Contents Pharmacodynamics ................................................................................................................... 3

Drug action ................................................................................................................................ 3

Principles of Drug action ............................................................................................................ 3

Stimulation ............................................................................................................................. 3

Depression ............................................................................................................................. 3

Replacement .......................................................................................................................... 3

Cytotoxic action ...................................................................................................................... 3

MODE AND MECHANISM OF ACTION ..................................................................................... 3

Through enzymes ............................................................................................................ 3

Through receptors ........................................................................................................... 3

Physical action ................................................................................................................ 3

Chemical action ............................................................................................................... 3

RECEPTOR ............................................................................................................................... 3

Agonist & Antagonist .................................................................................................................. 3

Agonist ................................................................................................................................... 3

Antagonist .............................................................................................................................. 3

Inverse agonist ....................................................................................................................... 4

Partial agonist ......................................................................................................................... 4

Affinity & Intrinsic activity ............................................................................................................ 4

Affinity: ................................................................................................................................... 4

Intrinsic activity: ...................................................................................................................... 4

Agonist ....................................................................................................................................... 4

Antagonist .................................................................................................................................. 4

Inverse agonist........................................................................................................................... 4

Partial agonist ............................................................................................................................ 4

Drug-Receptor interaction .......................................................................................................... 4

Assessment of Receptor Occupation ......................................................................................... 4

Measure of Affinity .................................................................................................................. 4

Drug-receptor interaction ........................................................................................................ 5

Classification of receptors .......................................................................................................... 5

Ion channels ........................................................................................................................... 5

DOSE RESPONSE CURVE ....................................................................................................... 5

Potency .................................................................................................................................. 5

Efficacy ................................................................................................................................... 5

Quantal dose response curves ................................................................................................... 6

Synergism .................................................................................................................................. 6

1. Additive effect: ................................................................................................................. 6

2. Supraadditive effect (potentiation): .................................................................................. 6

Antagonism ................................................................................................................................ 6

1. Physical: .......................................................................................................................... 6

2. Chemical: ........................................................................................................................ 6

3. Physiological antagonism ................................................................................................ 7

4. Receptor antagonism ...................................................................................................... 7

Upregulation of Receptors ......................................................................................................... 7

Factors affecting Drug Action ..................................................................................................... 8

Body Size/Wt .......................................................................................................................... 8

Age ......................................................................................................................................... 8

Route of drug administration ................................................................................................... 9

Pathological states ................................................................................................................. 9

Co-administration of other drugs ............................................................................................. 9

PHARMACODYNAMICS

General Concepts Introduction Pharmacodynamics: Study of the biochemical and physiologic effects of drugs and their mechanisms of action. Drug action The main ways by which drugs act are via interaction with cell proteins, namely receptors, ion channels, enzymes and transport/carrier proteins. In addition, drugs can work by themselves mechanically or chemically. Its useful to know what are the basic principles of drug action. Principles of Drug action Stimulation: Enhancement of the level of a specific biological activity (usually already ongoing physiological process). E.g. adrenaline stimulates heart rate. Depression: Diminution of the level of a specific biological activity (usually already ongoing physiological process). E.g. barbiturate depress the CNS. Replacement: Replacement of the natural hormones or enzymes (any substance) which are deficient in our body. E.g. insulin for treating diabetes. Cytotoxic action: Toxic effects on invading micro organisms or cancer cells. MODE AND MECHANISM OF ACTION A drug can produce all the said effects by virtue of any of the following action

Through enzymes: a drug can act by either stimulating or inhibiting an enzyme Through receptors: this is when a drug produces its response by attaching itself to a

protein called as receptor which in turn regulates the cell function. Receptor action is the most commonest way of producing action. Physical action: The physical property is responsible for drug action. E.g. radioisotope

I131 and other radioisotopes. Chemical action: The drug reacts extracellularly according to simple chemical

equations. E.g. antacids neutralising the gastric acid. RECEPTOR The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters and hormones. This class of receptors mediates the effects of many of the most useful therapeutic agents. Word ―Receptor‖ is used as a loose term Other Receptors Other classes of proteins that have been identified as drug receptors include

1. Enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate)

2. Transport proteins (eg, Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides)

3. Structural proteins (eg, tubulin) Agonist & Antagonist When a drug binds to a receptor the following can occur and based on this the drugs are classified. Agonist: when a drug binds to the receptor and activates it to produce an effect Antagonist: when a drug binds to a receptor and prevents the action of an agonist, but does not have an action on its own. Other terms

Inverse agonist: when a drug activates a receptor to produce an effect in the opposite direction to that of the agonist Partial agonist: when a drug binds to the receptor and activates it but produces a submaximal effect (by antagonising the full effect of the agonist) Affinity & Intrinsic activity Affinity: It is the ability of a drug to bind to the receptor (just bind) Intrinsic activity: It is the ability of a drug to activate a receptor following receptor occupation. Terms revisited Agonist Agonists are the chemicals that interact with a receptor, thereby initiate a chemical reaction in the cell and produces effect . Example—ACh is agonist at muscarinic receptor in heart cell. Will have both Affinity and maximal Intrinsic activity So, what is a receptor ―agonist‖?

