7. Pharmacodynamics

PharmacodynamicsPharmacodynamics describes the actions of a drug on the body and includes-

The principles of receptor interactions Mechanisms of the therapeutic & toxic

actions Dose-response relationships

Relationship between pharmacokinetics and Pharmacodynamics

The pharmacokinetic processes of absorption, distribution, metabolism and excretion determine how quickly and to what extent a drug will appear at a target site.

Pharmacodynamics concepts explain the pharmacological effects of drugs and their mechanism of action.

Figure: The relationship between pharmacokinetic and pharmacodynamic components.

ReceptorsAre protein macromolecules on the surface or within the cell that combine chemically with either an endogenous ligand or a drug to mediate a physiologic or pharmacologic effect.

Must be selective in their ligand-binding characteristics.

Drug + Receptor Drug-receptor complex

Biologic effect

Receptor interactions

There are mainly two functions of receptors:- Ligand or drug binding (receptor: things

that receive)Ligands are molecules which attach selectively to a particular receptor. It may be (drug, hormone, neurotransmitter) by different chemical interactions (covalent, ionic, hydrogen, Van der Waals)Ligand is any chemical substance that combines with the receptors and produce an effect.

- Activation of an effector system (message propagation)The signal from the ligand to several subcellular elements e.g. enzymes, second messenger, or ion channels ► intra-cellular biochemical response

EffectorsAre molecules that translate the drug-receptor interaction into a cellular activity. Commonly there are four types of effector mechanisms:

Figure: Known effector mechanisms.

1. IntracellularLipid soluble drugs or diffusible agents can cross cell membrane. For example thyroid and steroid hormones, nitric oxide, vitamin D.

These drugs can binds to cytosolic or nuclear receptors to form complexes (effectors) and interact with DNA to changes in protein synthesis in target tissues.

2, 3. TransmembraneSome ligands such as insulin bind to receptors that have both an extracellular and intracellular component. Binding of the extracellular component stimulates the intracellular component, which is coupled to an enzyme for example tyrosine kinase.

Binding of the ligand (for example insulin) ► activation of cytoplasmic tyrosine kinase enzyme ► phosphoryation of target proteins. i.e. Some receptors can also act as an effectors e.g. tyrosine kinase effector is part of the insulin receptor.

4. Ligand-gated ion channelsDrugs binds to these receptors, which then alter the conductance of ions through the cell membrane channels.

Ach + Nicotinic receptors ► Open Na+ channelsGABA + GABAA receptors ► Open Cl- channels

Simultaneous binding of two acetylcholine (ACh) molecules to the two α-subunits results in opening of the ion channel, with entry of Na+ (and exit of some K+), membrane depolarization, and triggering of an action potential.

5. Second messenger systemDrugs binds to receptors, that activate second messenger systems involving G proteins.

The receptor facilitates activation of G-protein (Guanine nucleotide binding protein) ► regulate activity of adenylyl cyclase enzyme (effector) ► change in the synthesis of cAMP from ATP.

e.g. Dopamine receptors, α & β adrenergic receptors, muscarinic receptors, opiate receptors.

Best known second messengers are: cAMP, Ca+

+ ion, cGMP, inositol triphosphate, DAG.

Agonist- An agonist is a drug capable of fully activating the effector system when it binds to the receptors.- Drugs mimic the endogenous regulatory substances such as neurotransmitter or hormone.- Drugs which stimulate the receptors.- Has affinity and efficacy.

Mechanisms of the therapeutic & toxic actions

Affinity: The chemical forces that cause the drug to associate with the receptor.

Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.

Dissociation constant (Kd):Measure of a drug’s affinity for a given receptor.Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors.

The smaller the Kd the greater the affinity of the drug for its receptor.

Spare receptors:If the maximal drug response is obtained at less than maximal occupation of the receptors.If the EC50 is less than Kd, spare receptors are said to exist. i.e. to achieve 50% of maximum effect, fewer than 50% of the receptors must be activated.

Spare receptors

Full agonistStrong affinityStrong intrinsic activity

Partial agonistStrong affinityWeak intrinsic activity

Log concentration [A]

Full agonist

Partial agonist

% o

f max

imum

eff

ect

100 ……………………………………………

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Antagonist- Drugs bind to receptors without directly altering the receptor function, but it prevents the binding and blocks the biologic actions of agonist molecules.- Drugs which block the receptors.- They have affinity but no efficacy.- They prevent the action of agonist.

Full antagonistStrong affinityNo intrinsic activity

Partial antagonistStrong affinityWeak intrisic activity

Pharmacologic antagonists1. Reversible competitive antagonists: - Antagonist compete with ligand or agonist for the same receptor.- Reversibly bind to receptors.- Can be displaced by excess agonist (conc. dependent).- Cause parallel shift of the log dose response curve to the right (decrease potency same efficacy of agonist).- Slope and maximal effect (Emax) are not changed.- Often (not always) these antagonists possess a very similar chemical structure to that of the agonist.

