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Pharmacology Dental 1 by veeru5656

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									Pharmacology

 By
 Prof. Dr. Amany Ibrahim El-Brairy
 Professor of Pharmacology
 H107
Why we study Pharmacology?

   Drug information : knowledge, skills,
    and attitude

    Rationale and safe prescribing in dental
    practice throughout the dental graduate
    career

   Self and continuous learner
The following scheme is used in discussion of a
drug
Name Of The Drug
1- Definition
2- Pharmacokinetics = What the BODY does
  to the DRUG = A. D. M. E.
  a- Absorption: Oral and/or Other
  b- Distribution: Binding to plasma proteins,
  Blood Brain Barrie & Placental barrier.
  c- Metabolism: Hepatic and/or other
  d- Excretion: Renal and/or other e.g. Milk
3- Pharmacodynamics = What the DRUG does to the BODY
   a- Mechanism of action
   b- Pharmacological actions:
       - Desirable = Therapeutic effects = Uses
       - Undesirable = Adverse effects
                     = Side effects and toxicity
4- Pharmacotherapeutics:
   a- Therapeutic uses = Indications
   b- Dosage
5- Side effects and toxicity:
   a- Manifestations
   b- Management
6- Contraindications
7- Drug interactions.
      Types of drug names
Chemical:
e.g. acetyl salicylic acid.
Generic (scientific):
e.g. aspirin.
Commercial (Trade):
e.g. Rivo, Aspocid, Rhonal..etc.
PHARMACOKINETIC

What the Body dose to the Drug?
Absorption,
Distribution,
Metabolism ,
Excretion
            ADME
                   Absorption


            Bound Drug


Excretion                  Free Drug   Distribution
            Metabolite/s               Site of Action
                                       Site of storage


                     Metabolism
 The study of pharmacokinetics is important to:

1- Design a proper dosage schedule
     (dose, route, frequency of administration)

2- Determine the drug’s bioavailability.
* Bioavailability:

1- The fraction (%) of administered drug that
  reaches the systemic circulation in an
  unchanged form.
2- Bioavailability is 100% after I.V. & most
  variable after oral administration
                    Absorption
          Rate & Efficiency = Bioavailability
  Oral



                        Systemic         I.V.
GIT         Liver       Circulation
pH &
Enzymes




           I.V.                   Oral
   Bioavailability of a Route =

Area under the curve (AUC) of the route
                                           x100
Area under the curve (AUC) of I.V. route
Trans-membrane Movement of Drugs
Passage of Drugs Across Biological
Membranes
                                 Lipid
Cell membrane is formed
 mainly of bimolecular LIPID
 sheet, interrupted by          Protein
 protein macromolecules
 (receptors, carriers, etc.),   Water

 water-filled pores & ion
                                 Ions
 channels
* Types of Passage of drugs
    A) Passive Transfer :
1- Simple Diffusion:
   a- Mostly across the LIPID phase of cell membrane.
   b- Water & water-soluble small M.W. drugs pass
    across the water-filled pores.
       * Characteristics:                   Lipid
1- Along concentration gradient.
                                         No Carrier
2- NO carrier.                           No Energy
3- NO energy.
Factors & Forces:
1-Gradient (Concentration of drugs )
  Higher gradient = Higher rate of passage
  across the membrane.
2-Molecular weight & size:
  The smaller is the faster.
*Passive Diffusion (cont.)

3-Solubility in water is a must.
4-Oil (lipid) / Water (O/W) partition coefficient.
  The higher is the better.            A 10 g B
                                       9     2
                                 Oil
                                       /     /
                                       1     8
                                 H2O
                                       9    1/4
  *Passive Diffusion (cont.)

5-Ionization:
 It depends upon pH of the medium & pKa of the
  drug (pH at which 50% of drug is ionized)
 Low Ionization = High lipid solubility = Better
  passage.
 Drugs are non-ionized when they are present in
  a similar medium (Acidic drugs in acid medium
  and basic drugs in alkaline medium).
   *Effect of pH on Oral Absorption & Renal
  Excretion of Drugs:
 -For weak base and acid drugs:
  a- The unionized (non-polar) form is lipid
  soluble and easily absorbed.
  b -Ionized (polar) form of drugs is lipid
  insoluble and not easily absorbed but easily
  excreted.
 Weak acid drugs are more unionized in acid
  & more ionized in alkaline media.
 Weak base drugs are more unionized in
  alkaline & more ionized in acid media.
   When drugs are present in a reverse medium
    → Ionized → not lipid soluble → not
    absorbed → Excreted.
   Aspirin is better absorbed in acid medium
    e.g. Stomach.
    Alkalinization of urine by sodium acetate, or
    citrate   its urinary excretion.
   Ephedrine is better absorbed in alkaline
    medium e.g. Intestine.
    Acidification of urine by ammonium chloride
      its urinary excretion.
2- Filtration:

Passage of drugs through Capillary endothelium
& Glomeruli
         * Characteristics:
 Along hydrostatic and osmotic gradients

                             Circulation
No carrier
No energy
2- Filtration )cont.)

