W2 Introduction Pharmacodynamics 1446.pdf

Pharmacodynamics Dr. Mohannad A. Almikhlafi Assistant Professor of Pharmacology and Toxicology Faculty of Pharmacy Taibah University  Pharmacodynamics of Drugs “What the DRUG does to the BODY” The action of a drug on the body, including the study of: I. The pharmacological actions o...

Pharmacodynamics Dr. Mohannad A. Almikhlafi Assistant Professor of Pharmacology and Toxicology Faculty of Pharmacy Taibah University  Pharmacodynamics of Drugs “What the DRUG does to the BODY” The action of a drug on the body, including the study of: I. The pharmacological actions of drugs; dose- response phenomena. II. The mechanisms of therapeutic and toxic actions of drugs. Mechanisms of drug actions Inhibition of Enzymes Enzymes are substances that speed up many chemical reactions and control a number of metabolic processes. Some drugs have the property of inhibiting the activity of some enzymes. In the patient (ACE inhibitors; NSAIDs) In microbes (sulfas, penicillins) In cancer cells (5-FU, 6-MP) Action on cell membrane; 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. Interference with Metabolic Pathway (Antimetabolites). The drug may be similar in structure to a substance (metabolite) which is used by the cells for their function. Thus, in the presence of the drug, the cell cannot use its endogenous metabolites and fails to multiply. Example: The anticancer agent. ❑ 6-mercaptopurine (6-MP) which competes with purine bases in the synthesis of DNA, interferes with cell division. ❑ Sulfonamide antibiotics compete with PABA in bacteria →  Synthesis of folic acid Drug-receptor interaction (receptor theory) 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. The drug is thought to fit onto a receptor rather as a key fits a lock (Key & Lock Theory). Drug-Receptor Theory Types of Ligands A) Stimulants = Agonists: A drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand. Example: Adrenaline actions on  &  adrenergic receptors (Agonist = affinity + efficacy).  Cont. The drug-receptor theory B) Blockers: Blocking receptors to prevent its activation. Blockers can be: 1- Antagonists: They are able to bind to target receptors because they possess strong affinity. They occupy the receptor without producing any effect and should have: a- Affinity. b- No = Zero efficacy “no intrinsic activity”→ No dose/response curve c- Slow dissociation from receptors. They block the action of agonists. (Antagonist = affinity, no efficacy). Examples: Prazosin, propranolol  Types of Antagonism  Antagonism could be chemical, physiological or pharmacological. 1. Pharmacological: A) Competitive Block: Antagonists bind REVERSIBLY with the receptors. Antagonists can be DISPLACED by excess agonists. B) Non-Competitive Block: If the antagonist binds to a site other than where the agonist binds, the interaction is noncompetitive or allosteric. Antagonist is NOT displaced by agonist. Types of Non-Competitive Block : a- REVERSIBLE : The antagonist binds REVERSIBLY to the receptor. Usually of Short duration of action. b- IRREVERSIBLE : The antagonist binds IRREVERSIBLY to the receptor. Usually of Long duration of action.  Types of Antagonism  Antagonism could be chemical, physiological or pharmacological. 2. Chemical antagonist: By combining with another drug and rendering it inactive. (e.g. Protamine neutralizes the anticoagulant effects of heparin by forming an inactive complex). 3. Physiologic antagonism: An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite to those of the agonist. This antagonism is also known as functional antagonist. (e.g. epinephrine antagonize the effect of histamine). 2- Partial Agonists = Dualists: They should have: Less maximum response (Emax) than agonists ; have efficacies (intrinsic activities) greater than zero, but less than that of a full agonist. They produce initial stimulation then block of the receptor. Example: Nicotine (NN). Cont. The drug-receptor theory Interaction of an agonist and antagonist with the receptors Molecule of Ac etylcholine Molecule of Ac etylcholine Muscarinic rec eptors Rec eptors are occupied by the in smmoth musc le ag onist and the musc el is stimulated Molecule of Ac etylcholine Atropine Rec eptors are bloc ked by atropine; acetylcholine has no effect Dose-Response Relationships  Dose-Response Relationships The magnitude of the drug effect depends on the drug concentration at the receptor site. As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The relationship between dose and response is a continuous one. Drug + Receptor Drug-Receptor Complex The response is a graded effect, meaning that the response is continuous and gradual. A graph of this relationship is known as a graded response curve. Plotting the magnitude of the response against increasing doses of a drug produces a graph that has the general shape shown in the following figure. The effect of dose on the magnitude of drug binding. The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose that shows fifty percent of maximal response. Drug A is more potent than Drug B because less Drug A is needed to obtain 50 percent effect.  Potency Potency is a measure of the amount of drug necessary to produce an effect of a given magnitude. EC50: The concentration producing an effect that is fifty percent of the maximum is used to determine potency. An important contributing factor to the dimension of the EC50 is the affinity of the drug for the receptor. By plotting the log of the concentration, the curves become sigmoid in shape. It is also easier to estimate the EC50.  Efficacy (intrinsic activity) This is the ability of a drug to produce a physiologic response when it interacts with a receptor. Efficacy is dependent on the number of drug-receptor complexes formed and the resulting cellular responses. The following Figure shows the response to drugs of differing potency and efficacy. Typical dose-response curve for 3 drugs showing differences in potency and efficacy. (EC50 = drug dose that shows fifty percent of maximal response.) Tolerance  Tolerance can be described as a decreased response to the usual dose of a drug after repeated administration.  Patient may need to increase dose to obtain the same effect.  It is sometimes described as desensitization or tachyphylaxis.  Dependence  This describes an aspect of drug abuse, which means that the individual is dependent on a certain drug.  When the drug is stopped, withdrawal symptoms occur. Dependence may be: a. Psychological dependence, e.g. tobacco smoking. b. Physical dependence, e.g. morphine, ethyl alcohol or barbiturates.  Drug-Drug Interactions When two drugs are administered together, one of the following phenomena could be observed: a) Additive effect: This occurs if the two drugs have similar effects. In this case, the effect produced due to the combined administration is equal to that produced by a double dose of an individual drug, i.e., 1+1=2. b) Synergism: Both drugs are biologically active, and when combined, the net effect is greater than the sum of their individual effects, i.e., 1+1>2.  Cont. Drug-Drug Interactions c) Potentiation:  It occurs when a drug which has no effect, by itself, increases the effect of another active drug, i.e., 0+1>1.  Example: Barbiturates potentiate the analgesic activity of salicylates although they have no analgesic action on their own. d) Antagonism: Discussed before.  Doses of Drugs 1- Therapeutic Dose: Average dose calculated for an Adult, Male, 20-60 year old & 70 Kg body weight. 2- Maximal Tolerated Dose; Highest dose without toxic effects. 3- Lethal or Fatal Dose: Dose that kill the patient or an experimental animal 4-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