Pharmacology Lecture PDF

Pharmacology Pharmaco-dynamics LECTURE (3) Pharmaco-dynamics (3) DR. El-Sawy 1  Pharmacology...

Pharmacology Pharmaco-dynamics LECTURE (3) Pharmaco-dynamics (3) DR. El-Sawy 1  Pharmacology Pharmaco-dynamics ❶ ❶ ❷ ❷ ❸ ❸ ❹ ❹ ❺ ❺ Drug shape (stereoisomerism):  Most drugs have multiple stereoisomers (enantiomers) (L- thyroxin & D- thyroxin).  The receptor site is usually sensitive for one stereoisomer and not suitable for another, like the hand and the glove. One isomer may be hundred times more potent than the other. One isomer is beneficial while the other is toxic. This phenomenon may explain how a single drug could act as agonist and antagonist (i.e. partial agonist) because many drugs are present in "racemic mixtures" rather than as pure isomers; or how one isomer is effective and the other isomer is toxic. DR. El-Sawy 2  Pharmacology Pharmaco-dynamics Molecular weight (MW):  Most drugs have MW between 100-1000 Da.  Drug particles larger than MW 1000 Da: Cannot be absorbed or distributed → should be given parenterally. Cannot cross placental barrier. Time of drug administration (Chronopharmacology):  The science dealing with tailoring drug medication according to the circadian rhythm of the body to get better response and/or to avoid possible side effects.  Many body functions (e.g. liver metabolism, RBF, blood pressure, HR, gastric emptying time, etc.) have daily Def circadian rhythm. Some enzymes responsible for metabolism of drugs are active in morning or evening. Many diseases (asthma attacks, myocardial infarction) are circadian phase dependent.  Episodes of acute bronchial asthma are common at night due to circadian variation of cortisol and other inflammatory mediators, so it is better to give the anti-asthmatic Examples medications in the evening.  Blood pressure is at its peak during afternoon, so it is better to give the antihypertensive medications at morning. Drug cumulation:  Occurs when the rate of drug administration exceeds rate of its elimination  Especially in patients with liver or renal disease.  Some drugs are cumulative due to their slow rate of elimination e.g. digoxin. DR. El-Sawy 3  Pharmacology Pharmaco-dynamics Drug combination:  Drug combination is very common in clinical practice. Def Example  The combined effect of two  Use of two simple drugs is equal to the sum of analgesics together. Summation their individual effects (1+1=2). or addition  Usually occurs between drugs having the same mechanism  The combined effect of two drugs is  Penicillin + aminoglycosides greater than the sum of their to exert bactericidal effect. individual effects (1+1=3) Synergism  The two drugs usually have different mechanisms of action  Similar to synergism but, effect of  Phenobarbitone has no one drug itself is greatly increased analgesic action but it can Potentiation by intake of another drug without potentiate analgesic action notable effect (1+0=2) of aspirin.  One drug abolishes the effect of Antagonism the other i.e. 1 + 1 = 0 DR. El-Sawy 4  Pharmacology Pharmaco-dynamics Age, sex, and weight. Pathological status:  Liver or kidney diseases significantly alter the response to drugs due to altered metabolism.  Failing heart is more sensitive to digitalis than the normal heart. Pharmacogenetic factors (idiosyncrasy):  Definition: Abnormal drug response due to genetic abnormality in drug metabolism.  Examples: Examples of heritable conditions causing EXAGGERATED drug response:  Succinylcholine is a neuromuscular blocker metabolized by pseudo-cholinestrase enzyme. a) Pseudo-  Some individuals with deficient PsChE, when they take cholinestrase succinylcholine, severe muscle paralysis occurs due to lack deficiency of succinylcholine metabolism, and may lead to death from respiratory paralysis (succinylcholine apnea).  G6PD is the most common human enzyme defect.  It catalyzes the reduction of NADP+ into NADPH which maintains glutathione in the RBCs in its reduced form. b) Glucose- -  Reduced glutathione keeps Hb in the reduced (ferrous) phosphate form and prevent formation of methemoglobin and cell dehydrogenase membrane injury (hemolysis) by oxidizing drugs. (G PD) deficiency  Individuals with deficiency of G6PD may suffer acute hemolysis if they are exposed to oxidizing drugs e.g. nitrates, antimalarial drugs, and others. DR. El-Sawy 5  Pharmacology Pharmaco-dynamics  It methylates thiopurine anticancer drugs (e.g. 6- mercaptopurine and 6-thioguanine) into less toxic compounds.  