Principles of pharmacodynamics Anton Kohút

How drugs act? Indirectly Directly drugs interact with specific only a few drug (osmotic diuretics, general anesthetics) act on the base their physicochemical properties  they need no specific binding site Directly drugs interact with specific protein macromolecule  special regulatory proteins: 1. enzymes 2. ion channels 3. carrier molecules 4. receptors

Targets - regulatory proteins . Receptors Enzymes aspirin  COX neostigmine  AChE methotrexate DH-folate reductase digoxin  Na+-K+-ase allopurinol  xanthine oxidase omeprazole  H+/K+- ATPase 3 . Ion channels Ca, Na, K 4. Carrier molecules  transport of glucose, amino acids  transport in renal tubules  re-uptake of neurotransmiters (NA, 5-HT)

No drugs are completely specific in their actions. In many cases, increasing the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side-effects.

Receptors

Regulatory proteins – receptors drugs act on receptors as agonists or antagonists bind to receptors and produce a response- effects of various types 2. Antagonists bind to receptors without producing a response and by occupying the receptors they prevent action of agonists.

1. Agonists  agonist I - the drug binds to the same site as the endogenous compounds and produce the same type of action  agonist II - the drug binds to a different site than does agonist I - allosteric action  inverse agonist – produces inactivation of active receptor

1. Agonists (cont.) Affinity - tendency to bind to the receptors (attraction between receptor and drug) Efficacy - ability once bound, to initiate changes, which lead to effect (is the capacity of drug to activate a receptor) Full agonists - can produce maximal effect when all receptors are occupied (high efficacy)  Partial agonists - can produce only submaximal effects even when all receptors are occupied

2. Antagonists competitive antagonism a. reversible b. ireversible  antagonists are able to displace the agonists from the receptors (one drug can be displaced by another drug),  may be abolished by adding an excess of agonist. a. reversible b. ireversible antagonist dissociates very slowly or not

2. Antagonists (cont.) non-competitive antagonism a. form bonds with the receptors usually at sites other than the endogenous agent. b. in some cases binding may be covalent and ireversible c. cannot be overcom by higher concentration of agonist

Receptors –types of receptors A. for fast neurotransmitters - coupled directly to an ion channel, e.g the nicotinic ACh receptor, GABA, glutamate, 5-HT3 B. coupled to G-protein - for many hormones and slow transmitters (neurohormonal receptors), muscarinic ACh receptors, adrenergic receptors C. coupled to tyrosine kinase - for insulin and various growth factors, D. cytosolic receptors - for steroids (are usually slow)

Adrenergic beta receptor Transduction system Agonist (noradrenaline) Receptor (1-2) G-protein (Gs, Gi) Effector enzyme (adenylcyclase, AC) Second messenger (cAMP) Drug action

Adrenergic beta receptor

Cholinergic receptor

Receptors - localization

of intracellular receptors A lipid-soluble drug diffuses across cell membrane and moves to the nucleus of the cell Mechanism of action of intracellular receptors Drug Drug TARGET CELL CYTOSOL Drug Inactive receptor NUCLEUS Activated receptor complex The drug binds to an intracellular receptor. Gene The drug-receptor complex binds to chromatin, activating the transcription of specific genes. mRNA mRNA Specific proteins according to Lippincott´s Pharmacology, 2006) Biologic effects

DOSE-RESPONSE RELATIONSHIPS A agent that can bind to a receptor and elicit a response. magnitude of the drug effect depends on its concentration at the receptor site, which in turn is determined by the dose of drug and by factors characteristic of the drug (e.g. rate of absorption, distribution, metabolism).

