and for poisoning by volatile hydrocarbons.
      Sorbitol is the most effective, but sodium sulfate and magnesium sulfate also are used; all
       act promptly and usually have minimal toxicity.
      Whole-bowel irrigation (WBI) is a technique that not only promotes defecation but also
       eliminates the entire contents of the intestines. This technique uses a high-molecular-weight
       polyethylene glycol and isosmolar electrolyte solution (PEG-E S) that does not alter serum
       electrolytes. It is available commercially as GOLYTELY and COLYTE.
      A position statement on WBI, issued by the American Academy of Clinical Toxicology and the
       European Association of Poisons Centres and Clinical Toxicologists, indicates that WBI should
       not be used routinely in the management of the poisoned patient. Even though volunteer
       studies have shown substantial decreases in the bioavailability of certain ingested drugs,
       evidence from controlled clinical trials is lacking. WBI may be considered in cases of acute
       poisoning by sustained-release or enteric-coated drugs and possibly toxic ingestions of iron,
       lead, zinc, or packets of illicit drugs.



Enhanced Elimination of the Poison

Biotransformation.

      Elimination of drugs metabolized by CYPs can be promoted by inducing CYP enzymes.
       However, induction of these oxidative enzymes is too slow (days) to be valuable in the
       treatment of acute poisoning by most chemical agents
      Many chemicals are toxic because they are biotransformed into more toxic chemicals. Thus
       inhibition of biotransformation should decrease the toxicity of such drugs. For example,
       ethanol is used to inhibit the conversion of methanol to its highly toxic metabolite, formic
       acid, by alcohol dehydrogenase
      Acetaminophen is converted by the CYP system to an electrophilic metabolite that is
       detoxified by glutathione, a cellular nucleophile. Acetaminophen does not cause
       hepatotoxicity until glutathione is depleted, whereupon the reactive metabolite binds to
       essential macromolecular constituents of the hepatocyte, resulting in cell death. The liver
       can be protected by maintenance of the concentration of glutathione, and this can be
       accomplished by the administration of N-acetylcysteine
      Some drugs are detoxified by conjugation with glucuronic acid or sulfate before elimination
       from the body, and the availability of the endogenous co-substrates for conjugation may
       limit the rate of elimination; such is the case in the detoxification of acetaminophen.
       Methods to replete these compounds will provide an additional mechanism to treat
       poisoning. Similarly, detoxication of cyanide by conversion to thiocyanate can be accelerated
       by the administration of thiosulfate.


Urinary Excretion

      Nonionized compounds are reabsorbed far more rapidly than ionized polar molecules;
       therefore, a shift from the nonionized to the ionized species of the toxicant by alteration of
       the pH of the tubular fluid may hasten elimination. Acidic compounds such as phenobarbital
       and salicylates are cleared much more rapidly in alkaline than in acidic urine.
      Urine alkalinization increases the urine elimination of chlorpropamide, 2,4-
       dichlorophenoxyacetic acid, diflunisal, fluoride, mecoprop, methotrexate, phenobarbital, and
       salicylate. However, urine alkalinization is recommended as first-line treatment only for
       patients with moderately severe salicylate poisoning who do not meet the criteria for
       hemodialysis.
      Urine alkalinization and high urine flow (approximately 600 ml/h) should also be considered
       in patients with severe 2,4-dichlorophenoxyacetic acid and mecoprop poisoning. Even
       though it has been shown to be effective in enhancing elimination of phenobarbital, urine
        alkalinization is not recommended as first-line treatment in cases of phenobarbital poisoning
        because multiple-dose activated charcoal has been shown to be superior.
       Urine alkalinization is contraindicated in the case of compromised renal function or failure.
        Hypokalemia is the most common complication but can be corrected by giving potassium
        supplements.
       Intravenous sodium bicarbonate is used to alkalinize the urine.
       Renal excretion of basic drugs such as amphetamine theoretically can be enhanced by
        acidification of the urine. Acidification can be accomplished by the administration of
        ammonium chloride or ascorbic acid. Urinary excretion of an acidic compound is particularly
        sensitive to changes in urinary pH if its pKa is within the range of 3.0 to 7.5; for bases, the
        corresponding range is 7.5 to 10.5.

