Pharmacodynamics PDF

Pharmacodynamics Introduction Pharmacodynamics denotes the actions of the drug on the body biologic systems, including its mechanism of action and therapeutic and toxic effects. Drugs mainly act through receptors but may act also through other mechanisms...

Pharmacodynamics Introduction Pharmacodynamics denotes the actions of the drug on the body biologic systems, including its mechanism of action and therapeutic and toxic effects. Drugs mainly act through receptors but may act also through other mechanisms e.g., physical (mannitol), chemical (sodium bicarbonate), cell membrane (lidocaine), cell division (cisplatin) or enzyme (digoxin). Receptors: specific molecules in a biologic system with which drugs interact to produce changes in the function of the system Receptors Most drug actions are mediated through the effects of drug (ligand) molecules on drug receptors in the body. Most receptors are large regulatory molecules that influence important biochemical processes (eg, enzymes involved in glucose metabolism) or physiologic processes (eg, ion channel receptors, neurotransmitter reuptake transporters, and ion transporters). Most are proteins; a few are other macromolecules such as DNA. The receptor site (AKA the recognition site) for a drug is the specific binding region of the receptor macromolecule and has a relatively high and selective affinity for the drug molecule. Effectors are molecules that translate (signal) the drug-receptor interaction into a change in cellular activity. The best examples of effectors are enzymes such as adenylyl cyclase. Some receptors are also effectors because a single molecule may incorporate both the drug-binding site and the effector mechanism. For example, a tyrosine kinase effector enzyme is part of the insulin receptor molecule, and a sodium-potassium channel is the effector part of the nicotinic acetylcholine receptor molecule. 1  Receptor Transmembrane Signaling N.B. Example of JAK-STAT receptors ligands are cytokines and most antiarrhythmic drugs target voltage-activated ion channels in the membrane for sodium, potassium, or calcium. Non-transmembrane-signaling mechanisms receptor-effector system may be an enzyme in the intracellular space (eg, soluble guanylyl cyclase, a target of nitric oxide) or in the membrane or extracellular space (eg, acetylcholinesterase). Neurotransmitter reuptake transporters (eg, the serotonin transporter, SERT; and the dopamine transporter, DAT) are receptors for many drugs, eg, antidepressants and cocaine. DRUG-RECEPTOR INTERACTIONS Current concepts of drug-receptor interactions consider the receptor can assume 2 conformations, Ri and Ra. In the Ri state, it is inactive and produces no effect, even when combined with a drug 2 (D) molecule. In the Ra state, it activates its effectors and an effect is recorded, even in the absence of ligand. In the absence of drug, the equilibrium between Ri and Ra determines the degree of constitutive activity. N.B. Allosteric agonist & allosteric antagonist: A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist 3 Drugs (ligands) bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker reversible electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds). If drug-receptor binding results in activation of the receptor molecule, the drug is termed an agonist; if inhibition results, the drug is termed an antagonist. Some drugs mimic agonist molecules by inhibiting metabolic enzymes that degrade endogenous agents, e.g., acetylcholinesterase inhibitors. Constitutive activity: Activity of a receptor-effector system in the absence of an agonist ligand Inverse agonist: A drug that binds to the nonactive state of a receptor molecule and decreases constitutive activity, i.e. has a higher affinity for the inactive Ri state than for Ra and decrease or abolish any constitutive activity. A full agonist is a drug capable of fully activating the effector system when it binds to the receptors and it has high affinity for the activated receptor conformation A partial agonist produces less than the full effect, even when it has saturated the receptors, i.e. regardless of the dose. In the presence of a full agonist, a partial agonist acts as an inhibitor. Biased agonism An agonist that activates the same receptor as other drugs “balanced agonists” in its group but also select which signaling pathways become activated upon binding to the receptor causing additional downstream effects that are not seen with other agonists in the group e.g. carvedilol. The mechanism of this effect is not understood but may involve changes induced in the conformation of the receptor that differ with different agonists. Pharmacologic antagonist: A drug that binds to the receptor without activating it and thereby prevents activation by an agonist: Competitive antagonist: A pharmacologic antagonist that can be overcome by increasing the concentration of agonist (Acetylcholine & Atropine) 