Pharmacodynamics by Dr. Sherif Ahmed Shaltout

1. PharmacodynamicsbyDr. Sherif Ahmed Shaltout

2. Types of pharmacodynamiceffects: • Local or topical action, where drugs act on site of application e.g. ointment or eye drops. • Systemic or general action, where the drug acts after administration and distribution by circulation to various tissues. • Reflex or remote action, where the drug acts locally at one site to produce reflex action elsewhere.

3. Mechanisms of drug actions: • Physical action: As adsorption e.g. kaolin and pectin in cases of diarrhea. • Chemical action: As neutralization of hyperacidity by antacids. • Interference with cell division as cytotoxic drugs. • Inhibition of enzymes e.g. choline esterase inhibitor drugs. • Interference with normal metabolic pathwayse.g. sulfonamide interfere with para-aminobenzoic acid which is essential metabolite for bacteria. • Action on cell membrane: e.g. local anesthetics.

4. action on cell receptors: The most common method by which most drugs generally act e.g. acetyl choline on cholinergic receptors, adrenaline on adrenergic receptors. Receptor:a chemically reactive (chemosensitive) macromolecule, protein in nature, present inside or on the surface of the cell .it is the site of drug attachment and action, can be stimulated by agonist drugs and blocked by antagonist drugs.

5. Classification of receptors: 1-Ligand gated ion channels: -Nicotinic Receptors : Stimulated by acetylcholine and results in sodium influx. -GABA-receptor : Stimulated by benzodiazepines and GABA and results in increased chloride influx

7. 2- G-Protein Coupled • Comprised of single peptide that has seven membrane-spanning regions, linked to a G-protein with 3 subunits – alpha (binds GTP) and beta gamma subunits. • Binding of appropriate ligand to extracellular region → activates G-Protein → GTP replaces GDP on alpha subunit → dissociation of G-Protein → both alpha-GTP and beta gamma interact with second messengers .Response last several seconds to minutes

9. 3. Receptors linked to Tyrosine Kinase (RTKs) • The receptor is formed of two domains: a. An extracellular domain, to which the agonist (e.g. insulin) binds. b. An intracellular domain, which is a tyrosine kinase enzyme (effector). • Binding of insulin causes 2 single tyrosine-kinases receptors to aggregate into a dimmer with subsequent autophosphorylation. Then, the activated-phosphorylated dimmer binds to relay proteins, activating them. These relay proteins trigger the cellular response through either production of a second messenger or turning on gene expression.

11. 4. Receptors Regulating Transcription (very slow) • Steroid hormones, estrogen, progesterone, enter the target cell and combine with intracellular receptor proteins associated with nuclear chromatin (DNA) to activate or inhibit transcription of the nearby gene. This will modify protein production and cause changes in the structure or function of the target tissue.

12. Types of ligands 1. Agonist • Interacts with the receptor (affinity) activating it (efficacy) → pharmacologic effect, i.e. it has affinity and efficacy, e.g. acetylcholine (Ach) activates nicotinic receptors → depolarization → skeletal muscle contraction. 2. Antagonist • Interacts with the receptor without activation (affinity without efficacy), e.g. curare blocks nicotinic receptors → prevents depolarization by Ach → relaxation. 2 types of antagonists: • Competitive antagonists: compete with agonists for the same recognition site of the receptors → the agonist behaves as if it were less potent. • Noncompetitive antagonists: preventbinding of the agonist or preventactivation of the receptor by the agonist.

14. Non Competitive antagonist • Reversible: 1-bind reversibly with receptor 2- Duration depends on metabolism of antagonist 3- short duration 4- e.g. succinylcholine • Irreversible: 1-bind irreversiblywith receptor 2- Duration depends on synthesis of new recep. 3- longduration 4- e.g. OPC.

15. 3. Partial Agonist (Agonist-Antagonist) it activates the empty receptor, but with lower efficacy than that of a full agonist Agonist present: block the receptor, if abscent: as weak agonist Example: succinylcholine → initially activates nicotinic receptors → fasciculations(agonistic effect) →followed by relaxation (antagonist effect). 4.Inverse agonist: Affinity for specific receptor. Efficacy is opposite to that of endogenous agonists Examples: B-carbonlinbinds to GABA receptors and produces CNS stimulation which is opposite to the effect of endogenous agonist GABA which binds to GABA and produces CNS depression.