Dialysis.

       limited use in the treatment of intoxication
       If a poison has a large volume of distribution, as is the case for the tricyclic antidepressants,
        the plasma will contain too little of the compound for effective removal by dialysis.
       Extensive binding of the compound to plasma proteins impairs dialysis greatly.
       The elimination of a toxicant by dialysis also depends on dissociation of the compound from
        binding sites in tissues; for some chemicals, this rate may be slow and limiting.
       Hemodialysis (extracorporeal dialysis) is much more effective than peritoneal dialysis and
        may be essential in a few life-threatening intoxications, such as with methanol, ethylene
        glycol, and salicylates.
       Passage of blood through a column of charcoal or adsorbent resin (hemoperfusion) is a
        technique for the extracorporeal removal of a poison. Because of the high adsorptive
        capacity and affinity of the material in the column, some chemicals that are bound to plasma
        proteins can be removed. The principal side effect of hemoperfusion is depletion of
        platelets.




To describe the physiological effects and principles of management of agents toxic
in overdose (including, cyanide, carbon monoxide, organophosphates/nerve
agents/herbicides, illicit drugs, alcohols/glycols)

Cyanide

Cyanide affects virtually all body tissues

Attaches itself to ubiquitous metalloenzymes and rendering them inactive.

Principal toxicity results from inactivation of cytochrome oxidase (at cytochrome a3), thus
uncoupling mitochondrial oxidative phosphorylation and inhibiting cellular respiration, even in the
presence of adequate oxygen stores. Cellular metabolism shifts from aerobic to anaerobic, with the
consequent production of lactic acid. Consequently, the tissues with the highest oxygen
requirements (brain and heart) are the most profoundly affected by acute cyanide poisoning.

Management

      Provide supportive care.

           o   Airway control, ventilation, 100% oxygen delivery

           o   Crystalloids and vasopressors as needed for hypotension

           o   Sodium bicarbonate titrated according to ABG and serum bicarbonate level

      Decontaminate the patient with removal of clothing/skin flushing and/or activated charcoal
       (1 g/kg) as appropriate. Activated charcoal should be given after oral exposure in alert
       patients who are able to protect the airway or after endotracheal intubation in unconscious
       patients.

      Administer Cyanide Antidote Kit (CAK) or hydroxocobalamin (Cyanokit) if the diagnosis is
       strongly suspected, without waiting for laboratory confirmation.

           o   Cyanide Antidote Kit contains amyl nitrite pearls, sodium nitrite, and sodium
               thiosulfate.

                      Amyl and sodium nitrites induce methemoglobin in red blood cells, which
                       combines with cyanide, thus releasing cytochrome oxidase enzyme. Inhaling
                       crushed amyl nitrite pearls is a temporizing measure before intravenous
                       administration of sodium nitrite.

                      Sodium thiosulfate enhances the conversion of cyanide to
                       thiocyanate , which is renally excreted. Thiosulfate has a somewhat delayed
                       effect and thus is typically used with sodium nitrite for faster antidote
                       action.

                      Avoid the sodium nitrite portion of the cyanide kit in patients with smoke
                       inhalation unless carboxyhemoglobin concentration is very low (<10%). The
                       induction of methemoglobinemiafrom the nitrites in addition to present
                       carboxyhemoglobinemia significantly reduces the oxygen-carrying capacity
                       of blood.

                      Vasodilatation leading to hypotension is another adverse effect of CAK.

                      Appropriate dosing of sodium nitrite has not been established in children,
                       who may develop excessive methemoglobinemia and/or hypotension.

           o   Hydroxocobalamin (Cyanokit),

                      Hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin
                       B-12), which is renally cleared.
                       Coadministration of sodium thiosulfate (through a separate line or
                        sequentially) has been suggested to have a synergic effect on detoxification.

