General Principles of Pharmacology

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					General Principles of
Heather Kappeler, Pharm.D.
• The therapeutic effect of a drug is determined by
  the concentration of drug at the receptor site of
  action. Even though the concentration of drug
  that reaches the target receptor is dependent
  upon the dose of the drug, there are other
  factors that influence the delivery of the drug to
  the target site. These include absorption,
  distribution, metabolism, and excretion. The
  study of these variables is called
• I. Absorption
  – Depends on patient compliance
  – Depends on rate and extent of transfer from the site
    of administration to the blood
  – Small, non-ionized, lipid soluble drugs permeate
    plasma membranes most readily
  – The plasma membrane is impermeable to polar,
    water-soluble substances
  – Bioavailability – fraction of unchanged drug reaching
    the systemic circulation following administration by
    any route
• I. Absorption
  – Depends on route of administration
     • 1. Oral (PO)
        – A. Site of absorption
            » 1. Oral mucosa – sublingual route
            » Direct access to systemic veins - will avoid hepatic first
               pass effect
            » Ex: nitroglycerin
            » 2. Stomach
            » Drugs that are weak acids tend to be absorbed here
            » Ex: aspirin, ethanol (these two examples in addition to
               phenytoin follow zero order kinetics – rate is independent
               of the concentration)
• I. Absorption
            » 3. Small intestine
            » Drugs that are weak bases tend to be absorbed here
        – B. Advantages of oral route
            » 1. Most convenient
            » 2. Least unpleasant method for most
            » 3. No equipment required
            » 4. Safest (drug absorbed more slowly)
        – C. Disadvantages of oral route
            » 1. Certain drugs destroyed by pH and/or enzymes
            » Ex: Insulin
            » Some drugs metabolized in gut wall by Cyp3A4
• I. Absorption
        – C. Disadvantages of oral route
            » Bacterial metabolism in gut can affect bioavailability
            » Ex: As a result, digoxin is only 70% bioavailable
            » 2. Slow onset of action
            » 3. Irregular absorption may occur due to:
            » a. Variation in process of solution
            » b. pH variation
            » If drug is too hydrophilic (i.e. atenolol), the drug
              cannot cross the lipid cell membrane; if too lipophilic
              (i.e. acyclovir), the drug is not soluble enough to
              cross the water layer adjacent to the cell
• I. Absorption
        – C. Disadvantages of oral route
            » c. Binding to food (e.g. tetracycline chelated to Ca++ and
              other heavy metals)
            » d. Variation in motility and emptying time of GI
            » e. Reverse transporter associated with P-glycoprotein
              process actively pumps drug out of gut wall cells back into
              the gut lumen
            » Tx: grapefruit juice – will inhibit P-glycoprotein and gut wall
            » 4. Cannot give to unconscious patient
            » 5. Irritating substances cause nausea and vomiting,
              resulting in drug loss
            » 6. Drug may have significant 1st pass effect from stomach
              or intestine because of direct access to portal veins
            » Liver can excrete drug into the bile
• I. Absorption
     • 2. Parenteral
        – A. Advantages of parenteral route
            » 1. More rapid and predictable absorption
            » 2. Used to administer drugs that would be destroyed by
              stomach acid or enzymes
            » 3. Use with unconscious or uncooperative patient
            » 4. More accurate dose selection
        – B. Disadvantages of parenteral route
            » 1. Strict asepsis must be maintained
            » 2. Pain associated with injection
            » 3. Self administration may be difficult
            » 4. More expensive
            » 5. Possibility of technical errors (rate of dosing, area
• I. Absorption
        – B. Disadvantages of parenteral route
            » 6. Difficult to correct overdose or error
            » 7. Risk of infection or local irritation
        – C. Parenteral routes
            » 1. Subcutaneous (SC) – drug is injected beneath the skin
              and permeates capillary walls to enter the blood stream
            » A. Advantages of subcutaneous route
            » 1. Slow absorption
            » 2. Smaller volume than IM
            » 3. Rate of absorption may be altered by:
            » a. Drug solution
            » b. Local vasoconstriction
            » c. Tourniquet or other manipulations altering blood flow
• I. Absorption
           » B. Disadvantages of subcutaneous route
           » 1. Irritating drugs may result in severe pain and local
           » 2. Intramuscular (IM) – drug passes through capillary walls
             to enter the blood stream
           » A. Advantages of intramuscular route
           » 1. Generally more rapid absorption than SC
           » 2. Larger volumes and relatively irritating substances may
             be given
           » 3. Absorption may be hastened or slowed by various
