Pharmacodynamics (Mode of Action of Drugs) nist prevents the action of an agonist on a receptor, but does not have any effect of its own (Fig 1.5.1) Receptors are mostly protein macromolecules The cholinergic, adrenergic, histaminergic and other receptors are ‘physiological receptors’ on which certain drugs act which mediate the responses to transmitters, autacoids etc Another type of receptor is ‘drug receptors’, which not have any known physiological ligands, for example thiazide receptor, benzodiazepine receptor etc + Agonist Receptor Agonistreceptor interaction Response + Antagonist Receptor Antagonist- No response receptor interaction Fig 1.5.1: Drug-receptor interaction: The agonist completely fits (interact) with the receptor site to produce a pharmacological response and antagonist only partially fit with the receptor site and is unable to produce any pharmacological response, and also prevents the agonist from combining with the receptors The ability of a drug to get bound to a receptor is termed as the ‘affinity of the drug’ for the receptor The ability of the drug to produce a pharmacological response after its interaction with the receptor is known as ‘intrinsic activity of the drug’, it also determines the degree of receptor response The agonists produce a maximal receptor response (high intrinsic activity), partial agonists have intermediate intrinsic activity and antagonists have low intrinsic activity and high affinity for the receptors 43 On the basis of affinity and efficacy, the drugs can be classified as agonists, which have both affinity as well as high intrinsic activity and can mimic the effects of the endogenous substance after combining with the receptor (e.g methacholine produces the effect of acetylcholine at cholinergic receptors) Antagonists have only the affinity but no intrinsic activity These drugs bind to the receptor, but not mimic (rather block) or interfere with the binding of an endogenous agonist (e.g atropine block the effect of acetylcholine on cholinergicmuscarinic receptors) Partial agonists have full affinity to the receptor but with lower intrinsic activity [e.g pentazocine is a partial agonist at µ receptor (subtype of opioid receptor)] Inverse agonist or negative antagonists have full affinity towards the receptor but their intrinsic activity is absolutely negligible and may be zero or in minus RECEPTOR TYPE On the basis of molecular structure and nature of transduction mechanism, receptor can be classified into following categories: i ii iii iv v G-protein and second messengers Ligand-gated channels Cytokine receptors Tyrosine kinases Intracellular receptors COMBINED EFFECT OF DRUGS SYNERGISM When two drugs are given simultaneously, and the action of one drug is increased by the other, they are treated as Section 1/ General Principles of Pharmacology 44 synergistic In the synergism, the drugs can have action in the same direction or when given alone, one may be inactive Synergism can be additive or supradditive in nature ADDITIVE When the effect of two drugs are in the same direction For example when aspirin is combined with paracetamol the combined effect is analgesic/antipyretic Another important example is combination of theophylline and ephedrine as bronchodilator, combination of sulfonamides as antibacterial etc SUPRADDITIVE In this the effect of combined therapy is greater than the individual effect of the one drug Examples are: • Levodopa and peripheral dopadecarboxylase inhibitor, carbidopa or benserazide in the treatment of parkinsonism • Sulfonamide and trimethoprim (well known preparation ‘Septran’) as antibacterial cyanomethaemoglobin and after sodium thiosulphate injection forms sodium thiocyanate which is easily excreted in urine On receptor basis, drug antagonism will be of two types competitive and noncompetitive antagonism COMPETITIVE ANTAGONISM In competitive antagonism, the antagonist binds with the same receptor as agonist If the log dose response curve with agonist is obtained in the presence of antagonist, it will be found that antagonist has no effect of its own and there is parallel rightward shift in the dose response curve of agonist (Fig 1.5.2) with no change in shape, slope or maximum response In competitive antagonism, the antagonist reduces affinity i.e potency of the agonist Example of competitive antagonism are: • Acetylcholine (as agonist) – atropine (as antagonist) • Acetylcholine – d-tubocurarine • Isoprenaline – propranolol DRUG ANTAGONISM Antagonism describes the situation, when one drug decreases or inhibits the action of another The antagonism may be physical in which the physical property of the drug can affect the absorption of another drug, chemical in which two drugs react chemically and form a biologically inactive compound This type of reaction may be used in the treatment of drug poisoning For example in cyanide poisoning nitrites form methaemoglobin which has high affinity for cyanide radical and forms Fig 1.5.2: Log dose response curve showing competitive antagonism tterer p p a h CCh 1.6 1.4 Adverse Drug Reactions ADVERSE DRUG REACTIONS Adverse drug reaction is an undesired or unintended effect of the drug, occurs at dose normally used by human being The adverse drug reaction requires treatment or decrease in dose if it is due to poisoning or overdose Adverse drug reaction may be defined as ‘any response to a drug which is noxious (injurious) and unintended, and which occurs at doses of an appropriately given drug used in man for prophylaxis, diagnosis or therapy excluding therapeutic failures.’ Adverse drugs reactions are not rare and have increased in number, which may be due to irrational use of multiple drug therapy, availability of most of the drugs as OTC (over the counter) i.e without prescription and self medication by the patients Adverse effects can be based on the pharmacodynamics of the drug i.e side effects (occur at therapeutic dose of the drug), toxic effects (occurs at overdose or poisoning) and drug withdrawal symptoms (i.e withdrawal of narcotic drugs) and secondly, the effects which are individual to individual like drug allergy (hypersensitivity to drugs), idiosyncracy Other types are teratogenicity (drug causing foetal abnormalities), carcinogenicity (drug causing cancer), iatrogenicity (drug induced diseases) SIDE EFFECTS There are undesirable and unavoidable pharmacological effect of the drug, which occur at therapeutic dose These unwanted effects of many drugs are based on their pharmacological actions Some important examples are: • Atropine causes dryness of mouth as side effect which is due to its antisecretory effect, and due to this action atropine is used in peptic ulcer • Acetazolamide (a carbonic anhydrase inhibitor) used as diuretic by increasing bicarbonate excretion and thus acidosis occur as side effect which is related to its pharmacological action ... react chemically and form a biologically inactive compound This type of reaction may be used in the treatment of drug poisoning For example in cyanide poisoning nitrites form methaemoglobin which... For example in cyanide poisoning nitrites form methaemoglobin which has high affinity for cyanide radical and forms Fig 1.5.2: Log dose response curve showing competitive antagonism tterer p p... preparation ‘Septran’) as antibacterial cyanomethaemoglobin and after sodium thiosulphate injection forms sodium thiocyanate which is easily excreted in urine On receptor basis, drug antagonism will