16. Dose-response Relationship I.Graded (quantitative) dose-responsecurve is obtained if the degree of response is depicted against log the dose e.g. decreases of blood glucose against the dose.

17. Parameters that can be obtained from the graded dose-response curve: 1. Efficacy (Emax):is the maximal effect produced by the drug (= the maximum value of the dose-response curve) 2. Potency • ED50 it is dose that produces 50% of the maximal response and is estimated similar to the “All or none curve”. The lower the ED50 the more potent the drug is • Slope of the middle portion of the curve (it reflects the effect of the drug produced by one unit of the dose. The steeper the curve (i.e. the higher the slope) the more potent the drug is.

18. II. All/None(quantal) dose-response curve is obtained if the percentage of patients who respond to the drug is depicted against log the dose e.g. the % of patients in whom the arrhythmia is terminated by different doses of an antiarrhythmic drug

19. Parameters that can be obtained from the All/None curve: 1. ED50: It is the dose that cures 50% of cases. It is used for comparison between drugs e.g. drug with a lower ED50 is > potent than that with a higher ED50. 2. LD50: relation between the % mortality in animals treated by the drug and the log of the dose, we will obtain the LD50 (the dose that kills 50% of animals). the drug with lower LD50 is considered more toxic than the drug with higher LD50 3. Therapeutic index (TI): It is the ratio between ED50 & LD50 →TI = LD50/ED50. It gives an idea about the safety of the drug: if the TI is large, i.e. the LD50 is much higher than the ED50 the drug is safer.

20. Factors affecting drug action 1-Dose: It is the amount of the drug given to the patient at a time. • Therapeutic dose:the average dose given to adult patient to produce therapeutic effect. • Maximal tolerated dose:the largest dose of drug that can be taken safely. • Initial dose:the dose used at start of treatment. • Maintenance dose:the dose required to maintain the therapeutic effect. • Toxic or lethal dose:the dose that produce toxicity or death. • Dose -response relationship

21. 2-Age, weight and surface area: • Adult doseis calculated depending on age from 20 to 60 years old, and weight about 70 kg. • Children dose: According to age: Young formula: • Child dose = adult dose x age in years / age in years + 12 Diling formula: • Child dose = adult dose x age in years / 20 According to weight (for infant less than 1 year): Infant dose = adult dosed in pounds / 150

22. Newborn infant especially premature infants are more susceptible to the effect of the drugs because: 1-Underdevelopment of many hepatic microsomal enzymes that detoxify drugs. 2-Reduced renal excretion of drugs due to low glomerular filtration and renal blood flow 3-Lower total plasma protein levels. 4-Immaturity of blood brain barriers (B.B.B). e.g. Infants are more sensitive to morphine and chlormphenicoal • The elderly dose: From 60 - 80 years old =3/4 adult dose. Above 80 years old =1/2 adult dose

23. 3-Sex: • Female patients need less dose than male patients because: 1-Female contain more fatty tissues (which have low oxidation rate and are inert tissues). 2-Estrogens inhibit hepatic microsomal enzymes, while androgens stimulate these enzymes. • Menstrual period: Salicylates • Pregnancy: Teratogenic • Lactation: Sedative, purgatives

24. 4-Route of administration • Magnesium sulfate: orally act as a purgative, while IV it cause depression to cardiac, skeletal, smooth muscles and C.N.S. 5-Time of administration : • Non irritant drugs: before meals • Irritant drugs: after meals . • C.N.S stimulant: not be given at night • Drugs producing drowsiness as antihistamine drugs not be given at day time.

25. 6-Tolerance: Failure of responsiveness to the usual dose of a drug. Types: 1-Acquired tolerance: • It occurs on repeated administration of the drug. • More drugs is needed to obtain the original effect. • It is reversible i.e. it disappears when the drug is stopped for some time. • Examples: morphine, nitrates, xanthines and barbiturates.

