Pharmacodynamics

What is Pharmacodynamics? Pharmacodynamics is the study of the effects of drugs on the body and the mechanisms of drug action and the relationship between drug concentration and effect. Pharmacodynamics is often summarized as the study of what a drug does to the body

DRUG ACTION 2. Depression 3. Irritation 4. Replacement The basic types of drug action can be broadly classed as: 1. Stimulation 2. Depression 3. Irritation 4. Replacement 5. Cytotoxic action

Stimulation Stimulation refers to selective enhancement of the level of activity of specialized cells E.g. adrenaline stimulates heart, pilocarpine stimulates salivary glands. However, excessive stimulation is often followed by depression of that function, e.g. high dose of picrotoxin, a central nervous system (CNS) stimulant, produces convulsions followed by coma and respiratory depression.

Depression Depression means selective diminution (decrease )of activity of specialized cells E.g. barbiturates depress CNS, omeprazole depresses gastric acid secretion. NB! Certain drugs stimulate one type of cells but depress the other, e.g. acetylcholine stimulates intestinal smooth muscle but depresses SA node in heart.

Irritation a nonselective, often noxious (harmful) effect and is particularly applied to less specialized cells (epithelium, connective tissue). This may result in diminution or loss of function.

Replacement This refers to the use of natural metabolites, hormones or their congeners in deficiency states E.g. levodopa in parkinsonism, insulin in diabetes mellitus, iron in anaemia.

Cytotoxic action Selective cytotoxic action on invading parasites or cancer cells, attenuating them without significantly affecting the host cells For cure of infections and neoplasms (tumours), e.g. penicillin, chloroquine, zidovudine, cyclophosphamide, etc.

DRUG ACTION’S MECHANISM Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Drugs act on target proteins, namely: -receptors -enzymes -carriers (transporters) -ion channels.

Enzymes Enzymes are macromolecular biological catalysts. Enzymes accelerate (or catalyze) chemical reactions. The molecules at the beginning of the process are called substrates and the enzyme converts these into different molecules, called products. Almost all metabolic processes in the cell need enzymes.

ION CHANNELS Proteins which act as ion selective channels par-ticipate in transmembrane signaling and regulate intracellular ionic composition. Certain drugs modulate opening and closing of the channels, e.g.: -Amiodarone block myocardial delayed rectifier K+ channel. -Nicorandil opens ATP-sensitive K+ channels. -Nifedipine blocks L-type of Ca 2+ channel. -Amiloride inhibits renal epithelial Na+ channels.

TRANSPORTERS substrates are translocated across membranes which facilitate diffusion in the direction of the concentration gradient or pump the metabolite against the concentration gradient using metabolic energy

Carriers

RECEPTORS Generally the term receptor indicates a recognition molecule for a chemical mediator. ‘Receptor’ is sometimes used to denote any target molecule with which a drug molecule has to combine in order to elicit its specific effect. In the more general context, the term receptor is used to describe various cell surface molecules involved in the cell-to-cell interactions that are important in immunology, cell growth, migration and differentiation etc.

Receptor in pharmacology Protein regulatory macromolecules or the sites on them whose function is to recognise the drug (signal molecule) and respond to endogenous chemical signals. Itself has no other function. Other macromolecules with which drugs interact to produce their effects are known as drug targets.

Terms Agonist - An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule. Antagonist - An agent which combine at the same site without causing activation, and block the effect of agonists on that receptor Does not have any effect of its own.

TERMS Partial agonist - An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist. Ligand (Latin: ligare—to bind) Any molecule which attaches selectively to particular receptors or sites. The term only indicates ability to bind with receptor.