                       Adverse effects of hydroxocobalamin administration include transient
                        hypertension (a benefit in hypotensive patients), reddish-brown skin,
                        mucous membrane and urine discoloration, and rare anaphylaxis and
                        anaphylactoid reactions. It also interferes with co-oximetry and blood
                        chemistry (liver enzymes, bilirubin, creatinine, creatine kinase, phosphorus,
                        glucose, magnesium, and iron level) testing due to its bright red color.

                       Certain medications should not be administered simultaneously or through
                        the same line as hydroxocobalamin. These include diazepam, dopamine,
                        dobutamine, and sodium thiosulfate.



carbon monoxide

Pathophysiology

CO toxicity causes impaired oxygen delivery and utilization at the cellular level. CO affects several
different sites within the body but has its most profound impact on the organs (eg, brain, heart) with
the highest oxygen requirement.

Toxicity primarily results from cellular hypoxia caused by impedance of oxygen delivery. CO
reversibly binds hemoglobin, resulting in relative functional anemia. Because it binds hemoglobin
230-270 times more avidly than oxygen, even small concentrations can result in significant levels of
carboxyhemoglobin (HbCO).

An ambient CO level of 100 ppm produces an HbCO of 16% at equilibration, which is enough to
produce clinical symptoms. Binding of CO to hemoglobin causes an increased binding of oxygen
molecules at the 3 other oxygen-binding sites, resulting in a leftward shift in the oxyhemoglobin
dissociation curve and decreasing the availability of oxygen to the already hypoxic tissues.

CO binds to cardiac myoglobin with an even greater affinity than to hemoglobin; the resulting
myocardial depression and hypotension exacerbates the tissue hypoxia. Decrease in oxygen delivery
is insufficient, however, to explain the extent of the CO toxicity. Clinical status often does not
correlate well with HbCO level, leading some to postulate an additional impairment of cellular
respiration.

CO binds to cytochromes c and P450 but with a much lower affinity than that of oxygen; in
experimental studies, it was shown that exposure to CO produces marked decrease in cytochrome
oxidase suggesting direct toxic effects.

Studies have indicated that CO may cause brain lipid peroxidation and leukocyte-mediated
inflammatory changes in the brain, a process that may be inhibited by hyperbaric oxygen therapy.
Following severe intoxication, patients display central nervous system (CNS) pathology, including
white matter demyelination. This leads to edema and focal areas of necrosis, typically of the bilateral
globus pallidus. Interestingly, the pallidus lesions, as well as the other lesions, are watershed area
tissues with relatively low oxygen demand, suggesting elements of hypoperfusion and hypoxia.

Studies have demonstrated release of nitric oxide free radical (implicated in the pathophysiology of
atherosclerosis) from platelet and vascular endothelium, following exposure to CO concentrations of
100 ppm. A recent study suggests a direct toxicity of CO on myocardium that is separate from the
effect of hypoxia.1

HbCO levels often do not reflect the clinical picture, yet symptoms typically begin with headaches at
levels around 10%. levels of 50-70% may result in seizure, coma, and fatality.

CO is eliminated through the lungs. Half-life of CO at room air temperature is 3-4 hours. One
hundred percent oxygen reduces the half-life to 30-90 minutes; hyperbaric oxygen at 2.5 atm with
100% oxygen reduces it to 15-23 minutes.

Management

       Cardiac monitor: Sudden death has occurred in patients with severe arteriosclerotic disease
        at HbCO levels of only 20%.

       Pulse oximetry: HbCO absorbs light almost identically to that of oxyhemoglobin. Although a
        linear drop in oxyhemoglobin occurs as HbCO level rises, pulse oximetry will not reflect it.
        Pulse oximetry gap, the difference between the saturation as measured by pulse oximetry
        and one measured directly, is equal to the HbCO level. However, new pulse CO-oximetry
        units are available which can screen for CO toxicity at the bedside.7

       Continue 100% oxygen therapy until the patient is asymptomatic and HbCO levels are below
        10%. In patients with cardiovascular or pulmonary compromise, lower thresholds of 2% have
        been suggested.