2. Irreversible non-competitive antagonists:- Antagonist binds to the same receptor as agonist irreversibly.- The antagonist cannot overcome by excess agonist or increase ED50.- Decreases efficacy of the agonist but does not alter EC50.- Causes non-parallel (downward) shift of dose-response curve to the right (until spare receptors are present).- Slope and maximal effect are decreased.Phenoxybenzamine, an irreversible α–adrenoreceptor antagonist.

EC50

Agonist

Agonist + Antagonist

3. Allosteric antagonists:- Non-competitive mechanism, conc. independent.- Antagonist and agonist bind to different site on same receptor.- Binding of antagonist to receptor alter the shape of binding site for agonist.- The bound antagonist may prevent conformational changes in the receptor required for receptor activation after the agonist binds.

Physiologic antagonistsTwo drugs have opposite effects through differing mechanismsA drug that binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing. e.g. Antagonism of a bronchoconstrictor effect of histamine by epinephrine bronchodilator action.

Chemical antagonistsA drug that interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target.e.g. Dimercaprol, a chelator of lead and some other toxic metals.e.g. Pralidoxime which combines with the phosphorous in organophosphate cholinesterase inhibitors.

1. Graded dose-response relationsThe effect of a drug is most easily analyzed by plotting the magnitude of the response versus the drug dose, this is, a graded dose-response curve, which is reflected by a rectangular hyperbolic curve (A), but it is frequently convenient to plot the magnitude of effect versus log dose, because a wide range of drug concentrations is easily displayed. In this case, the result is the symmetric sigmoidal log dose-effect curve (B). This curve is steep in the middle and even in both extremities.

Dose-response relationships

Dose-response curve

Dose

0

20

40

60

80

100

0 200 400 600 800 1000

Resp

ons

e

After this point, increasing dose do not produce a stronger effect

Dose-response curve

Dose

Resp

ons

e

0

20

40

60

80

100

0.1 1 10 100 1000 10000

Ceiling

ED50

ThresholdEC50

Rectangular hyperbolic curve Sigmoidal curve

Aim of plotting the dose-response curve is to compare the relative potencies and efficacies of different drugs:

Efficacy: Efficacy is the maximal response (Emax) produced by a drug. It depends on the number of drug-receptor complexes formed and the efficiency with which the activated receptor produces a cellular action. It can be measured with a graded dose-response curve only.For example, if two drugs, Drug A and Drug B, are both claimed to reduce a patient’s heart rate by 25%, then both drug have the same efficacy.

Potency: Absolute amount of drug required to produce an effect.Potency of a drug termed effective dose or concentration, is a measure of how much drug is required to elicit a given response. The lower the dose required for a given response, the more potent the drug.The smaller the EC50, the greater the potency of the drug.For example, only 1 mg of drug A needs to be given to achieve a reduction in heart rate, where as 10 mg of drug B are needed. Therefore, drug A is considered as more potent drug than B.

EC50

Potency is most often expressed EC50.The EC50 is the concentration of the drug that produces a response equal to the 50% of the maximal response.

The smaller the EC50, the greater the potency of the drug.

2. Quantal dose-response relationsQuantal dose-response is the relationship between no. of patients response and dose. It describes the relationship that how many patients have exhibited the predefined response (say like 20% decrease in blood pressure) at the specified dose (how much minimum amount of drug is required to reach at 20% decrease in blood flow.)In quantal dose response curve ED50, TD50 and LD50 are potency variables.

Normal distribution Cumulative frequency

Therapeutic indexThe therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals.

Therapeutic index = TD50/ED50 or

LD50/ED50TD50(Median toxic dose): The drug dose that produces a toxic effect in half of the population.ED50(Median effective dose): The drug dose that produces the desired therapeutic effect in half of the population.

LD50(Median lethal dose): The dose of a drug that produces death in 50% of the animal population tested.

Drug’s safety marginMust be >1 for drug to be usableDigitalis has a TI of 2Penicillin has TI of >100

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Regulation of receptorsContinued stimulation of cells with agonists generally results in a state of desensitization such that the effect that follows continued or subsequent exposure to the same concentration of drug is diminished.

An example is attenuated response to the repeated use of receptor agonists as bronchodilators for the treatment of asthma Desensitization can be the result of temporary inaccessibility of the receptor to agonist or the result of fewer receptors synthesized and available at the cell surface (down regulation).

Hyperractivity (up-regulation of the receptors):Antagonists may raise the number of receptors in a cell by preventing down regulation caused by endogenous agonists.

When the antagonist is withdrawn, the elevated receptor number allows an exaggerated response to physiological concentration of agonists.

For example, severe tachycardia or arrhythmias which could occur after sudden withdrawal of propranolol. So the dose must reduced gradually.