           » Rate of absorption depends on formulation: oil based
             preparation has slow rate of absorption; aqueous
             preparation has rapid rate of absorption
• I. Absorption
           » B. Disadvantages of intramuscular route
           » 1. Vasoconstriction (e.g. epinephrine) cannot be used to
             slow absorption as in SC
           » 2. More painful than SC
           » 3. Intravenous (IV) – agent injected directly into blood
           » A. Advantages of intravenous route
           » 1. Rapid onset of action, controlled
           » 2. Most irritating substances may be given. Have to be
             soluble drugs
           » 3. Large volumes may be given
           » 4. Useful in emergency situations (i.e. when patient is
           » 5. 100% bioavailability
• I. Absorption
             » B. Disadvantages of intravenous route
             » 1. Dangers associated with too-rapid delivery of large
               volumes (embolisms, elevated blood pressure, etc.) or with
               toxic doses of a drug
             » 2. Technical difficulties of administering the drug (getting
               the correct rate for dosing)
     • 3. Other routes of administration
         – A. Inhalation
             » Rapid absorption due to large surface area and large # of
               blood capillaries lining alveoli
         – B. Rectal (PR) – suppositories
             » Useful for unconscious or voming patients or small children
– B. Rectal (PR)
     » Absorption is unreliable:
     » Lower rectum – enter vessels that drain into inferior vena
       cava and by-pass liver
     » As a suppository moves upward in the rectum, access to
       superior hemorrhoidal vein is more likely and this leads to
       the liver
– C. Topical
     » To maximize the drug concentration at the site of action
       and minimize it elsewhere, particularly for those drugs
       which have toxic effects if adminstered systemically
     » Ex: dermatologic, ophthalmologic, nasal, vaginal, and otic
– D. Transdermal – drug seeps out of patch, through skin and
  into capillary bed
     » Slow absorption
     » To prolong the duration of drug absorption
     » Convenient for self administration – increases compliance
• I. Absorption
  – Mechanisms for drug transport across membranes
     • A. Passive (simple) diffusion
         – 1. Rate of transfer of substances are directly proportional to
           the concentration gradient on both sides of the membrane
         – 2. Rapid for lipophilic, nonionic, small molecules
         – 3. No energy or carrier required
     • B. Aqueous channels
         – 1. Small hydrophilic drugs (<200 MW) diffuse along conc
           gradient by passing through pores (aqueous channels)
         – 2. No energy required
• C. Specialized transport
   – 1. Facilitated diffusion – drugs bind to carrier
       » No energy is required
   – 2. Active transport – identical to facilitated diffusion
     except that ATP (energy) powers drug transport against
     conc gradient
• D. Pinocytosis and phagocytosis
   – Engulfing of drug
   – Ex: Vaccines
• II. Distribution
  – Takes place after the drug has been absorbed
    into the blood stream
  – Distribution of drugs through various body
    compartments (to various tissues) depends
     •   Size of the organs (tissues)
     •   Blood flow through tissues
     •   Solubility of the drug in the tissues
     •   Binding of the drug to macromolecules in blood or
• II. Distribution
   – The following factors influence drug distribution:
      • 1. Protein binding
          – Two factors determine degree of plasma protein binding:
              » 1. Affinity of drug for plasma protein
              » 2. # of binding sites available
          – Weak acid drugs bind to albumin (phenytoin, salicylates,
            and disopyramide are extensively bound)
          – Weak basic drugs bind to serum globulins → α-1 acid
            glycoprotein (quinidine, lidocaine, propranolol)
• II. Distribution
• Examples of highly protein bound drugs:

          •    Glyburide       >99% bound
           •   Warfarin         97% bound
           •   Phenytoin        97% bound
           •   Amitriptyline    96% bound
           •   Diazepam         96% bound
           •   Indomethacin     90% bound
           •   Prednisolone     90% bound
• II. Distribution
     • 1. Protein binding
        – Limits the drug conc in tissues because bound
          drug cannot enter tissues, as a result, leads to
          high concs of drug in the plasma (bound + free
        – Bound drug is not therapeutically active
        – There is an equilibrium between the free drug
          and the bound drug
           » Drug is gradually released from the protein (acts as
             storage for drug) as the free drug is utilized and
• II. Distribution
     • 1. Protein binding
        – Is nonselective
        – The # of binding sites on plasma protein is limited
        – Drugs will compete with other drugs, hormones, or other
          endogenous substances for protein binding sites
            » Ex: Glyburide (sulfonamide) can be displaced by a
              warfarin, phenytoin, salicylates, etc.. and cause ↑
              hypoglycemic effects (more free drug in body)
            » Ex: Warfarin can be displaced by indomethacin,
              aspirin, etc.. which can ↑ bleeding.