* Factors & Forces:
1- Molecular weight
2- Not bound to plasma proteins
3- Hydrostatic and osmotic gradients
4- Blood flow
B) Special Transfer:

    1- Facilitated Diffusion:
Along concentration gradient
Needs Carrier  Site for Saturation
No energy

                                Carrier
Example: Glucose uptake        No Energy
B) Special Transfer (cont.)


2- Active Transport:
Against concentration gradient
Needs Carrier  Site for Saturation &
 Competition (Interaction)
Energy & Enzymes                         Carrier
Example: Na+/K+ pump &                   Energy

Renal tubular excretion of penicillins
B) Special Transfer (cont.)


3- Pinocytosis (Cell Drinking):
Energy dependent
Example: Absorption of Vit B12 + Intrinsic
 factor by terminal ileum
  Characteristics    Simple Diffusion     Facilitated   Active Transport
                                            Diffusion
1- Gradient:              Along            Along            Against
2- Carrier:                NO               Yes              Yes
3- Saturation &            NO               Yes              Yes
   competition:
4- Energy:                  NO               NO              Yes
5- Example:         Lipid soluble drugs    Glucose       Na/+K +pump
             I- Absorption



   Transfer of drugs from their site of
    administration to the systemic
    circulation
*Factors Affecting Absorption:
    A) Factors Related to the Patient

1-Route of Administration: I.V. > I.M. > S.C. >
  Oral > Skin
2-Absorbing Surface:
a-Vascularity: Alveoli > Skeletal muscle >
  Subcutaneous
b-Surface area: Alveoli > Intestine > Stomach
c-State of health: Diarrhea & mal-absorption
  inhibit Oral absorption
3-Systemic circulation: Shock & Heart failure 
  Absorption

4-Specific factors: Intrinsic factor for Vit B-12

5-Presence of other drugs & food:
 a-Adrenaline S.C . V.C . Absorption of
  Local anesthetics Long duration of action
 b-Milk (Calcium)   Oral absorption of
  Tetracyclines (Antibiotic)
B )Factors Related to the Drug:
1-Water and lipid solubility:
Drugs MUST be Water soluble as well as Lipid
  soluble.
Drugs must be completely dissolved in water to
  be absorbed.
   Drugs insoluble in water e.g. Barium
  chloride (BaCl2) are NOT absorbed.
More lipid solubility  High Lipid/Water
  partition coefficient  Better absorption
2-Ionization :
Non-ionized drugs are more lipid soluble 
  Better absorption
Depends on pKa of the drug & pH of the
  medium.
Tertiary amines Non-ionized  Better
  absorption.
Streptomycin has high pKa  Always ionized
  Not absorbed
Sulfaguanidine Not ionized yet  not lipid
  soluble  Poor absorption
3- Valency: Ferrous iron (Fe2+) is better absorbed
  than Ferric Iron (Fe3+).
4- Nature: Inorganic (small molecules) > Organic
  (Big molecules)
5- Pharmaceutical Preparation:
  a- Dosage form: Solution > Suspension >Tablet
  b- Shape & size of particles and rates of
  disintegration & dissolution of tables:
      Rapid with paracetamol & propranolol
     Slow with digoxin
  c- Excepient (Filler)e.g. CaCO3 & Ca Phosphate
    Absorption of Tetracyclines.
Routes of Administration

   Enteral
    1- Buccal e.g. Sublingual
    2- Oral
    3- Rectal
   Others
    1- Parenteral e.g. Injection
    2- Inhalation
    3- Topical
Effect Of Administered Drug:

1-Systemic (General):
If drug is absorbed and distributed

2-Local (Topical):
If drug is not absorbed nor distributed
    Enteral Route
 1-Sublingual  Absorbed directly Systemic
  circulation  Good Bioavailability
 2-Oral  Stomach & Intestine  pH changes &
  enzymes  Portal circulation  Liver metabolism
   Systemic circulation  Most variable
  Bioavailability
 3-Rectal (Suppository) 