Any drug that binds to a receptor and stimulates the functional activities e.g.: Ach Antagonist A drug that binds to the receptor and blocks the effect of an agonist for that receptor Atropine is antagonist of ACh at Muscarinic receptors. Will have only Affinity but no Intrinsic activity So, what is a receptor ―antagonist‖?

Any drug that prevents the binding of an agonist eg: Atropine (an anticholinergic drug)

Inverse agonist Inverse Agonists are the chemicals that interact with a receptor, but produces opposite effect of the well recognized agonist for that receptor Will have Affinity and negative Intrinsic activity Example: Flumazenil is an inverse agonist of Benzodiazepine Inverse agonist Any drug that binds to a receptor and produces an opposite effect as that of an agonist Partial agonist Partial agonist activates receptor to produce an effect. Less response than a full agonist . Partial agonist blocks the agonist action. Will have Affinity but sub maximal Intrinsic activity Partial agonist Produces a submaximal response Major Concepts Drugs often work by binding to a ―receptor‖ Receptors are found in the cell membrane, in the cytoplasm, and in the nucleus Anything that binds to a receptor is a ―ligand‖ Drug-Receptor interaction In most cases, a drug (D) binds to a receptor (R) in a reversible bimolecular reaction Antagonists can bind to the receptor and occupy its binding site and, therefore, participate only in the first equilibrium. Agonists, on the other hand, have the appropriate structural features to force the bound receptor into an active conformation (DR*). This conformational change leads to a series of events causing a cellular response. Assessment of Receptor Occupation Measure of Affinity kd is a relative measure of affinity of a drug for its receptor. It varies inversely with the affinity of the drug for its receptor

High-affinity drugs have lower kd values and occupy a greater number of drug receptors than drugs with lower affinities. Drug-receptor interaction Generally the intensity of response increases with dose The drug receptor interaction obeys the law of mass action Emax X [D] KD+[D] Law of mass action E is observed effect at dose [D] of a drug Emax is the maximal response KD is the dissociation constant of a drug receptor complex KD is usually equal to the dose of a drug at which half maximal response is produced Classification of receptors

G-protein coupled receptors Ion channels Enzymatic receptors Intracellular receptors (regulates gene expression)

Ion channels The cell surface enclose ion channels specific for Ca2+, K+, or Na+ These ion channels are controlled by the receptors E.g. Gs opens Ca2+ channels in the myocardium and skeletal muscle and Gi opens the K+ channels in heart Some receptors also modulate the ion channels without the intervention of coupling proteins or 2nd messengers E.g. benzodiazepines modulating Cl- channels in the brain Ion channels Dose-response relationship Dose Vs Response Increases in response until it reaches maximum, Later it remains constant despite increase in dose .. Plateau effect DOSE RESPONSE CURVE Log dose response curve The dose response curve is a rectangular hyperbola If the doses are plotted on a logarithmic scale, the curve becomes sigmoid A linear relationship between log of dose and the response can be seen Efficacy and Potency Efficacy is the maximal response produced by a drug It depends on the number of drug-receptor complexes formed Potency is a measure of how much drug is required to elicit a given response The lower the dose required to elicit given response, the more potent the drug is ED50 It is the dose of the drug at which it gives 50% of the maximal response A drug with low ED50 is more potent than a drug with larger ED50 Efficacy and Potency Potency Dose of a drug that required to produce 50% of maximal effect (ED 50) Relative Positions of the DRC on x-axis More left the DRC, more potent the drug Efficacy Maximum effect of the drug

Height of the curve on x-axis indicates the efficacy of the drug Taller the DRC ,more efficacious the drug Quantal dose response curves The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect. Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50) If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined Quantal dose-effect curves are used to generate information regarding the margin of safety (Therapeutic index) Quantal DRC Therapeutic index Therapeutic index (TI) Lethal dose (LD50) is estimated only in preclinical animal studies LD50 is not calculated in humans-OFCOURSE So we use the term ―safety margin‖ of a drug or ―therapeutic window‖ Therapeutic window It is a more clinically relevant index of safety It describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose E.g. theophylline has an average minimum plasma conc of 8 mg/L and the toxic effects are observed at 18 mg/L The therapeutic window is 8 – 18 mg/L Clinical significance Drugs with a low TI should be used with caution and needs a periodic monitoring (less safe) E.g. warfarin, digoxin, theophylline Drugs with a large TI can be used relatively safely and does not need close monitoring (highly safe) E.g. penicillin, paracetamol Other terms used: wide safety margin, narrow safety margin Combined effect of drugs Synergism and antagonism When two drugs are given together or in quick succession 3 things can happen:

1. Nothing (indifferent to each other) 2. Action of one drug is facilitated by the other (synergism) 3. Action of one drug may decrease or inhibit the action of other drug (antagonism)

Synergism Two types:

1. Additive effect: the effect of two drugs are in the same direction and simply add up. Effect of drug A + B = effect of drug A and B

2. Supraadditive effect (potentiation): the effect of combination is greater than the individual effect of the components.