            » These interactions may necessitate a dosage
              adjustment or discontinuation of the other drug
• II. Distribution
      • 2. Membrane permeability
         – For a drug to enter an organ (tissue), it must permeate all
           membranes that separate the organ from the site of drug
         – A. Blood brain barrier (BBB) – lipid membrane located between
           plasma and the extracellular space in the brain
             » The entry of drugs is restricted into the CNS and CSF
               (cerebrospinal fluid)
             » Lipid solubility and cerebral blood flow limit permeation of
               the CNS
             » Highly lipophilic drugs can pass the BBB (i.e.
             » It is difficult to tx the brain or CNS, however, the difficulty of
               passage into the brain can also serve as a protective
               barrier when treating other parts of the body
• II. Distribution
     • 2. Membrane permeability
        – B. Blood-placenta barrier – the fetus is exposed to most
          drugs the mother ingests at anytime during the
          pregnancy. The placenta is not a barrier.
        – C. Mammary transfer of drugs – breast milk is acidic so
          basic drugs concentrate in this fluid
            » Nonelectrolyte drugs (do not depend on pH gradient
              – i.e. alcohol) readily reaches the same
              concentration as in the plasma, independent of the
              pH of breast milk
• II. Distribution
      • 3. Storage Depots
         – Drugs may collect in certain body tissues
             » A. Fat – lipophilic drugs accumulate here and are released
               slowly (due to low blood flow)
             » Ex: thiopental (or other anesthetic) – causes ↑ sedation in
               obese patients
             » B. Bone – Ca++ binding drugs accumulate here
             » Ex: tetracycline can deposit in bone and teeth → will
               cause mottling or discoloration of teeth
             » C. Liver – many drugs accumulate in the liver due to an
               affinity for hepatic cells
             » Ex: quinacrine (antimalarial agent) – has higher conc
               (22,000 times) in the liver than in plasma due to long term
• II. Distribution
      • 3. Storage Depots
              » D. Skin – some drugs accumulate here
              » Ex: griseofulvin (antifungal of skin, hair, and nails) binds to
                keratin protecting the skin from new infection
   – Redistribution – after a drug has accumulated in
     tissue, i.e. thiopental in fatty tissues, drug is gradually
     returned to the plasma
   – Apparent volume of distribution – the volume that
     would be required in the body to contain the
     administered dose if that dose was evenly distributed
     at the concentration measured in plasma, blood, or
     plasma water
• II. Distribution
      • Vd = total amt of drug in body
      concentration of drug in blood or plasma
      • Drugs with very high volumes of distribution have much
        higher concentrations in extravascular tissue than in the
        vascular compartment (plasma membrane)
      • When drugs are protein bound, it can make the apparent
        volume smaller
      • Clinical prediction:
          – If Vd = 2L, you can assume drug is distributed in plasma only
          – If Vd = 18L, you can assume drug is distributed in plasma and
          – If Vd > 46L, the drug is likely stored in a depot because the
            body only contains 40-46L of fluid
• II. Distribution
  – Apparent Volume of distribution
     • See Table 3-2
     • Variances:
        – Obese patients need to have their volumes calculated
          using their ideal body weight
            » Ideal body weight (IBW) (> 18 yo):
            » IBW (males) = 50 + (2.3 x hgt in inches over 5ft)
            » IBW (females)= 45.5 + (2.3 x hgt in inch over 5ft)
        – Since some drugs do not penetrate fat (tobramycin and
          digoxin), Vd could be overestimated
• II. Distribution
  – Apparent volume of distribution
     • Variances