a-Upper rectum  Portal circulation  Liver
  metabolism  Systemic circulation
b-Lower rectum  Systemic circulation
1- Oral Route
Characteristics:
1- Suitable:
a- Small amount or volume
b- Palatable: If bad taste 
   - Dilute with milk or fruit juice
   - Use sugar coated or effervescent form
b- Non-irritant: If Mild irritant 
   - Take after meal
   - Use enteric coated form: Covered with acid
  resistant coat
Advantages:
Convenient (Safe, easy & economic)
Disadvantages:
1-NOT in emergency  Delayed onset
2-NOT in uncooperative patients e.g. coma, insane or very
  young
3-NOT in vomiting or severe diarrhea
4-NOT in very irritant drugs e.g. Emetine HCl
5-NOT in unabsorbed drugs when systemic effect is wanted
6-NOT for drugs with extensive First Pass Effect (Metabolism):
  a-pH changes: Benzyl penicillin is destroyed by gastric
  acidity
  b-Digestive enzymes: Insulin
  c-Hepatic enzymes: Nitroglycerin
 D) Factors Affecting Oral Absorption:
1- State of Health of G.I.T. Mucosa e.g. Mal-absorption
  Syndrome.
2- Specific Factors e.g. Intrinsic Factor for Vit B12
  Absorption.
3- Gastric Emptying:
a- Metoclopramide (Primperan, Anti-emetic)  Emptying 
       -  Absorption of Paracetamol (Rapid rates of
   Disintegration & Dissolution).
        -  Absorption of Digoxin (Slow rate of Disintegration &
   Dissolution)
   b- Atropine   Emptying  The REVERSE Effects.
4- Gut Motility: Marked alterations (e.g. Morphine)  
   Absorption.
5- pH
a- Gastric Acidity   Absorption of Salicylates &
   Barbiturates
   b- Intestinal Alkalinity   Absorption of Ephedrine &
   Amphetamine.
6- Presence of FOOD & Other DRUGS:
  a- Bad  Food dilutes Drugs & may compete with them
  for absorption e.g. amino-acids compete for the same
  carrier of L-DOPA
  b- Good  with IRRITANT drugs e.g. aspirin & iron.
  c- Milk (Ca2+) & Anti-acids  Interfere with Tetracycline
  absorption.
  d- Tea (Tannic Acid) & Tetracycline   Iron absorption.
  e- Cholestyramine & Activated Charcoal   Absorption
  of Most Drugs.
7- First Pass Effect (Pre-Systemic Metabolism):
 Bioavailability
   a- Gut First Pass Effect:
- Gastric Acidity: Benzyl Penicillin.
- Digestive Enzymes: Insulin & Pituitary hormones
- Mucosal enzymes: Tyramine, L-DOPA, -Methyldopa
   &Chlorpromazine
- Flora: Histamine
   c- Hepatic First Pass Effect:
- Extensive: Nitroglycerine, Lidocaine & Natural sex hormones.
- Partial: Propranolol & Morphine.
- Minimal: Atenolol, Nadolol & Barbitone.
   d- How to OVERCOME Hepatic First Pass Metabolism?
- Increase the oral dose of the drug e.g. Morphine & Propranolol
- Use other routes )NOT ORAL) e.g. Sublingual “Nitroglycerine”.
8- Factors related to the DRUG e.g. Lipid Solubility.
     2-Sublingual (Pellet or Linguat)

*Example: Isoprenaline & Nitroglycerine.

*Advantages:
1- Easy.
2- Escape gut and hepatic first pass effect 
  Good bioavailability.
3- Rapid onset.
4- Proper control of dose by either spitting or
  swallowing excess of the drug.
                  3-Rectal:
1- Solid (Suppository): Drug (Aminophylline) in a
  cone of gelatin or cocoa butter.
2- Fluid (Enema):
  a- Evacuant (Cleansing) enema e.g. for
  constipation:
            -Large volume (1 liter)
            -High head pressure
            -Mild irritant (chamomile)
  b- Retention enema e.g. Nutrient:
            -Small volume (1/4 liter)
            -Low head pressure
            -Non-irritant
B) Advantages:
a- Escape gut & hepatic first pass effects
b- Useful in patients with vomiting
c- Useful in uncooperative patients e.g.
coma & young children
d- Useful in mild irritant drugs e.g. aspirin
and aminophylline
e- Useful in large volume drugs
             Parenteral Routes
All drugs must be STERILE and PYROGEN-FREE

A)Subcutaneous Pellet Implantation:
  Sterile pellet under the skin  Fibrosis 
  Slow absorption  Long duration e.g. some
  hormones (Contraceptives).

