Pharmacodynamics

 

·        Concept of receptor as mediators of drug actions.

·        Structure-activity relationship.

·        Mechanisms of action.

·        Drug-receptor interactions.

·        Stereoselectivity.

·        Graded and Quantal dose response.

·        Clinical potency and efficacy.

·        Therapeutic index.

·        Bioassay and standardization

 

Drug receptor theory

 

1.    Drug receptor: any component of a biological system that interacts with a drug and thereby leads to the drug effect.

 

2.    Drugs act by binding to receptors to alter its function selectively.

 

3.    Drug-receptor interaction follows the law of mass action:

                                                K1   

D + R ⇌ DR

      K2

 

4.    Affinity:

 

a.    A measure of the probability that a drug molecule will interact with its receptor to form a DR complex.

 

b.    At the same concentration, the drug with a higher affinity will form more DR complex than the drug with a lower affinity.

 

 

5.    Drug response:

 

a.    The response is elicited due to receptor occupation by the drug.

 

b.    The magnitude of the response is proportional to receptor occupancy, i.e. [DR].

 

6.    Intrinsic activity: a measure of the biological effectiveness of the DR complex the drug forms with its receptor.

 

7.    Receptor and disease:

 

a.    Autoimmune disease: in myasthenia gravis, the body produces antibodies that attack the nicotinic receptors at the neuromuscular junction.

 

b.    Receptor mutation can result in permanently altered level of effector activity: a mutation of the thyrotrophin receptor cause the effector system to be permanently switched on, leading to over-secretion of thyroid hormones.

 

8.    Receptor Polymorphism:

 

a.    Increasingly recognized to be important in pharmacology and therapeutics.

 

b.    Current attention is on the polymorphism of the drug metabolizing enzymes (cytochrome enzymes) leading to variations in the pharmacokinetics of a drug in different populations or individuals.

 

 

Structure-Activity relationship

 

1.    Receptor groups/sites: the chemical groups of the receptor that participate in the drug-receptor combination and the adjacent portions of the receptor that favor or hinder access of the drug to the active groups.

 

2.    Drugs and receptors interact via covalent or non-covalent bonds.

 

3.    Covalent bonding:

 

a.    Involves mutual sharing of electron pair with consequent high bond energy.

 

b.    Usually irreversible; e.g. MAO inhibitors and organophosphates.

 

c.    Often, the receptors are enzymes and catalyze the formation of the covalently bonded drug-receptor complex.

 

4.    Non-covalent bonding:

 

a.    Responsible for most drug-receptor interactions.

 

b.    Include: ionic bonds, hydrogen bonding, van der Waals forces and hydrophobic interactions.

 

c.    Usually reversible.

 

5.    Drug-receptor interactions involving these binding forces require the interacting moieties of the drug molecule to come into very close proximity with the appropriate interacting moieties of the receptor.

 

6.    The structural arrangement of the binding site of a given receptor thus imposes a strict structural requirement on the drugs that are able to interact or bind to this site.

 

 

Mechanisms of Drug Action

 

Site of drug action

Examples

Cell Membrane

Specific receptors

·        Morphine and Naloxone on opioid receptors.

·        Histamine and ranitidine on H2 receptors.

·        Epinephrine and propranolol on b-receptors.

Interference with ion flux across membranes.

·        Verapamil inhibiting Ca2+ across ‘L-type’ voltage-gated calcium channels.

·        Benzodiazepines binding on specific site on GABA/CI- complex, increasing its frequency of opening and CI- influx.

·        Sulphonylureas binding to ATP-dependent K+ channel decreasing K+ efflux.

Inhibition of membrane bound enzymes

·        Membrane-bound Na+-K+ ATPase by cardiac glycosides.

·        TCAs block pump by which amines are taken up into nerve cells.

·        Loop diuretics inhibit Na+-CI- cotransporter on apical membrane of renal tubular cells.

Physicochemical interactions

·        General and local anaesthetics act on lipid and protein components of nerve cell membranes.

Metabolic processes within the cell

Enzyme inhibition

·        Monoamine oxidase by phenelzine.