       Calculate a gross estimate of the necessary duration of therapy using the initial level and
        half-life of 30-90 minutes at 100% oxygen.

            o   In uncomplicated intoxications, venous HbCO levels and oxygen therapy are likely
                sufficient. Evaluate patients with significant cardiovascular disease and initial HbCO
                levels above 15% for myocardial ischemia and infarction.

            o   Consider immediate transfer of patients with levels above 40% or cardiovascular or
                neurologic impairment to a hyperbaric facility, if feasible. Persistent impairment
                after 4 hours of normobaric oxygen therapy necessitates transfer to a hyperbaric
                center. Pregnant patients with lower carboxyhemoglobin levels (above 15%) should
                be considered for hyperbaric treatment.

       Serial neurologic examinations, including funduscopy, CT scans, and, possibly, MRI, are
        important in detecting the development of cerebral edema. Cerebral edema requires
        intracranial pressure (ICP) and invasive blood pressure monitoring to further guide therapy.
        Head elevation, mannitol, and moderate hyperventilation to 28-30 mm Hg PCO2 are
        indicated in the initial absence of ICP monitoring. Glucocorticoids have not been proven
        efficacious, yet the negative aspects of their use in severe cases are limited.
            o   Do not aggressively treat acidosis with a pH above 7.15 because it results in a
                rightward shift in the oxyhemoglobin dissociation curve, increasing tissue oxygen
                availability. Acidosis generally improves with oxygen therapy.

            o   In patients who fail to improve clinically, consider other toxic inhalants or thermal
                inhalation injury. Be aware that the nitrites used in cyanide kits
                cause methemoglobinemia, shifting the dissociation curve leftward and further
                inhibiting oxygen delivery at the tissue level. Combined intoxications of cyanide and
                CO may be treated with sodium thiosulfate 12.5 g intravenously to prevent the
                leftward shift.

            o   Admit patients to a monitored setting and evaluate acid-base status if HbCO levels
                are 30-40% or above 25% with associated symptoms.



organophosphates/nerve agents/herbicides

Pathophysiology
The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester
hydrolases, particularly acetylcholinesterase (AChE). AChE is an enzyme that degrades the
neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and
peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs).

Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the
active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and
establishment of a covalent bond with AChE.

Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in
overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of
the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the enzyme can undergo one of the following:
     Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases
     Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
     Irreversible binding and permanent enzyme inactivation (aging)
Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected. Although most
patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific
compound, amount, route of exposure, and rate of metabolic degradation.3


Medical Care
Airway control and adequate oxygenation are paramount in organophosphate (OP)
poisonings. Intubation may be necessary in cases of respiratory distress due to
laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate aggressive use of
atropine may eliminate the need for intubation. Succinylcholine should be avoided because it
is degraded by acetylcholinesterase (AChE) and may result in prolonged paralysis.

       Continuous cardiac monitoring and pulse oximetry should be established; an ECG
        should be performed. Torsades de Pointes should be treated in the standard manner.
        The use of intravenous magnesium sulfate has been reported as beneficial for
          organophosphate toxicity. The mechanism of action may involve acetylcholine
          antagonism or ventricular membrane stabilization.
         Remove all clothing and gently cleanse patients suspected of organophosphate
          exposure with soap and water because organophosphates are hydrolyzed readily in
          aqueous solutions with a high pH. Consider clothing as hazardous waste and discard
          accordingly.
         Health care providers must avoid contaminating themselves while handling patients.
          Use personal protective equipment, such as neoprene gloves and gowns, when
          decontaminating patients because hydrocarbons can penetrate nonpolar substances
          such as latex and vinyl. Use charcoal cartridge masks for respiratory protection when
          decontaminating patients who are significantly contaminated.
         Irrigate the eyes of patients who have had ocular exposure using isotonic sodium
          chloride solution or lactated Ringer's solution. Morgan lenses can be used for eye
          irrigation.