4  Irreversible/ allosteric antagonist: A pharmacologic antagonist that cannot be overcome by increasing agonist concentration (Epinephrine & Phenoxybenzamine), it binds to the receptors by strong covalent bonds. Physiologic antagonist: A drug that counters the effects of another by binding to a different receptor and causing opposing effects (Histamine & Epinephrine) Chemical antagonist: A drug that causes chemical deactivation of another drug (protamine sulfate & heparin) RECEPTOR REGULATION Receptors are dynamically regulated in number, location, and interaction with other molecules. Changes can occur over short times (seconds to minutes) and longer periods (days). Frequent or continuous exposure to agonists often results in short-term reduction of the response, sometimes called tachyphylaxis. N.B. long term reduction of the response is called tolerance. Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) may occur when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation. Tachyphylaxis (tolerance) may be caused by:  Intracellular molecules may block access of a G protein to the activated receptor molecule. For example, the molecule β-arrestin has been shown to bind to an intracellular loop of the β adrenoceptor when the receptor is continuously activated.  Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules e.g. morphine receptors and beta- adrenoceptors. 5  Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects. For example, depletion of endogenous thiol cofactors may be responsible for tolerance to nitroglycerin. In some cases, repletion of the missing substrate (eg, by administration of glutathione) can reverse the tolerance. Graded dose-response curve A graph of the increasing response to increasing drug concentration or dose The efficacy (Emax) and potency (EC50 or ED50) parameters are derived from these data. EC50, ED50, TD50 is the concentration or dose that causes 50% of the maximal effect (E) or toxicity (T). The smaller the EC50 (or ED50), the greater the potency of the drug. The therapeutic index & window The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose. The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. 6  Quantal dose-response curve A graph of the increasing fraction of a population that shows a specified response at progressively increasing doses EC50, ED50, LD50 is the concentration or dose that causes a specified response in 50% of the population under study 7  The therapeutic index & window The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose. The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. Spare receptors Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than 100% occupation of the receptors (Bmax). In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd). If the EC50 is less than the Kd, spare receptors are said to exist. This might result from one of two mechanisms. First, the duration of the effector activation may be much greater than the duration of the drug-receptor interaction. Second, the actual number of receptors may exceed the number of effector molecules available. Spare receptors increase sensitivity to the agonist. 8  Adverse drug reactions The beneficial effects of drugs are coupled with the inescapable risk of untoward effects. The morbidity (hospitalizations) and mortality from these ADRs often present diagnostic problems because they can involve every organ and system of the body and may be mistaken for signs of underlying disease. N.B. The most common “adverse” drug effect may be failure of efficacy. Teratogenic means induction of congenital malformation, iatrogenic means doctor induced whether due to malpractice or not. ADRs can be classified in two broad groups. Type A reactions result from exaggeration of an intended pharmacologic action of the drug, such as increased bleeding with anticoagulants or bone marrow suppression with some antineoplastics and tend to be dose-dependent or drug interactions. Type B reactions result from toxic effects unrelated to the intended pharmacologic actions. The latter effects are often unanticipated (especially with new drugs) and frequently severe and may result from recognized (often immunologic as penicillin induced hemolytic anemia and heparin induced thrombocytopenia, also allergic including anaphylaxis) as well as not fully comprehended mechanisms leading to rapid, rare and serious (idiosyncratic) ADRs, such as hematologic abnormalities, arrhythmias, severe skin reactions, or hepatic or renal dysfunction. Type B reactions may occur at low dosages and are often termed dose-independent and it’s very important to stress that prescribers need to be cautious in the prescription of new drugs and alert for the appearance of previously unrecognized ADRs. Drug-drug interactions Could lead to addition (alcohol and CNS depressants), potentiation e.g. (caffeine and paracetamol), synergism (penicillin and garamycin) or antagonism (antacids and tetracyclines). 9