·        Xanthine oxidase by allopurinol.

·        Cholinesterase by pyridostigmine.

Inhibition of transport processes

·        Blockade of anion transport in renal tubule cell by probenecid to delay excretion of penicillin & enhance elimination of urate.

Incorporation into larger molecules.

·        5-fluorouracil is incorporated into mRNA in place of uracil.

·        Cytabarine is incorporated into mRNA in place of cytidine.

Structural analogues

·        Spironolactone is an analogue of aldosterone.

·        Sulphonamides are analogues of P-aminobenzoic acid (PABA).

·        Tamoxifen is an analogue of estrogen.

Mimicking natural hormones

·        Prednisolone as a glucocorticoid.

·        Diethylstilbesterol as estrogen.

·        L-Dopa is converted to dopamine in CNS.

Enhancing natural processes

·        Heparin activating antithrombin III.

·        Biguanides enhancing glucose uptake in peripheral tissues.

Altering metabolic processes

·        Inhibition of folic acid synthesis by trimethoprim.

·        Inhibition of synthesis of transcription factor that mediates cytokine signaling by corticosteroids.

·        Inhibition of transfer of mycolic acid to mycobacterial cell wall by ethambutol.

Outside cells

Direct chemical interaction

·        Antacids binding theophylline, tetracyclines, propranolol and phenytoin.

·        Cholestyramine binds digoxin, warfarin, thiazides and statins.

Osmosis

·        Magnesium sulphate increasing osmolality of intestinal lumen.

·        Mannitol increasing the osmolality of renal tubules.

 

 

Drug-Receptor Interactions

 

1.    Agonists:

 

a.    Interact with receptor and elicits a direct response.

 

b.    Activate receptors as they resemble the natural transmitter or hormone.

 

c.    Value in clinical practice rests on their greater capacity to resist degradation and to act for longer than the natural substances.

 

2.    Antagonists:

 

a.    Interact with receptor without eliciting a direct response.

 

b.    Occupy it without activating a response, thereby preventing the natural agonist from exerting its effect.

 

c.    Pure antagonists have no activating effect whatever on the receptor.

 

3.    Partial agonists:

 

a.    Some drugs, in addition to blocking access of the natural agonist to the receptor are capable of a low degree of activation.

 

b.    Produces a lower maximal response, at full receptor occupancy, than does a full agonist.

 

c.    Example: pindolol has intrinsic sympathomimetic activity.

 

4.    Inverse agonists:

 

a.    Produce effects that are specifically opposite to those of the agonist.

 

b.    Example: b-carbolines binding to benzodiazepine receptors in CNS to produce stimulation, anxiety, increased muscle tone and convulsions.

 

5.    Competitive antagonism:

 

a.    An antagonist that binds reversibly to a receptor can be displaced from the receptor by mass action of the agonist.

 

b.    Example: patients on b-blockers can raise their sympathetic drive to release enough norepinephrine to diminish the degree of receptor blockade.

 

6.    Non-competitive antagonism:

 

a.    Prevents the agonist from producing its maximal effect at a given receptor site.

 

b.    Results from irreversible binding of drug to receptor.

 

c.    Not surmountable.

 

d.    Restoration of the response after irreversible binding requires elimination of the drug from the body and synthesis of new receptor.

 

e.    Affinity of agonist for receptor is not diminished.

 

f.     Effect persist long after drug administration has ceased.

 

g.    Example: MAO inhibitors have short half-life, but their anti-depressant effects persist for weeks.

 

7.    Physiological Antagonism:

 

a.    Two drugs causing opposing effects that arise through different mechanisms.

 

b.    Example: the antagonist effects of acetylcholine and norepinephrine on the heart are mediated by both drugs acting as agonists on their respective cardiac receptors.

 

 

Stereoselectivity

 

1.    Many drugs, especially those of natural origin, exhibit chirality, i.e. a single drug existing as two enantiomers, the (-) S and (+) R isomers.