TERMS Affinity - The tendency and ability of a drug to bind to the receptors Efficacy (intrinsic activity)- the tendency to activate the receptor and produce effect

Agonists have both affinity and maximal intrinsic activity (100%). Partial agonists have affinity and submaximal intrinsic activity (1 - 99%) Antagonists have affinity but no intrinsic activity (0%)

Receptor subtypes Located on the surface or inside the effector cell Surface (membrane) receptors can be grouped into categories: 1) G-protein coupled receptors 2) Ion channel receptor (also called ligand gated ion channels) 3) Transmembrane enzyme-linked receptors Nuclear receptors - regulate gene expression(steroidal hormones (glucocorticoids, mineralocorticoids, androgens, estrogens, progeste-rone), thyroxine, vit D and vit A)

Functions of receptors To propagate regulatory signals from outside to inside the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. To amplify the signal. To integrate various extracellular and intra-cellular regulatory signals. To adapt to short term and long term changes in the regulatory melieu (environment)

DOSE-RESPONSE RELATIONSHIP describes the change in effect on an organism caused by differing levels of exposure (or doses) to a drug after a certain exposure time. the intensity of response increases with increase in dose

Dose–response curve A dose–response curve (DRC) is a simple X–Y graph relating the magnitude of a drug to the response of the receptor the DRC is a hyperbola or sigmoidal ( if we use logarithm of the dose that is plotted on the X axis

Drug potency drug potency - refers to the amount of drug needed to produce a certain response. A DRC positioned rightward indicates lower potency. if 1 mg of A = 10 mg of B as analgesic, so A is 10 times more potent than B

Drug efficacy Drug efficacy refers to the maximal response that can be elicited by the drugs. B produces a degree of analgesia more then C—B is more efficacious than C.

Drug B is less potent but equally efficacious as drug A. Drug C is less potent and less efficacious than drug A. Drug D is more potent than drugs A, B, & C, but less effica-cious than drugs A & B, and equally efficacious as drug C.

Therapeutic index Median effective dose (ED50) is the dose which produces the specified effect in 50% individuals Median lethal dose (LD50) is the dose which kills 50% of the recipients

Therapeutic window The amount of a medication between the amount that gives an effect (min effective dose) and the amount that gives more adverse effects than desired effects (max effective dose). The range of drug dosages which can treat disease effectively without having toxic effects For instance, medication with a small pharmaceutical window must be administered with care and control

DRUG DOSAGE Effective dose (ED) is the dose (amount of drug) that produces a therapeutic response or desired effect Toxic Dose Lethal Dose Prophylactic dose Single dose Daily dose

FACTORS MODIFYING DRUG ACTION Body size Age Sex Species and race Genetics Route of administration time of administration Pathological states Cumulation Tolerance

COMBINED EFFECT OF DRUGS SYNERGISM (Greek: Syn—together; ergon—work) When the action of one drug is increased by the other, they are said to be synergistic. In a synergistic pair, both the drugs can have action in the same direction or given alone one may be inactive but still enhance the action of the other when given together.

Synergism can be: Additive - The effect of the two drugs is in the same direction and simply adds up: 1+1=2 Potentiation (Supraadditive)- The effect of combination is greater than the individual effects of the components: 1+1=3 Sensitization : 0+1=1,5

ANTAGONISM One drug decreases the action of another Antagonism may be: -Physical antagonism -Chemical antagonism -Physiological/functional antagonism -Receptor antagonism Receptor antagonism can be competitive or noncompetitive.

Competitive antagonism The antagonist is chemically similar to the agonist, competes with it and binds to the same site as the agonist molecules. Antagonist binding is reversible and depends on the relative concentration of the agonist and antagonist molecules, higher concentration of the agonist progressively overcomes the block.

Noncompetitive antagonism The antagonist is chemically unrelated to the agonist, binds to a different site of the receptor in a such way that it is unable to combine with the agonist. Because the agonist and the antagonist are combining with different sites, there is no competition between them—even high agonist concentration is unable to reverse the block completely.

At home Pharmacodynamics Factors modifying drug actions Clinical trials Pharmacovigilance ADR

Thank you!