- effect of the dose on the magnitude of pharmacologic response. 100 Semilogaritmic - effect of the dose on the magnitude of pharmacologic response. 100 Drug A Drug B 50 Percentage of maximum effect EC50 log [Drug] The potency of drug can be compared using the EC50, the smaller the EC50 the more potent the drug. (according to Lippincott´s Pharmacology, 2006)

Log-concentration-effect curve 10-8 10-7 10-6 10-5 10-4 potency (affinity) efficacy 50% EC50 slope of the curve

EC50 for Drug A EC50 for Drug B EC50 for Drug C Typical dose-response curve for drug showing differences in potency and efficacy. (EC50 = drug dose that shows fifty percent of maximal response.) Drug A is more potent than Drug B, but both show the same efficacy. Drug C shows lower potency and lower efficacy than Drugs A and B. 100 Drug A Biologic effect 50 Drug B Drug C Log drug concentration EC50 for Drug A EC50 for Drug B EC50 for Drug C (according to Lippincott´s Pharmacology, 2006)

3. Antagonism by receptor block Antagonists in this sense are the drugs that bind to receptors but do not activate them. Reversible competitive antagonism: competitive antagonists bind reversibly with receptors at the same site as the agonist. The response can be returned to normal by increasing the dose of agonist. ! Competitive antagonist has no intrinsic efficacy ! Reversible competitive antagonism is the commonest and most important type of antagonism; Two main characteristics: ― in the presence of the antagonist, the agonist log DRC is shifted to the right without change in slope or maximum, the extent of the shift being a measure of the dose ratio ― the dose ratio increases linearly with antagonist concentration

Drug with competitive antagonist Drug with non- competitive antagonist Effects of drug antagonists Drug with competitive antagonist Drug with non- competitive antagonist Drug alone Biologic effect Drug concentration EC50 or drug alone or in presence of a noncompetitive antagonist EC50 for drug in the presence of a competitive antagonist (according to Lippincott´s Pharmacology, 2006)

Variation in receptor numbers Continued stimulation or inhibition of living systems tends to induce compensatory processes. Thus individuals continually exposed to an agonist - predictably require larger doses to achieve a given effect than would a naive subject. This tolerance is thought to results from a decrease in reception numbers - down-regulation. ( The opposite may also occur: in patients on long-term beta-blocker therapy, it is thought that catecholamine receptor numbers are increased - up-regulation  the tendency to a marked rise in blood pressure if the drug is stopped suddendly (rebound hypertension).

Desensitisation (tachyphylaxis) and tolerance The loss of a drug’s effect, commonly seen when it is given repeatedly or continuously. The onset and recovery : varies from seconds to minutes (called TACHYPHYLAXIS) to days or weeks (called TOLERANCE) Many mechanisms: ― changes in receptors ― loss of receptors (down regulation) ― exhaustion of mediators ― enhanced drug metabolism ― active efflux of drugs ― compensatory physiological mechanisms

Desensitization of receptors - -- down-regulation - types of desensitization - when receptors are (they undergoe endocytosis – they are not available for further agonist action). These receptors may be recycled to the cell surface, restoring sensitivity, or may be further degraded, decreasing the total number of receptors available. Some receptors (particularly voltage-gated channels) - they require a rest period following stimulation before they can be activated again. During this recovery phase they are said to be "refractory" or "unresponsive."

Desensitization of receptors tachyphylaxis Repeated administration of an agonist (such as epinephrine) over a short time period, results in diminished response of the cell. Response Time 50 10 50 10 50 10 40 20 40 20 40 20 30 30 30 Repeated injection of drug Following a period of rest, administration of the drug results in a response of the original magnitude. (according to Lippincott´s Pharmacology, 2006)

Tachyphylaxis after repeated administration of ephedrine (decrease in its effect on blood pressure) E = administration of ephedrine

Log concentration of drug in plasma Cumulative percentage of patients responding to plasma levels of a drug B: Penicillin: Large therapeutic index Therapeutic window 100 Percentage of patients 50 Desired therapeutic effect Unwanted adverse effect Log concentration of drug in plasma (arbitrary units) (according to Lippincott´s Pharmacology, 2006)

QUANTAL DOSE-RESPONSE CURVES TI = ----- Therapeutic range = TD50 - ED50 ED50

Therapeutic index 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 = LD50/ED50 or TD50/ED50 TD50 = the dose that produces a toxic effect in half the population, LD50 = the dose that produces a death in half the population ED50 = the dose that produces a therapeutic or desired response in half the population. The therapeutic index = a measure of a drug's safety – a large value = there is a wide margin between doses that are effective and toxic.