26. Mechanism of acquired tolerance 1- PK.: 1- Decreased intestinal absorption of drugs. 2-Increased renal excretion of drugs. 3-Increased metabolism of drugs due to enzyme induction. 2- PD.: 1- Decreased Sensitivity of receptors. 2- Down regulation: Decreased number of receptors 3- Development of antihormone against insulin &parathormone. Special types of acquired tolerance: 1-Tachyphylaxis:-acute rapid -not obtained by increasing dose. Example:ephedrine on blood pressure. (3D: dissociation, downregulation, depletion)

27. 2-Cross-tolerance:e.g. morphine and pethidine. 3-Tissue tolerance: to some actions of the drug. e.g. morphine tolerance not to its miotic and constipating actions . 4-Bacterial resistance to antibiotics. 2-Congential tolerance • Racial: ephedrine is not mydriatic in negros . • Species: rabbits tolerate large amounts of atropin • Individual tolerance.

28. 7-Drug intolerance (hypersusceptibility): • It is exaggerated pharmacological response to the usual dose of the drug e.g. adrenaline in thyrotoxicosis. 8- Genetic a bnormalties(idiosyncrasy): • It is congenital abnormal reactions to drugs due to genetic abnormality. • antimalarials(primaquien) , sulpha, salicylates may induce hemolytic anemia in patients with congenital G-6-PD deficiency • Isoniazidinduces peripheral neuritis in patients with congenital slow acetylator

29. Malignant hyperthermia: may occur in some patients following halothane anaethesia or succinylcholine administration • Succinyl choline apnea: occur in patients with congenital deficiency of plasma pseudo-choline esterase enzyme. 9-Pathological state: • Aspirin lower body temperature in case of fever • The dose reduced in patients with renal impairment and hepatic impairment • The effect of subcutaneous drugs is delayed in patients with shock or heart failure

30. 10-Cumulation: when the rate of administration of the drug exceedsthe rate of its metabolism or excretion which leads to toxic effect e.g. digitalis. 11- Drug interactions: • Addition or summation: 1 + 1 = 2 e.g. histamine and ACH on B.P. • Synergism:1 + 1 = 3 e.g. sulphonamide and trimethoprim. • Potentiation: 0 + 1 = 2 . e.g. barbiturates potentiate the analgesic effect of salicylates.

31. Antagonism: • Physiological: 2 drugs with opposing actions on 2 receptors e.g. histamine and adrenaline. • Chemical:one drug reacts chemically with an active drug e.g. heparin and protamine sulphate. • Pharmacological: Competitive antagonism: Non-Competitive antagonism 12-Emotional factors: • Administration of placebo (inert medication formed of sucrose or lactose) may give therapeutic effect in psychic patient just to please him).

32. 13-Drug dependence: • Habitation: psychological or emotional dependence . No physical disturbance Ifsudden stoppage….> emotional distress. e.g. coffee and tea habits. Addiction: psychological + physical dependence . Ifsudden stoppage….> withdrawal symptoms e.g. morphine, barbiturates

33. 14-Drug allergy (hypersensitivity): • It is acquired abnormal reactions to drugs due to antigen - antibody reaction. • It is unrelated to the dose. • It occurs when the drug is given repeatedly. • as penicillin, aspirin, sulpha. • Mechanism • Types of drug allergy Type I: • Ag + IgE on mast cells • anaphylactic shock. • penicillin

34. Type II • Ag + IgM & IgG on blood cells. • blood dyscrasias e.g. quinine-hemolytic anemia, α methyl dopa- thrombocytopenia. Type III • Ag + IgM & IgG in plasma + Complement sys. • Organ degenratione.g.hepatitis, nephritis with antithyroid, antiepileptics Type IV • Ag + lymphocytes (delayed cell mediated type). • Inflammatory mass e,g. BCG

35. Manifestations of drug allergy: • Acute allergy (anaphylactic reactions): -within one hour -shock, acute bronchial asthma, laryngeal oedema, generalized urticaria and conjunctivitis • Subacute allergy: -1 - 24 hours -skin rash, bronchial asthma, rhinitis, fever. • Delayed allergy: - e.g. thrombocytopenic purpura, agranulocytosis and heamolytic reactions.

36. Adverse effects During After stopp. Predictable Unpredict. Side effects & Toxicity Hypersensitivity Tolerance(addiction) & Intolerance Idiocyncrasy Teratogenicity & Carcinogenicity Iatrogenic