Effect of drug A + B > effect of drug A + effect of drug B Antagonism Different types of antagonism

1. Physical: based on physical property of a drug. E.g. activated charcoal adsorbs alkaloids and prevents their absorption (in alkaloid poisoning)

2. Chemical: based on chemical properties resulting in an inactive product. E.g. chelating agents complex metals (used in heavy metal poisoning) Contd..

3. Physiological antagonism: two drugs act on different receptors or by different mechanisms, but have opposite effects

E.g. histamine and adrenaline on bronchial smooth muscle and BP E.g. several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin.

4. Receptor antagonism This when an antagonist interferes with the binding of the agonist with its receptor and inhibits the generation of a response Receptor antagonism is specific E.g. an anticholinergic will decrease the spasm of intestine induced by cholinergic agonists but not the one induced by histamine Receptor antagonism can be competitive and noncompetitive Competitive antagonism Competitive --- Surmountable Competes with agonist in reversible fashion for same receptor site Necessary to have higher concentration of agonist to achieve same response Competitive agonist Noncompetitive antagonism Noncompetitve --- Insurmountable Antagonist binds to a site different to that of an agonist No matter how much agonist -- antagonism cannot be overcome Competitive Vs Noncompetitive Antagonism COMPETITIVE Antagonist binds with same receptor Chemical resemblance with agonist Parallel rightward shift of DRC Apparently reduces potency of agonist Intensity of response depends both on antagonist and agonist concentration Eg: Acetylcholine and Atropine NONCOMPETITIVE Another site of receptor binding Does not resemble Flattening of DRC Apparently reduces efficacy of agonist Intensity of response depends mainly on antagonist concentration Eg: phenoxybenzamine (for pheochromocytoma) Receptor Numbers and Responses The NUMBER and AFFINITY of receptors may change An increase in receptor number is called UPREGULATION A decrease in receptor number is called DOWNREGULATION Upregulation of Receptors Upregulation: An increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent. 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 Downregulation of Receptors Eg: Downregulation:

prolonged use of propranolol can DECREASE the number of 1 receptors

Prolonged & frequent use of short acting 2 receptor agonists decrease the number of 2 receptors Clinical relevance:

A patient’s response to drug therapy may change over time Tolerance Gradual reduction in response to drugs is called as tolerance Requirement of higher dose to produce a given response It occurs over a period of time E.g. tolerance to sedative-hypnotics Many reasons for tolerance

1. Pharmacokinetic reasons-chronic use leads to enhanced clearance-less effective concentration

2. Pharmacodynamic reasons (reduced number and/or affinity of the receptors to the drugs)-downregulation

Tachyphylaxis Rapid desensitization to a drug produced by inoculation with a series of small frequent doses. A rapidly decreasing response to a drug following its initial administration E.g. ephedrine, tyramine, nicotine. Spare receptors In some cases, the response elicited by a drug is proportional to the fraction of receptors occupied More commonly, a maximal response can be achieved when only a small fraction of receptors are occupied by an agonist Receptors are said to be spare when maximal response can be elicited by an agonist at a conc. that does not result in occupancy of the full complement of available receptors No qualitative difference form non spare receptors Graphical representation of a spare receptor (refer to notes section below for explanation) Spare receptors, KD and EC50 KD is the concentration of the agonist at which 50% of the receptors are occupied If the number of receptors increase many fold (spare receptors) THEN: A much lower concentration of agonist is sufficient to produce 50% of maximal response (EC50) Occupation of spare receptors is determined by comparing the EC50 with Kd If EC50 is less than Kd, spare receptors are said to exist Factors affecting Drug Action It is a rule rather than an exception that there is a large variation in the drug response for the same dose in different individuals. Pharmacokinetic handling of the drug Number or state of receptors Variations in neurogenic/hormonal tone Body Size/Wt. The average adult dose refers to individuals of medium built For exceptionally obese and lean and for children the dosage should be calculated based on body wt. Individual Dose = BW (Kg)/70 x average adult dose Dosage calculation based on surface area more appropriate for children Age Extreme care has to be taken while administering drugs to children and elderly Drug metabolizing enzymes are very poor and in case of elderly they might have some other diseases Reduced doses are ideal for these age groups. Genetics Deficiency of some enzymes may lead to drug toxicity because of poor or absence of metabolism

Route of drug administration IV route has quicker and prominent action when compared to oral route Psychological role is also a major determinant of drug effect Pathological states Any underlying pathology may alter the drug response Special care is taken if the patient has renal or hepatic impairment as the drugs are not eliminated and it may lead to severe drug toxicity. Alzheimer’s disease – memory loss- failure to take medications Co-administration of other drugs One drug may affect the drug action of others, it may be useful or it may be harmful. Drug interactions play a very important part of therapeutics. Diet & environmental factors too play a important role in deciding the drug action.