Surgical Care
Patients with trauma or blast injury should be treated according to standard advanced
trauma life support (ATLS) protocol. Patient decontamination should always be considered
to prevent medical personnel poisoning.
Medication
The mainstays of medical therapy in organophosphate (OP) poisoning include atropine,
pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). Initial management must focus
on adequate use of atropine. Optimizing oxygenation prior to the use of atropine is
recommended to minimize the potential for dysrhythmias.

Low-dose (1-2 g slow IV) 2-PAM is the current recommendation. Studies are underway to
assess the role of low-dose 2-PAM. Improved survival has been shown in moderately severe
OP poisoned patients who received early, continuous 2-PAM infusion compared with those
who received intermittent boluses.

optimal supportive care along with discriminate use of 2-PAM, especially early in the course
of treatment of moderately to severely OP poisoned patients, are the hallmarks of treatment.

Intravenous glycopyrrolate or diphenhydramine may provide an alternative centrally acting
anticholinergic agent used to treat muscarinic toxicity if atropine is unavailable or in limited
supply.


Atropine
0.05 mg/kg IV, repeat q1-5min prn for control of airway secretions

Pralidoxime (2-PAM, Protopam)
1-2 g (20-40 mg/kg) IV in 100 mL isotonic sodium chloride soln/D5W over 15-30 min; repeat in 1 h if muscle weakness is not
relieved; then repeat q3-8h if signs of poisoning recur




Alcohols

Pathophysiology
Ethanol

Ethyl alcohol (ethanol; CH3 -CH2 -OH) is a low molecular weight hydrocarbon, which is derived from
the fermentation of sugars and cereals. It is widely available both as a beverage and as an ingredient
in food extracts, cough and cold medications, and mouthwashes.

Ethanol is rapidly absorbed across both the gastric mucosa and the small intestines, reaching a peak
concentration 20-60 minutes after ingestion. Once absorbed, it is converted to acetaldehyde. This
conversion involves 3 discrete enzymes: the microsomal cytochrome P450 isoenzyme CYP2E1, the
cytosol-based enzyme alcohol dehydrogenase (ADH), and the peroxisome catalase system.
Acetaldehyde is then converted to acetate, which is converted to acetyl Co A, and ultimately carbon
dioxide and water.1

Genetic polymorphisms coding for alcohol dehydrogenase, the amount of alcohol consumed, and
the frequency at which ethanol is consumed all affect the speed of metabolism. Chronic alcoholics
and those with severe liver disease have increased rates of metabolism. However, as a general rule,
ethanol is metabolized at a rate of 20-25 mg/dL in the nonalcoholic but at an increased rate in
chronic alcoholics.

Isopropanol

Isopropyl alcohol (isopropanol; CH3 -CHOH-CH3) is a low molecular weight hydrocarbon. It is
commonly found as both a solvent as well as a disinfectant. It can be found in many mouthwashes,
skin lotions, and rubbing alcohol. Because of its widespread availability, lack of purchasing
restrictions, and profound intoxicating properties, it is commonly used as an ethanol substitute.

Isopropanol is rapidly absorbed across the gastric mucosa and reaches a peak concentration
approximately 30-120 minutes after ingestion. Isopropanol is primarily metabolized via alcohol
dehydrogenase to acetone. A small portion of isopropanol is excreted unchanged in the urine. The
peak concentration of acetone is not present until approximately 4 hours after ingestion. Both the
CNS depressant effects and the fruity odor on the patient's breath are due to acetone.

Methanol

Methyl alcohol (methanol; CH3 OH) is widely used as an industrial and marine solvent and paint
remover. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Although
toxicity primarily occurs from ingestion, it can also occur from prolonged inhalation or skin
absorption.2,3 Methanol is rapidly absorbed from the gastric mucosa, and achieves a maximal
concentration 30-90 minutes after ingestion.