B)Intradermal Injection (I.D.): e.g. Sensitivity
  tests & Vaccinations.
C)Subcutaneous Injection (S.C.):
1-Drugs should be:
a- Non-irritant     (If irritant or oily  Inflammation)
b- Aqueous Solution or fine suspension.
2-Absorption can by Enhanced by:
 a- Use a solution           b- Massage of injection area
 c- Application of heat d- Add hyaluronidase enzyme
3-Absorption can be Slowed by:
 a- Use a suspension         b- Application of cold
 c- Add adrenaline (V.C.) to local anesthetics
d- Add gelatin to heparin
      D) Intramuscular (I.M.):

1- Drugs can be: Solution, suspension, oily, non-
  irritant or mild irritant.

2- Better absorption than S.C.

3- Some drugs (Diazepam & Phenytoin)  Bound
  to muscle proteins  Irregular absorption.
E) Intravenous (I.V.):

  Either SLOW bolus injection or Infusion
  (Drip) method.
 Water solution ONLY.

 Advantages:

Useful in Emergencies
  a- 100% bioavailability
  b- Immediate onset
  c- High plasma concentration
  d- Useful for Irritant & Large volume drugs
 Disadvantages:
MOST DANGEROUS ROUTE
 a- If Allergy  Anaphylactic shock
 b- If Very Irritant  Thrombophlebitis
 c- If Extravasation of irritant drug  Severe
 pain and inflammation
 d- If Rapid I.V.  Velocity reaction 
 Cardiac problems (Aminophylline)
 e- Pyrogenic reaction by phospho-lipo-protein
 of microorganisms
 f- Transmission of diseases e.g. Viral
 Hepatitis C & AIDS.
F) Other Injections:
1- Intra cardiac e.g. Adrenaline in cardiac resuscitation
2- Intra-umblical = I.V. in new born e.g. Lobeline in
   neonatal asphyxia
3-Intra-bone marrow = I.V.
4- Intra-arterial e.g. Angiography and cancer
   chemotherapy
5- Intra-peritoneal as substitute for Hemodialysis
6- Intra-thecal (CSF) e.g. spinal anesthesia, antibiotics
   in meningitis & Radiography
7- Intra-articular e.g. Steroids in osteoarthritis
8- Intra-cameral (Into aqueous humor)
                 Inhalation

- Inhaled drugs may be in the form of:
  a-Gas e.g. Oxygen & Nitrous oxide
  b-Vapor of Volatile liquid e.g. Halothane
  (General anesthesia)
  c-Solution e.g. Salbutamol (B2-agonist in
  Bronchial asthma)
  d-Powder e.g. Di-sodium-cromoglycate
     (Mast cell stabilizer in Bronchial asthma)
          absorption because of:
- Excellent
 a-Wide surface area
 b-High vascularity
 c-Thin porous membrane of the alveoli
       Topical e.g. Skin & M.M.
1-Usually  Local effect.
However highly lipid soluble drugs can be absorbed
  from the skin.
2-Skin absorption can be enhanced by:
  a-Iontophoresis by the aid of galvanic electric
  current e.g. Methacholine in P.V.D.
  b-Inunction by the aid of rough rubbing.
  c-Transdermal Drug Delivery System (TDDS) e.g.
  Skin patch of nitroglycerine
      - Prolonged blood level with minimal fluctuations
      - Better patient compliance
      - Avoid gut & hepatic first pass effect
3-Usually skin absorption is not wanted and
  harmful:
  a-Estrogen hormone in females  Cancer
  breast.
  b-Cortisone in infants  Moon face.
  c-Insecticides  Toxicity.
                      II-Distribution
 Patterns Of Distribution:                   Total Body Fluid

                     Extra-cellular             Intra-cellular

 Intra-vascular               Interstitial               Cells
Free fraction     Bound Fraction    Low M.W.            Low M.W.
High M.W. (Poly) & Bound
                                    NOT lipid soluble   Lipid Soluble
    A) Binding To Plasma Proteins:

 A fraction of Most drugs binds Reversibly to
  plasma proteins Mainly albumin .
The Bound fraction of the drug 
 NOT Active

 NOT Filtered

 NOT Metabolized

 NOT Excreted  Depot Form.

 More binding = More Depot = Longer duration.
The Free fraction of the drug 
 Active,

 Metabolized

 Excreted.

