7. Pharmacodynamics

Pharmacodynamics Pharmacodynamics 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.

Receptor interactions Recepto rs Are 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 characteristics.

in

their

ligand-binding

Drug + Receptor  Drug-receptor complex Biologic effect

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 (message propagation)

an

effector

system

The signal from the ligand to several subcellular elements e.g. enzymes, second messenger, or ion channels ► intra-cellular biochemical response

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

Figure: Known effector mechanisms.

1. Intracellular Lipid 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. Transmembrane Some 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 channels Drugs binds to these receptors, which then alter the conductance of ions through the cell membrane channels. Ach + Nicotinic receptors ► Open Na+ channels GABA + 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

5. Second messenger system Drugs 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, ++

Mechanisms of the therapeutic & toxic actions 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.

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

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 agonist Strong affinity Strong intrinsic activity

Partial agonist Strong affinity Weak intrinsic activity

% of maximum effect

100

……………………………………………

Full agonist

……………………………………………

Partial agonist

Log concentration [A]

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 antagonist Strong affinity No intrinsic activity

Partial antagonist Strong affinity Weak intrisic activity

Pharmacologic 1. Reversible competitive antagonists: 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.

2. Irreversible antagonists:

non-competitive

- 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 doseresponse curve to the right (until spare receptors are present). Phenoxybenzamine, an irreversible α–adrenoreceptor antagonist. - Slope and maximal effect are decreased.

Agonist

Agonist + Antagonist

EC50

3. Allosteric antagonists: Non-competitive independent.

mechanism,

conc.

- 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 Two drugs have opposite effects through antagonists differing mechanisms A 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 antagonists A 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.

Dose-response relationships 1. Graded dose-response relations The 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 doseeffect curve (B). This curve is steep in the middle and even in both extremities.

Dose-response curve

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

100

Respons e

80 60 40 20 0 0

200

400

Dose

600

800

1000

Dose-response curve

Ceiling

100

Respons e

80 60

EC ED50

40 20

Threshold

0 0.1

1

10

Dose

100

1000

10000

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 doseresponse 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

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

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 relations Quantal 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 index The 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/ED50 TD50(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 margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100

?? mg ED50

…………..…..

…………..…..

……………………………….

?? mg TD50

?? mg ED50

…………..…..

…………..…..

………………………………….…………….

?? mg TD50

Regulation of receptors Continued 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 β 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 receptors):

(up-regulation

of

the

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