Methanol is primarily metabolized in the liver via alcohol dehydrogenase into formaldehyde.
Formaldehyde is subsequently metabolized via aldehyde dehydrogenase into formic acid, which
ultimately is metabolized to folic acid, folinic acid, carbon dioxide, and water. A small portion is
excreted unchanged by the lungs. Formic acid is responsible for the majority of the toxicity
associated with methanol. Without competition for alcohol dehydrogenase, methanol undergoes
zero-order metabolism, and is thus is excreted at a rate of 8.5 mg/dL/h to 20 mg/dL/h. Once
methanol experiences competitive inhibition, from either ethanol or fomepizole, the metabolism
changes to first order. In this later scenario, the excretion half-life ranges from 22-87 hours.

Ethylene glycol

Ethylene glycol (CH2 OH-CH2 OH) is an odorless, colorless, sweet-tasting liquid, which is used in many
manufacturing processes. Around the house, it is probably most commonly encountered in
antifreeze. It is absorbed somewhat rapidly from the gastrointestinal tract, and peak concentrations
are observed 1-4 hours after ingestion.

Ethylene glycol itself is nontoxic, but it does get metabolized into toxic compounds. Ethylene glycol is
oxidized via alcohol dehydrogenase into glycoaldehyde. Glycoaldehyde subsequently undergoes
metabolism via aldehyde dehydrogenase into glycolic acid.4 The conversion to glycolic acid is
somewhat rapid. In contrast, the conversion of glycolic acid to glyoxylic acid is slower and is the rate-
limiting step in the metabolism of ethylene glycol.

Glyoxylic acid is subsequently metabolized into several different products, including oxalic acid
(oxalate), glycine, and alpha-hydroxy-beta-ketoadipate. The conversion to glycine requires
pyridoxine as a cofactor, while the conversion to alpha-hydroxy-beta-ketoadipate requires thiamine
as a cofactor. The oxalic acid combines with calcium to form calcium oxalate crystals. In the presence
of normal renal function and no competitive inhibition for alcohol dehydrogenase, the excretion
half-life of ethylene glycol is approximately 3 hours. However, in the presence of fomepizole or
ethanol, alcohol dehydrogenase undergoes competitive inhibition, and the resulting excretion half-
life increases to approximately 17-20 hours.