 There equilibrium between the bound
  & the free fractions of the drug.
 Drugs extensively bound to plasma
  proteins e.g. Thiopentone (I.V.
  Anesthesia) have to be injected rather
  Rapidly I.V.
 Drugs have specific binding sites on
  plasma proteins = Non-functioning
  receptors  Site for competition &
  drug interactions.
 Site for Drug Interactions:
 Aspirin (NSAID) & Sulfa drugs
  displace:
  1- Oral Anti-coagulants e.g. Warfarin
   Hemorrhage.
  2- Oral Hypoglycemics e.g.
  Tolbutamide  Hypoglycemia.
  3- Bilirubin in neonates  Jaundice &
  Kernictrus.
  B) Patterns Of Distribution:
1- Intra-vascular (Single Compartment):
Drug is retained in the blood compartment.
Drugs that can NOT filtrate through capillary
  endothelium.
Examples High MW > 500 e.g. Polypeptides
  (Plasma proteins & Drugs bound to
  plasma proteins) & Polysaccharides
  (Heparin & Dextrans).
2- Extra-cellular (Two compartments =
  Intra-vascular + Interstitial):
Drugs that can filtrate (Small MW) but
  can NOT pass cell membrane (Not
  lipid soluble).
Ionized form of drugs (Neostigmine),
  Mannitol, Na+, Cl- & SO4.
3- All over the body (Multi-compartment
  = Intra + Extra-cellular):
Drugs that can filtrate (Small MW) &
  Can pass cell membrane (Lipid
  soluble).
Non-ionized form of drugd
  (Physostigmine), Alcohol, Aspirin &
  Barbiturates.
4- Tissue Reservoirs:
a- Hair: Arsenic
b- Thyroid: Iodine
c- Heart: Digitalis
d- Liver: Vit B12 & Chloroquine
e- Fat: Thiopentone
f- Bone: Ca2+
5- Blood Brain Barriers:
Lipid cellular barrier composed of Brain Capillary
  Endothelium (Which lacks the water channels)
  and the adjacent Glial tissue.
Only lipid soluble Non-ionized drugs can pass
  B.B.B. along their concentration gradient.
Inflammation (Meningitis) increases permeability
  of B.B.B.
Penicillins can pass inflamed meninges but NOT
  normal ones.
6- Placental Barrier:
Lipid cellular barrier composed of Epithelium of
  Fetal Villi & Capillary endothelium.
Rich in enzymatic activity e.g. M.A.O.
Drugs that pass placental barrier may cause:
 During pregnancy  Teratogenicity e.g.
  Thalidomide & Tetracyclines
 During Labor  Neonatal asphyxia e.g.
  Morphine & Barbiturates.
 Metabolism (Biotransformation)

Chemical alteration of the drug
AIMING to convert: Drugs (Active,
 Non-ionized & Lipid soluble) 
 Metabolite (Inactive, Ionized & water
 soluble)  Easily excreted in urine &
 bile.
* Types of Metabolism:
      A) Phase-I (Non-Synthetic) 
  Oxidation, Reduction & Hydrolysis
  1- Oxidation:
- Phenacetin (Active)  Paracetamol
  (Active)
  2- Reduction:
- Chloral hydrate (Active)  Tri-chloro-
  ethanol (More active)
  3- Hydrolysis:
- Di-acetyl-morphine (Heroin)  Acetic acid
  + Morphine (Active)
B) Phase-II (Synthetic, Conjugation):
- Usually leads to inactivation
- May lead to activation e.g. Morphine 
  Morphine-6-Glucoronoid (More active)
- Types:
1- Glucuronic acid  Aspirin, Paracetamol,
  Morphine & Chloramphenicol.
2- Acetic acid (Acetylation)  Isoniazide,
  Sulfonamides & Hydralazine.
3- Methylation  Noradrenaline ( Active
  Adrenaline) & Histamine.
4- Glycine  Aspirin
* Site Of Biotransformation:
 Organs:

a- Liver (Hepatic) is the main site for
   biotransformation
b- Lung  Nicotine, Prostaglandins &
   Angiotensin (ACE).
c- Kidney  Vitamin D
d- G.I.T. & Gut flora  Tyramine & Histamine
e- Skin  Vitamin D
f- Plasma (Cholinesterase)  Succinylcholine
      * Factors Affecting Hepatic
         Microsomal Enzymes
A) Hepatic Microsomal Enzyme Inducers
  (Activators):
Examples: Phenytoin, Carbamazepine,
  Rifampicin, Testosterone, Cortisol & Tobacco
  smoking.
They  Metabolism of other drugs e.g. Oral
  anti-coagulants, Oral hypoglycemics & Oral
  contraceptives   Their duration of action.
They  Their own metabolism (Auto-induction)
   Tolerance.
B) Hepatic Microsomal Enzyme Inhibitors:
Specific: Grapefruit, Estrogen, Cimetidine,
  Chloramphenicol, Erythromycin &
  Ciprofloxacin.
Non-specific (General):
  a- Hepato-toxic drugs: Carbon monoxide,
  Carbon tetrachloride & Ozone.
  b- Drugs  Hepatic blood flow: -Blockers
  (Propranolol) & H2-Blockers (Cimetidine)
C) Age:
H.M.E. Activity is inhibited in extremities of age.
Premature neonate can NOT conjugate
  chloramphenicol  Fatal Grey Baby
  Syndrome.
D) Liver disease, Starvation & Cancer  
  H.M.E. Activity
E) Genetic Abnormality (Idiosyncrasy): Favism
  & Abnormal Pseudo-Ch.E.
                 Excretion
A) Renal:
Non-volatile drugs and metabolites are
  excreted in the urine.
The clearance of some drugs depends mainly
  on renal excretion (Little or no metabolism)
  e.g. Atenolol, Nadolol, Barbitone & Gallamine
   Caution in Renal patients.
Renal excretion is the result of glomerular
  filtration
  and active tubular secretion & reabsorption
 Passive Glomerular filtration for water
  soluble Non-bound drugs with M.W. <
  500 e.g. Mannitol.
 Active Tubular Excretion (Saturable &
  Site for competition & Drug Interaction):
   Weak acid drugs e.g. Penicillin,
  Frusemide, Uric acid & Probenecid.
   Weak base drugs e.g. Digoxin &
  Quinidine
   Changes in urinary pH  Affect excretion of
    weak Acid & Base drugs:
   Alkalinization of urine (Na or K Acetate,
    Bicarbonate ) 
      Renal excretion of weak Acid drugs e.g.
    Aspirin
   Acidification of Urine (NH4Cl or “Vit C”) 
    Renal excretion of weak Base drugs e.g.
    Ephedrine & Amphetamine.
B) Lung
Gases (CO2) & Volatile Liquids (Halothane)
C) Alimentary Tract:
1- Saliva (pH = 8): Morphine & Aspirin

2- Stomach  Morphine.

3- Bile  Intestine  Either:
a- Excreted in large intestine
b- Reabsorbed  Entero-Hepatic Circulation e.g.
   Morphine& Indomethacin,
c- Some anti-microbials are excreted in bile in an
   active form e.g. Ampicillin & Rifampicin  Useful in
   treatment of Cholecystitis & Typhoid carrier.

4- Large Intestine: Either via the bile or unabsorbed
   oral drugs.
D) Skin Glands:
1- Sweat  Vit B-1, Hg, As & Rifampicin 
  Red discoloration of sweat.
2- Milk  May affect suckling baby e.g.
  Morphine, nicotine, Purgatives, Tetracyclines
  & Chloramphenicol.
PHARMACODYNAMICS
(What the DRUG does to the BODY)
   This science deals with Mechanism &
    pharmacological Actions of drugs.
   Drugs are chemical substances that modify
    increase or decease already present cell
    function but do not create a new one.
    However, genetic engineering and gene
    therapy may change this concept.
* Types of Drug Action:

1- Local or Topical Action:
NO Absorption from site of administration 
  NO Distribution  NO Systemic actions.
The drug acts at site of application.
Examples: Most of eye & ear drops, intra-
  articular injections & skin ointment.
2- Systemic or General Action:
The drug is absorbed and distributed from site
  of administration.
Examples: Oral aspirin, Subcutaneous (SC)
  adrenaline & Sublingual (SL) isoprenaline.
  3- Reflex or Remote Action:
The drug acts at a site to provoke an effect
  away from its site of action.
Examples : SC Camphor  Irritation  Reflex
   Respiratory center = Reflex Analeptic.
* Mechanism of Drug Action:
1- Physical:
a- Adsorption: Kaolin & Activated charcoal in diarrhea.
b- Osmotic: MgSO4 as a purgative.
c- Demulcent: Liquorice as an anti-tussive.
d- Astringent: Tannic acid mouth wash in gingivitis
2- Chemical:
a- Neutralization:
   - NaHCO3 (Antacid) + HCl in treatment of hyperacidity.
b- Chelation: Organic compound + Heavy metal  Non-
   toxic easy excreted complex.
  - Dimercaprol (British Anti-Lewisite) for Mercury (Hg)
3- Interference with Cell Division: Anti-cancer
  drugs e.g. Nitrogen mustard.
  4- Interference with Metabolic Pathway:
  Sulfonamides compete with PABA in bacteria
    Synthesis of folic acid.
  5- Inhibition of Enzymes: Physostigmine (
  Cholinesterase) &
Aspirin ( Cyclooxygenase, COX).
  6- Action on Ion Channel:
Local anesthetics block Sodium (Na+)
  channels.
Calcium channel blockers (CCB) e.g.
  Verapamil block L-type of voltage gated
  calcium channels of heart & blood vessels.
Some pharmacologists consider ion channels
  as an especial type of receptors.
  7- Action on Receptors:
  A Receptor is a chemo-sensitive & chemo-
  selective cellular macromolecule that reacts
  specifically with a Ligand (drug, transmitter or
  hormone) to produce a biological response:
               Affinity (Ka)                        Efficacy or
Drug + Receptor              Drug/Receptor Complex                  Response
                   (Kd)                            Intrinsic Activity
1- Affinity = Ability of a drug to fit onto a receptor to
  form Drug/Receptor complex.
2- Efficacy or Intrinsic Activity = Ability of D/R
  complex to evoke a response.
3- Ka = Association constant with the receptor
4- Kd = Dissociation constant from the receptor
* Types of Ligands
A) Stimulants = Agonists:
 These drugs stimulate the receptors directly
  and produce their effects by their own. They
  should have:
1- Affinity.
2- High intrinsic activity or efficacy to stimulate
  the receptors.
3- Rapid rates of association (Ka) &
  dissociation (Kd).
Examples: Adrenaline ( &), A.Ch. (M & N) &
  Morphine ( &).
B) Blockers:
These drugs produce their effects indirectly by
   blocking the receptors and blocking the actions of
   internal chemical transmitters and/or hormones.
   They are:
   1- Antagonists: They should have:
a- Affinity.
b- No = Zero efficacy  No dose/response curve
c- Slow dissociation from receptors.
They block the action of agonists.
Examples: Prazosin, propranolol, atropine & naloxone
2- Partial Agonists = Dualists: They should have:
a- Affinity.
b- Low intrinsic activity = Weak efficacy
          Less maximum response (Emax) than agonists.
c- Moderate rates of association & dissociation.
They produce initial stimulation then block of the receptor
 If used alone  Weak stimulation of the receptor 
    Weak response
 If used in presence of an agonist  Block the action of
    the agonist.
Examples: Ergotamine ( + 5-HT), Oxprenolol (),
    Nicotine (NN) & Succinylcholine (N-M).
* Types of Block:
A) Competitive Block:
- Antagonists bind REVERSIBLY with the receptors.
- Antagonists can be DISPLACED by excess agonists 
   Surmountable
-They produce PARALLEL shift of the curve to the RIGHT  
   Potency.
They produce NO effect on the maximum response (E-max) =
   Same Efficacy.
Examples: Propranolol, atropine & naloxone.
B) Non-Competitive Block:Response
- Antagonist is NOT displaced by agonist  Non-
   surmountable
- Non-Parallel shift of cure to the Right =  Potency.
- Decrease maximum response (E-max) =  Efficacy.
- Types of Non-Competitive Block :
   a- REVERSIBLE :
   - The antagonist binds REVERSIBLY to the receptor.
   - The block ends by the Metabolism of the blocker.
   - Usually of Short duration of action.    -
   Examples : succinylcholine.
   b- IRREVERSIBLE :
    - The antagonist binds COVALENTLY to the receptor.
    - The block ends by Resynthesis of new receptors.
    - Usually of Long duration of action.
    - Examples: organophosphorus compounds.
                   :Types of Ligands *

                  Stimulant              Blocker
Characteristics   =Agonist
                                Antagonist   Partial Agonist
                                                 = Dualist

1-Affinity           +++         +++             +++
2-Efficacy           +++        No = Zero      Moderate
3-Ka & Kd            Rapid        Slow         Moderate
4-Effect          Stimulation    Block        Stimulation
                                               then Block
Competitive                            Non-Competitive

1-Blocker is displaced by excess       1-Blocker is not displaced by excess agonist
agonist = Surmountable                    =Non-surmountable
2-Parallel shift of curve to right    2-Non-parallel shift of curve to the right  
 Potency                              Potency
3-Same Emax = Same Efficacy            3-Decreased Emax   Efficacy
4-Example: Atropine & Propranolol      4-Types: Reversible & Irreversible


                                       Reversible             Irreversible

                                       1-Block ends by        1-Block ends by
                                       metabolism of the      resynthesis of new
                                       blocker                receptors
                                       2-Short acting         2-Long acting
                                       3-Example:             3-Example:
                                       Succinylcholine        Phenoxybenzamine
NB )Chronic Use of Drugs Affects the No. &
Sensitivity of Receptors:
Long use of Agonists   No. & Sensitivity
of Receptors Down Regulation.