        – Patients with edema, ascites, or pleural effusion offer a
          large volume of distribution to aminoglycoside antibiotics
          (tobramycin) (which are hydrophilic and have small
          volumes of distribution) than is predicted by body weight
             » Subtract the ~ wgt (kg) of the excess fluid from the
               body weight
             » After calculating the Vd, add 1L to Q 1kg of excess
               fluid subtracted
• III. Metabolism (Biotransformation)
   – Process of making a drug more polar and water soluble to be
     excreted out of the body (lead to termination)
   – Drug metabolism often results in detoxification or inactivation of
     drugs where the metabolites are less active or inactive
     compared to the parent drug
   – Some metabolites may be equally or even more active than the
     parent drug. Prodrug – inactive drug that is activated by
     metabolism (ex: enalapril)
   – Some drugs can be metabolized to toxic compounds
       • Ex: When acetaminophen exceeds therapeutic doses, it can
         deplete glutathione and accumulate a toxic metabolite which causes
         hepatotoxicity. N-acetylcysteine is given within 8-16 hours of
         overdosage to decrease toxicity
• III. Metabolism (biotransformation)
   – Some drugs have more than one metabolite
   – Xenobiotics – are foreign compounds that can be absorbed
     across the lungs or skin or ingested in food or drinks or taken as
     “recreation drugs”
       • Absorbed substance can be converted to active metabolite
   – All drugs are foreign substances
   – Every tissue has some ability to metabolize drugs (i.e. GI tract,
     lungs, skin, kidneys); however, the liver is the principal organ for
     drug metabolism
   – First-pass effect – some drugs go straight from the GI tract to the
     portal system where they undergo extensive metabolism in the
     liver (ex: morphine) before entering the systemic circulation
• III. Metabolism (biotransformation)
  – First-pass effect
     • This can limit the bioavailability of certain drugs
     • It can be greatly reduced by giving drug by other route of
  – Extraction ratio – an expression of the effect of first-
    pass hepatic elimination on bioavailability. ER =
    Clliver/Q (hepatic blood flow)
     • Highly extracted drugs: isoniazid, morphine, propranolol,
       verapamil, and several TCAs
     • Poorly extracted drugs: phenytoin, theophylline, warfarin,
• III. Metabolism (biotransformation)
  – General pathways of drug metabolism
     • Phase I reaction – (oxidation, reduction,
        – Generally, the parent drug is oxidized or reduced to a
          more polar metabolite by introducing or unmasking a
          functional group (-OH, -NH2, -SH)
        – The more polar the drug, the more likely excretion will
        – This reaction takes place in the smooth (no ribosomes)
          endoplasmic reticulum in liver cells (hepatocytes)
• III. Metabolism (biotransformation)
  – Phase I reaction
     • The smooth microsomes are relatively rich in enzymes
       responsible for oxidative drug metabolism
         – Important class of enzymes – mixed function oxidases
             » The activity of these enzymes requires a reducing
               agent, NADPH and molecular oxygen (O2)
             » Two microsomal enzymes play a key role:
             » 1. NADPH-cytochrome P450 reductase, a
             » 2. Cytochrome P450, a hemoprotein, the terminal
• III. Metabolism (biotransformation)
  – Phase I reaction
     • Cytochrome P450
        –   Is a family of isoenzymes (Table 4-2)
        –   Drugs bind to this enzyme and are oxidized or reduced
        –   Can be found in the GI epithelium, lung and kidney
        –   Cyp3A4 alone is responsible for more than 60% of the clinically
            prescribed drugs metabolized by the liver
     • Cytochrome P450 enzyme induction
        – Stimulation of hepatic drug metabolism by some drugs
        – Enzyme inducers stimulate their own metabolism and also
          accelerate metabolism of other drugs
        – Ex of inducers: phenobarbital, rifampin, phenytoin,
