Pharmacodynamics PDF

Pharmacodynamics The drug after reaches to the cell , interacts with specific molecule called the receptor. The Receptor Pharmacology defines a receptor as any biologic molecule (protein) to which a drug binds and produces a measurable response. The response ; is alterations in biochemical and/o...

Pharmacodynamics The drug after reaches to the cell , interacts with specific molecule called the receptor. The Receptor Pharmacology defines a receptor as any biologic molecule (protein) to which a drug binds and produces a measurable response. The response ; is alterations in biochemical and/or biophysical activity of a cell, and consequently, the function of an organ. (Drugs act as signals, and receptors act as signal detectors). Major Receptor types A. Ligand-gated ion channels Like calcium channel , sodium channel , and chloride channel Example ; when γ-aminobutyric acid (GABA ) react with chloride channel leading to influx of chloride ion into cell (nerve cell) (GABA ; is inhibitory neurotransmitter) B. G protein–coupled receptors and second messengers G protein when activated by a drug resulting in activation intracellular enzyme (like adenylyl cyclase ) , leading to synthesis of second messenger (like cAMP) and then protein phosphorylation and amplifying of intracellular response. (G=Guanosine)  C. Enzyme-linked receptors Example ; Receptors linked to tyrosine kinase ( intracellular enzyme) which can stimulated by insulin. D- Intracellular receptors Example ; DNA and RNA , which interact with steroid hormones to produce proteins. the drug must be more lipid soluble to reach to these receptors. DOSE–RESPONSE RELATIONSHIPS The magnitude of the drug effect depends on receptor sensitivity to the drug and the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination. As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect) 1. Potency Potency is the amount of drug necessary to produce an effect. The concentration of drug producing 50% of the maximum effect (EC50) is often used to determine potency of the drug. For example, the therapeutic dose for candesartan is 32 mg, as compared to 300 mg for irbesartan. Therefore, candesartan is more potent than irbesartan (irbesartan has a lower EC50 value). 2. Efficacy Efficacy is the magnitude of response that caused by a drug when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug (its ability to activate the receptor and cause a cellular response). Maximal efficacy of a drug (Emax). Agonist and Antagonist A. agonist ; a drug can stimulate a receptor called agonist. agonist types; 1- Full agonists ‫ينطيني استجابة تشبه االستجابة‬ ‫اليحققهة الجسم مثل هرمون او‬ ‫ناقل عصبي‬ If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand, it is a (full agonist). For example, phenylephrine is a full agonist at α1 -adrenoceptors, because it produces the same Emax as the endogenous ligand, norepinephrine. 2- Partial agonists when a drug have intrinsic activities greater than zero but less than full agonist. Even when all the receptors are occupied, partial agonists cannot produce the same Emax as a full agonist. Ion channels ‫نوع املستقبل مالتهة‬ 3-Inverse agonists Some substances produce effects that are specifically opposed to those of the agonist. The agonist action of benzodiazepines on the benzodiazepine receptor in the central nervous system produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances called β-carbolines, which also bind to this receptor, cause stimulation, anxiety, increased muscle tone and convulsions; they are inverse agonists. (β-carbolines ; widely distributed in nature, including plants, marine creatures, insects.) inverse agonist ‫هذه‬ ‫يستخدم بعالج تحفيز االعصاب والعضالت‬ benzodiazepines‫لل‬ B. Antagonists or blockers ‫ يدخل‬drug ‫يتحد وية املستقبل ويقفلة ف ميكدر ال‬ Antagonists bind to a receptor with high affinity but have zero intrinsic activity. It can decrease the effect of an agonist when present. Antagonism may occur either by blocking the (agonist drug’s) ability to bind to the receptor or by blocking its (agonist) ability to activate the receptor. Antagonists types ; ‫ممكن تتغلب على‬ 1.Competitive antagonists; If the antagonist binds to the same site on the ‫هذا النوع من ال‬ ‫ اذا‬antagonists receptor as the agonist in a reversible manner. ‫زيدنة الجرعة‬ However, increasing the concentration of agonist relative to antagonist can overcome this inhibition. 2. Irreversible antagonists ; they bind permanently to receptors. In contrast to competitive antagonists, addition of more agonist does not overcome the effect of irreversible antagonists. 3. Allosteric antagonists; An allosteric antagonist binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by the agonist. 4. Functional antagonism ; An antagonist may act at a completely separate ‫مستقبل‬ ‫يشتغل على‬ ‫واحد‬ receptor, initiating effects that are functionally opposite those of the agonist. (example ; histamine cause bronchoconstriction, epinephrine cause ‫ويعكس الوظيفة‬ bronchodilation). Desensitization and down regulation of receptors: ‫هنا الخلل يصير باملستقبالت من تكون ماخذ فولتارين قبل‬ desesitization ‫ يصير بيهن‬receptor ‫وميشتغل الن ال‬ ‫هنا الزم نغير الدواء للبروفني مثال‬ Desensitization of receptors ; too much agonist stimulation to the receptor may make the receptor desensitized , resulting in a diminished response. This phenomenon, called tachyphylaxis. Down-regulation of receptors ; An decrease in the number of receptors on the surface of target cells, making the cells less sensitive to further agonist ( hormone or drug). For example, insulin receptors may be downregulated in type 2 diabetes. Up –regulation of receptors ; repeated exposure of a receptor to an antagonist, result in An increase in the number of receptors on the surface of target cells can make cells more sensitive to agonists (hormone or drug) and/or more resistant to effects of the antagonist. For example, there is an increase in uterine oxytocin receptors in the third trimester of pregnancy, promoting the contraction of the smooth muscle of the uterus. Beta receptor blockers (antagonists) withdrawal syndrome (beta receptor antagonists used to treat hypertension) These symptoms and signs following sudden cessation of beta-blockers are called the “beta-blocker rebound phenomenon”. Adult patients may exhibit ‫ننطي بيتا بلوكر وفجاء نسحبهة‬ hypertension, headache, palpitation, sweating, and chest pain. ‫الحد الفاصل بني‬ ‫الجرعة العالجية‬ Therapeutic index ‫والتسمم‬ The therapeutic index (TI) of a drug is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces effective response (ED50) in half the population: The TI is a measure of safety of a drug. TD = toxic dose ED = effective dose warfarin, an oral anticoagulant with a low TI (when the dose increased cause toxicity ) penicillin, an antimicrobial drug with a large TI. (when dose increased cause no toxicity ) For low TI drugs, the bioavailability critically alters the therapeutic effects For large TI drugs , the bioavailability does not critically alter the therapeutic or clinical effects.