Long use of Antagonists or drugs that
transmission   No. & Sensitivity of
Receptors  Up Regulation.
              Doses of Drugs (Posology)
1- Therapeutic Dose: Average dose calculated for an
   Adult, Male, 20-60 year old & 70 Kg body weight.
2- Initial Dose; Initial large dose aiming to reach the
   therapeutic plasma concentration
3- Maintenance Dose: Small daily dose required to
   replace eliminated drug from the body to maintain
   the achieved therapeutic plasma concentration.
4- Maximal Tolerated Dose; Highest dose without toxic
   effects.
5- Lethal or Fatal Dose: Dose that kill the patient or an
   experimental animal
6- Therapeutic Index:
Ratio = LD50 / ED50
 LD50 = Lethal dose in 50% of animals
 ED50 = Effective dose in 50% of animals
A good guide to determine & compare SAFETY
  of drugs
The Higher the therapeutic index  The Safer
  the drug
                Factors Affecting The Dose &
                Action of Drugs
1.   Biological variation Range of dose. Start by minimal effective
     dose then increase the dose gradually as needed.
2.   Age Decrease the dose in extremities of age.
       A.   Geriatrics (Elderly > 60 years):
               a. They have exhausted drug-elimination mechanisms
                   (metabolism & excretion).
               b. Use 2/3 or 3/4 of the adult dose.
       B.   Pediatrics (Young < 12 years):
               a. They have immature drug-elimination mechanisms
                   (metabolism & excretion).
               b. Calculate the dose by:
                   - Infant (< 1 year) dose (Clark’s Formula) = Adult dose X
                   (Weight of infant in Pounds/150)
                   - Child (1 – 12 year) dose (Young’s Formula) = Adult dose X
                   [Age in years / (Age + 12)]
                        or (Dilling’s Formula) = Adult Dose X (Age in Years / 20)
                        or = Adult Dose X (wt of child in Kg / 70)
     Factors Affecting The Dose & Action of Drugs (cont.)
3.   Body Weight & Surface Area:
     a.   Skeletal muscle weight is more important than fat or edema.
     b.   Surface area =  Height in cm X weight in Kg / 3600
     c.   Surface area is more accurate in calculating doses for children & infants.
4.   Sex:
     a.   Males need higher doses than females:
            Males have bulky muscle tissue & Androgens (HME Inducers)

            Females have bulky fat tissue & Estrogen (HME Inhibitor)

     b.   Some drugs are contraindicated in Females during physiological periods:
            Menstruation: Aspirin & Cathartics   Bleeding

            Pregnancy: Sex hormones, Oxytocics (Ergotamine) & Teratogens
             (Phenytoin)
            Labor: Barbiturates & Morphine  Neonatal asphyxia

            Lactation: Drugs excreted in milk eg Purgatives, Tetracyclines &
             Chloramphenicol
     Factors Affecting The Dose & Action of Drugs (cont.)
5.     Route & Time Of Administration:
         Affect the dose: usually I.V. dose < Oral dose
         Affect the effect: Mg SO4
                  After meal  No effect
                  Orally  Empty stomach  4 g  Cholagogue
                                               15 g  Saline purgative
                  I.V.   CNS,  Smooth, Skeletal & Cardiac muscle
                  Retention Enema  Dehydrating agent e.g. in brain edema
         If drug is irritant  Use after meals
         If drug is sedative  Use at bed time

6.       Commutation:
      a.   Occurs with zero-order kinetics when the rate of intake > rate of
           elimination.
      b.   Examples: Digitalis, Aspirin L.D., Phenytoin L.D. & Ethanol L.D.
      c.   To avoid cumulation either  The dose or  Frequency of
           administration.
Factors Affecting The Dose & Action of Drugs (cont.)

7. Psychological Effect:
  Some patients improve by Psychological (Suggestion)
      rather than Pharmacological effect of the drug (Placebo
      effect).
  Placebo (Dummy medication) is an inert substance
      (Lactose, starch, etc.) used in a dosage form (Tablet,
      capsule, etc). Useful in:
        Treatment of patients by psychological
         suggestion
        As a comparison when testing new drugs
     Factors Affecting The Dose & Action of Drugs (cont.)
8.   Pathological Condition:
     a.   Some drugs act ONLY in presence of disease:
             Aspirin acts as an antipyretic ONLY in fever
             Digitalis acts as a diuretic ONLY in heart failure
     b.   Pathology may cause supersensitivity:
             a- Adrenaline in thyrotoxicosis
             b- -Blockers in bronchial asthma
     c.   Pathology may affect drug kinetics: Achlorhydria  
          Intrinsic factor   Absorption of Vit B-12  Pernicious
          anemia.
          Liver and/or kidney disease may affect the dose of some
          drugs.
 Factors Affecting The Dose & Action of Drugs (cont.)


8. Idiosyncrasy (Pharmacogenetics)  Abnormal
   response
9. Supersensitivity (Intolerance)   Dose of the
   drug
10. Tolerance   Dose of the drug

11. Drug interactions  Summation, Synergism,
   Antagonism & Reversal.

								
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