          carbamazepine, griseofulvin, cigarette smoking
• III. Metabolism (biotransformation)
  – Phase I reaction
     • Cytochrome P450 enzyme inhibition
        – Some drugs may decrease the activity of hepatic drug-
          metabolizing enzymes
        – Could lead to increase levels of active drug in the body
        – Ex of inhibitors: alcohol, allopurinol, grapefruit juice, cimetidine,
          amiodarone, ciprofloxacin, clarithromycin, erythromycin,
          fluoxetine, isoniazid, metronidazole, verapamil, omeprazole,
          oral contraceptives
        – Two different mechanisms examples:
             » Cimetidine binds tightly to Cyp450 and through competitive
               inhibition reduces metabolism of other drugs
             » Erythromycin is metabolized at Cyp3A, its metabolite forms
               complex with enzyme and renders it catalytically inactive
• III. Metabolism (biotransformation)
  – Phase II reaction
     • This involves coupling the drug or it’s polar metabolite with
       an endogenous substrate (glucuronic acid, sulfate, glycine, or
       amino acids)
     • The endogenous substrates originate in the diet, so nutrition
       plays a critical role in the regulation of drug conjugation
     • Drugs undergoing phase II conjugation reactions
       (glucuronidation, acetylation, methylation, and glutathione,
       glycine, and sulfate conjugation) may have already
       undergone phase I transformation
     • Some parent drugs may already possess a functional group
       that may form a conjugate directly
• III. Metabolism (biotransformation)
  – Enterohepatic recirculation – some drugs, or their
    metabolites, which are concentrated in the bile then
    excreted into the intestines, can be reabsorbed into
    the bloodstream from the lower GI tract
  – Biotransformation in the fetus or neonate
     • These individuals are very vulnerable to the toxic effects of
     • Their liver and metabolizing enzymes are under-developed
     • They also have poorly developed blood brain barrier
         – Can get hyperbilirubinemia which leads to encephalopathy
     • Have poorly developed kidneys which can alter excretion
       and cause jaundice
• III. Metabolism (biotransformation)
  – Biotransformation in the elderly
     • Hepatic enzymes and other organs deteriorate over time
  – Variations in drug metabolism:
     • Generally, men metabolize faster than women (ex: alcohol)
     • Diseases can affect drug metabolism (ex: hepatitis, cardiac
       (↓ blood flow to the liver), pulmonary disease)
     • Genetic differences
         – Ex: Slow acetylators (autosomal recessive trait mostly found in
           Europeans living in the high northern latitudes and in 50% of
           blacks and whites in the US)
• IV. Excretion
  – Elimination of unchanged drug or metabolite from the
    body – terminating its activity
  – Drugs may be eliminated by several different routes:
    exhaled air, sweat, saliva, tears, feces, and urine
  – Urine is the principle route of excretion
  – Three mechanisms for renal excretion:
     • 1. Glomerular filtration – passive diffusion
         – Small nonionic drugs pass more readily. Drugs bound to
           plasma proteins do not
     • 2. Tubular secretion - drugs which specifically bind to
       carriers are transported (ex: penicillin)
     • 3. Tubular reabsorption – Small nonionic drugs pass more
       readily (ex:diuretics)
• IV. Excretion
  – Clearance
      • The measure of the ability of the body to eliminate the drug
      • The rate of elimination is directly proportionate to drug
      • CL = rate of elimination/concentration of drug in biologic fluid
      • CLsystemic = CLrenal + CLliver + CLother
          – Other = lungs or other sites of metabolism
  – Half-life (t1/2)
      • The time required for the plasma concentration of a drug to
        be reduced by 50%
      • 4 half-lives must elapse after starting a drug dosing regimen
        before full effects will be seen
      • > 90% steady state concentration

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