 

2.    Molecules that contain one or more chiral centers can exist in isomeric forms.

 

3.    Stereoisomers have identical chemical groups but they are not identical because the groups have different spatial arrangement.

 

4.    The pharmacological significance of stereoisomerism lies:

 

a.    Drug potency: S (-) warfarin is 4 times more potent than R (+) warfarin.

 

b.    Metabolism: R (+) propranolol is more extensively metabolized than S (-) propranolol.

 

5.    As stereoisomers exist commonly as racemic mixtures for therapy, the relative proportions of the two stereoisomers will affect drug potency in various drug brands and formulations.

 

 

Graded and Quantal dose response

 

Graded dose response

Quantal dose response

·        A response that varies in magnitude in a dose-dependent manner.

·        All-or-none response: dose of drug required a specified magnitude of effect in a large number of individuals.

·        Used for measurable variables: blood pressure, heart rate, diuresis.

·        Used for nominal variables: convulsions, pain relief, deaths.

·        EC50: concentration of drug that produces 50% of maximal effect.

·        ED50: dose at which 50% of individuals exhibit specified quantal effect.

·        Curve: drug effect against log of concentration or dose.

·        Curve: number of individuals who exhibit effect against log of concentration or dose.

·        Tells us about the potency and maximum efficacy of a drug.

·        Use to generate information on the margin of safety to be expected from a particular drug used to produce a specific effect.

 

 

Clinical Potency and Efficacy

 

Potency

Efficacy

·        Dose required to produce a given degree of response; the lower the dose.

·        The lower the dose required; the higher the potency.

·        Measured by EC50.

·        Capacity of a drug to produce an effect and refers to the maximum such effect.

·        Depends on affinity of the drug for binding and the intrinsic activity of the drug-receptor complex.

·        However, a large part depends on pharmacokinetic process that determine drug concentration at receptor site.

·        Depends more on its intrinsic ability to trigger off a secondary response mediated by the drug-receptor complex rather than on pharmacokinetic processes.

·        This ability lies in the inherent properties of the drug, the drug-receptor binding and the intrinsic activity of the complex formed.

·        Used to compare between two drugs that produce similar effects.

·        Relative potency: the ratio of doses of two drugs needed to produce the same magnitude of the specified effect.

·        Tells us nothing about the dose.

·        Simply an indication of a drug’s maximal effect.

·        A drug with high efficacy produces a greater maximal effect than a drug with a lower efficacy.

·        A potent drug may not have a high therapeutic efficacy.

·        A drug with high efficacy may not be potent if it requires a large dose to elicit the desired response.

 

 

Therapeutic Index

 

1.    The dose of a drug required to produce a desired effect to that which produces an undesired effect.

 

2.    An indication of a drug’s potential to cause toxic effects.

 

3.    Therapeutic index (TI) can be calculated from the following equation:

 

TI = TD50 / EC50

 

TD50: the dose that produces toxic effects in 50% of patients treated with the drug.

EC50: the dose that produces a stated therapeutic effect in 50% of patients treated with the drug.

 

4.    Drugs with low therapeutic index must be used with extra caution and requires constant monitoring to detect any possible adverse effects, e.g. digoxin, methotrexate.

 

5.    However, this does not mean that drugs with a high therapeutic index are completely safe and without side effects, e.g. diazepam causes drowsiness and hangover at therapeutic doses.

 

6.    The therapeutic index of a drug can be different if it is being used for different therapeutic effects, e.g. aspirin as an antiplatelet drug has a much higher therapeutic index than aspirin as an anti-rheumatic drug.

 

 

Bioassay and Standardization

 

1.    Biological assay (bioassay) is the process by which the activity of a substance is measured on living material.

 

2.    It is used only when chemical or physical methods are not practiceable as in the case of a mixture of active substances, or an incompletely purified preparation, or where no chemical method has been developed.

 

3.    Biological Standardization:

 

a.    A specialized form of bioassay.

 

b.    It involves matching of material of unknown potency with an International or National Standard with the objective of providing a preparation for use in therapeutics and research.

 

c.    The results are expressed as units of a substance, e.g. insulin, vaccines.

 

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