As with all emergency patients, initial treatment should focus on the airway, breathing, and
circulation. Gastric decontamination is rarely necessary for any of the alcohols. An exception to this
may be a patient who presents immediately after ingestion of a toxic alcohol in whom one might
reasonably expect to be able to recover a significant amount of the toxin via aspiration through a
nasogastric tube.
                                                                                    9
     Treatment of ethanol and isopropanol intoxication is largely supportive. Because of the
         hemorrhagic gastritis that can follow isopropanol ingestion, H2 blockade or proton-pump
         inhibitors may be helpful. Hemodialysis, while effective, is rarely indicated, and should only
         be used in the setting of profound hemodynamic compromise.
     Once either methanol or ethylene glycol intoxication are suspected, treatment should be
         initiated without delay. Fortunately, since both alcohols are metabolized by alcohol
         dehydrogenase, the treatment is the same, and differentiating which of the two toxic
         alcohols is responsible is not necessary before implementing treatment.9
              o The primary antidotal treatment of methanol or ethylene glycol involves blocking
                  alcohol dehydrogenase. This enzyme can be inhibited by either ethanol or
                  fomepizole.10,11,12 Toxic alcohol levels are frequently not immediately available. Thus,
                  ideally, if methanol or ethylene glycol poisoning is suspected, the patient should
                  receive a loading dose of fomepizole while the levels are being obtained. Because
                  the next dose of fomepizole is not due for an additional 12 hours, this strategy
                  allows 12 hours for the blood to be processed at a reference laboratory before
                  additional treatment is needed. Inhibition of alcohol dehydrogenase with ethanol
                  may be substituted for treatment with fomepizole (see below), though recent
                  studies have highlighted the greater safety of fomepizole as a treatment, when
                  available.6,4 In some patients, treatment with fomepizole alone may represent
                  definitive treatment and can prevent the need for hemodialysis.13
              o In addition to blocking alcohol dehydrogenase, significant metabolic acidosis should
                  be treated with sodium bicarbonate infusions. If methanol is suspected, folinic acid
                  should be administered at a dose of 1 mg/kg, with a maximal dose of 50 mg. It
                  should be repeated every 4 hours. If folinic acid is not immediately available, folic
                  acid can be substituted at the same dose. If ethylene glycol overdose is suspected,
                  the patient should also receive 100 mg of intravenous thiamine every 6 hours and 50
                  mg of pyridoxine every 6 hours. The purpose of the thiamine and pyridoxine is to
                shunt metabolism of glyoxylic acid away from oxalate and favor the formation of
                less toxic metabolites.
            o In methanol overdose, sodium bicarbonate should be administered liberally, with
                the goal being to completely reverse the acidosis. Based on experimental studies,
                formate appears to be excreted in the kidneys at a much higher rate when the
                patient is not acidotic. In addition, when the patient is not acidotic, formic acid
                dissociates to formate at lower rates so that less formate crosses the blood-brain
                barrier. Thus, in methanol intoxication, correcting the acidosis actually speeds up
                elimination of the toxic compound and decreases toxicity.
            o If ethanol is used, the recommended target serum concentration is 100-150 mg/dL.
                Because ethanol inhibits gluconeogenesis, hypoglycemia is common in patients on
                an ethanol infusion.14Hypoglycemia is particularly prevalent in pediatric patients on
                such drips. Thus, serum glucose levels must be checked frequently, at least every 2
                hours. In addition, because it is difficult to attain a steady serum concentration of
                ethanol, the ethanol level also must be checked frequently, and titrations made.
                      A 5% or 10% ethanol solution can be made in the pharmacy. If giving
                         ethanol, a loading dose of 600 mg/kg should be given, followed by a drip of
                         66-154 mg/kg/h with chronic alcoholics requiring doses at the higher end of
                         the scale. Ethanol can be given either intravenously or orally.
                      In addition to hypoglycemia, additional adverse effects from ethanol
                         infusion include inebriation, CNS depression, pancreatitis, and local
                         phlebitis. Because of the phlebitis that occurs with ethanol infusions, some
                         advocate that ethanol should only be administered via a central venous line.
      Ethanol infusions are not only labor intensive, but once the costs of the frequent blood
       glucose and serum ethanol levels are accounted for, the cost of the ethanol drip is
       frequently more expensive than fomepizole. Thus, because of the lower overall cost and the
       ease of administration and safety considerations, fomepizole has become the preferred
       antidote for methanol or ethylene glycol poisoning. Fomepizole should be administered as a
       loading dose of 15 mg/kg. Subsequent doses should be at 10 mg/kg every 12 hours for 4
       doses. Because fomepizole actually induces its own metabolism after 48 hours of treatment,
       if additional doses are needed, the dose should be increased to 15 mg/kg. Fomepizole needs
       to be re-dosed during hemodialysis. The package insert or local poison center can help with
       the re-dosing strategy. Fomepizole should be continued until the serum ethylene glycol or
       methanol concentrations are less than 20 mg/dL.
      Hemodialysis is frequently required in patients with significant methanol or ethylene glycol
       ingestions.9,13Indications for hemodialysis include (1) arterial pH <7.10, (2) a decline of >0.05
       in the arterial pH despite bicarbonate infusion, (3) pH <7.3 despite bicarbonate therapy, (4)
       rise in serum creatinine level by 90 mmol/L, and (5) initial plasma methanol or ethylene
       glycol concentration >50 mg/dL.




To describe the physiological and pharmacological basis for the treatment of
poisoning with select agents with specific antidotes

				
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