Genetic deficiency in TPMT leads to increased conversion of c) Thiopurine parent thiopurine drugs into more toxic compounds, leading to methyl- transferase severe myelotoxicity and bone marrow suppression which (TPMT) may be fatal. deficiency  TPMT deficiency prevalence is 1:300.  Screening for TPMT deficiency is necessary in patients treated by thiopurine anticancer drugs.  Many drugs are metabolized in liver by acetylation (isoniazid).  Acetylation reaction is under genetic control and people can be classified according to their rate of acetylation into: a. In rapid acetylators: Excessive isoniazid toxic metabolites accumulate in the liver causing hepatocellular necrosis. b. In slow acetylators: Isoniazid accumulates in peripheral tissues causing d) Acetylator peripheral neuropathy due to interference with phenotypes pyridoxine metabolism So pyridoxine "vit B6" is added to isoniazid therapy to prevent neurotoxicity.  Some drugs that are metabolized by acetylation can cause systemic lupus erythematosis-like syndrome (SLE) in slow acetylators : 1. Hydralazine (+++) 4. Quinidine (+) 2. Procainamide (++) 5. Phenytoin (+) 3. Isoniazid (+) DR. El-Sawy 6  Pharmacology Pharmaco-dynamics Examples of heritable conditions causing DECREASED drug response:  In normal individuals, warfarin anticoagulant acts by inhibiting the enzyme vit K epoxide reductase responsible Resistance to for reduction of the oxidized vit K (inactive) to its coumarin reduced form (active). (warfarin)  Some individuals have another variant of this enzyme anticoagulants making them needing 20 times the usual dose of coumarin to get the response.  Children with vit D-resistant rickets need huge doses of vit D to be treated. Resistance to vit D (vit D-resistant rickets)  Dark eyes are genetically less responsive to the effect of Resistance to mydriatics. mydriatics DR. El-Sawy 7  Pharmacology Pharmaco-dynamics Hyporeactivity to drugs: Tolerance Tachyphylaxis  Progressive decrease in drug response  Acute type of tolerance. with successive administration.  Occurs over long period.  Occurs very rapidly.  The same response could be obtained by higher doses. Mechanisms:  Receptor desensitization: Prolonged exposure to drug → slow conformational changes in the receptors by which the receptor shape becomes no longer fitted well with the drug. Pharmacodynamic  Receptor down-regulation: tolerance Prolonged exposure to drug → decrease number of the functional receptors.  Exhaustion of mediators: e.g. depletion of catecholamines by amphetamine.  Due to ↑ metabolic degradation of a drug by induction Pharmacokinetic of hepatic enzymes tolerance  e.g. chronic administration of ethanol.  It occurs by a drug independent learning of the brain Behavioral how to actively overcome a certain drug-induced tolerance effect through practice  e.g. with psychoactive drugs. DR. El-Sawy 8  Pharmacology Pharmaco-dynamics Hyperreactivity to drugs: Rebound effect Withdrawal effect (syndrome) Recurring of symptoms in exaggerated form  When a drug is suddenly stopped  plus addition of new symptoms after long period of administration. when a drug is suddenly stopped  Prolonged administration of  Withdrawal effects that occur after antagonist → up-regulation sudden stopping of opioids in opioid (increase number) of receptors. addicts.  When antagonist is suddenly stopped → severe reaction occurs e.g. severe tachycardia & arrhythmia after sudden stopping of beta-blockers. DR. El-Sawy 9  Pharmacology Pharmaco-dynamics N.B. Some examples of drugs should not be stopped suddenly: Drug Sudden withdrawal can lead to  Severe tachycardia, arrhythmia, and even myocardial Beta-blockers infarction. Clonidine  Severe hypertension (hypertensive crisis). Cimetidine  Severe hyperacidity and even peptic ulceration. Corticosteroids  Acute Addisonian crisis. Morphine  Withdrawal symptoms. Warfarin  Thrombotic catastrophes DR. El-Sawy 10