Pharmacodynamics

1. Pharmacodynamics • Pharmacodynamics is the study of the biochemical and physiological effects of drugs, in certain period. • In brief, it can be described as what the drug does to the body. • Drug receptors • Effects of drug • Responses to drugs • Toxicity and adverse effects of drugs

2. MECHANISMS OF DRUG ACTION • Drugs can act through: 1. Physical action: Drug can produce a therapeutic response because of it’s physical properties. e.g: Mannitol as diuretic because it increase osmalerity, Radio-isotopes : emit ionizing radiation 2. Simple chemical reaction: Drug may act through a chemical reaction. e.g: Gastric antacids work by neutralizing the stomach acidity with a base, Chelating agents that bind heavy metals in body. 3. Receptors: A receptor is a specialized target macromolecule mostly protein, present on the cell surface or intracellular, that binds a drug and mediates it’s pharmacological actions.

3. Receptors can either be enzymes, nucleic acids or structural proteins to which drugs may interact. •  A molecule that binds to a receptor is called a ligand,and can be a peptide or another small molecule like a neurotransmitter, hormone, or drug. • Ligand binding changes the conformation (three-dimensional shape) of the receptor molecule. This alters the shape at a different part of the protein, changing the interaction of the receptor molecule with associated biochemicals, leading in turn to a cellular response mediated by the associated biochemical pathway.

4. TYPES OF LIGAND-RECEPTOR INTERACTIONS Not every ligand that binds to a receptor also activates the receptor. The following classes of ligands exist: 1. (Full) agonists are able to activate the receptor and result in a maximal biological response. The natural endogenous ligand with greatest efficacy for a given receptor is by definition a full agonist (100% efficacy). 2. Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists (efficacy between 0 and 100%). 3. Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of agonists and inverse agonists. `4. Reverse agonist

5. TYPES OF LIGAND-RECEPTOR INTERACTIONS Agonist e.g. important therapy in asthma Hormone binds 2 receptor in lung  bronchial relaxation Antagonist control heart beat binds 1 receptor in heart muscle  increased heart rate

6. CLASSIFCATION OF RECEPTORS • 1. Transmembrane ligand-gated ion channels:These receptors are present in the walls of ion channels in cell membranes. When activated by their specific agonist, they open these ion channels & lead to movement of ions across cell membrane. • These mediate diverse functions, including neurotransmission, cardiac conduction, and muscle contraction. This is based on the type of the transduction mechanism that these receptors activate when stimulated by their agonists:

7. Examples : 1. Nicotinic receptors for acetylcholine (Ach.) : when stimulated, they open receptor-operated Na+ channels, and thus increase influx of sodium ions across membranes of neurons or NMJ(neuromuscular junction) in skeletal muscle and therefore activation of contraction in muscle. 2. γ-aminobutyric acid (GABA) receptors: Benzodiazepines enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell.

8. 2. Transmembrane G protein–coupled receptors: • When these receptors are stimulated by their specific agonists, they will activate a regulatory G-protein in cell membrane which in turn change activity of membrane enzymes ( either adenyl cyclase or phospholipase C ) leading to a change in intracellular level of a second messenger like cAMP (cyclic adenosine monophosphate), or IP3 (inositol triphosphate), respectively, and this would lead to cell response. • Examples :e.g. Receptors for transmitters : Stimulation of muscarinic receptors (M1 and M3) for (Ach) will activate G and leads to increase intracellular level of IP3

9. guanosine triphosphate (GTP), guanosine diphosphate (GDP)

10. 3. Enzyme-linked receptors: • These membrane receptors have an extra-cellular site that binds to specific agonists and an intra-cytoplasmic domain which contains tyrosine and other amino acids. • Binding to specific agonist and activation of these receptors usually lead to phosphorylation of tyrosine in intra-cellular domain which then acquires kinase activity and leads to activation of intracellular substrates or enzymes that finally leads to cell response. • Examples: Receptors for insulin, Receptors for growth factors like EGF or PDGF, Receptors for immune cytokines

12. 4. Intracellular receptors: • These receptors are located incytoplasm (e.g. steroid receptors) or nucleus (receptors for thyroid hormones or vitamin D3) . • The specific agonist must cross cell membrane to inside of cell, binds and activates these receptors, which will then bind to DNA gene response elements in nucleus and lead to change in gene transcription , and thus synthesis of new proteins

14. Types of drug-receptor bonding Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: 1. Covalent: It is very strong and in many cases not reversible under biologic conditions. Thus, the duration of drug action is frequently, but not necessarily, prolonged (irreversible) 2. Electrostatic: is much more common than covalent bonding in drug-receptor interactions. These vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces. Electrostatic bonds are weaker than covalent bonds. (reversible)

15. 3. Hydrophobic: are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets.“ • Drugs which bind through weak bonds to their receptors are generally more selective than drugs which bind through very strong bonds. • This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur

16. Duration of Drug Action Termination of drug action at the receptor level results from one of several processes: • The effect lasts only as long as the drug occupies the receptor, so that dissociation of drug from the receptor automatically terminates the effect. 2. The action may persist after the drug has dissociated, because, for example, some coupling molecule is still present in activated form. 3. Drugs that bind covalently to the receptor, the effect may persist until the drug-receptor complex is destroyed and new receptors are synthesized. 4. Many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods

17. Relation between Drug Dose & Clinical Response In order to make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underlie 1. The relations between dose and response in patients 2. The nature and causes of variation in pharmacologic responsiveness 3. The clinical implications of selectivity of drug action.

18. These relations are exhibited as following: A. Graded dose–response relationships ( individual): The response is a graded effect, meaning that the response is continuous and gradual B. Quantal dose–response relationships (population) describes an all-or-no response

19. A. Graded dose–response relationships • The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug pharmacokinetic profile, such as rate of absorption, distribution, and metabolism. • As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. • Plotting the magnitude of the response against increasing doses of a drug produces a graph, the graded dose–response curve. • Two important properties of drugs, can be determined by graded dose–response curves which are: • Potency • Efficacy

20. 1. Potency: • A measure of the amount of drug necessary to produce an effect of a given magnitude. • The concentration of drug producing an effect that is 50 percent of the maximum is used to determine potency and is commonly designated as the EC50 • Drug A is more potent than Drug B, because a lesser amount of Drug A is needed when compared to Drug B to obtain 50-percent effect.

21. Potency is affected by: 1. Receptor concentration or density in tissue, 2. Efficiency of stimulus-response coupling mechanism in tissue 3. Affinity: the strength of the interaction (binding) between a ligand and its receptor. 4. Efficacy • Potent drugs are those which elicit a response by binding to a critical number of a particular receptor type at low concentrations (high affinity) compared with other drugs acting on the same system and having lower affinity and thus requiring more drug to bind to the same number of receptors

22. 2. Efficacy • Efficacy is dependent on: • 1. Number of drug–receptor complexes formed • 2. the efficiency of the coupling of receptor activation to cellular responses. • A drug with greater efficacy is more • therapeutically beneficial than one that is more potent. • Maximal efficacy (Emax) of a drug assumes that all receptors are occupied by the drug, and no increase in response will be observed if more drugs are added • The height of maximal response is used to measure maximal efficacy of agonist drug, and to compare efficacy of similar acting agonists It is the ability of a drug to elicit a response when it interacts with a receptor.

23. Effect of drug concentration on receptor binding The quantitative relationship between drug concentration and receptor occupancy is expressed as follows: Drug + Receptor ←→ Drug–receptor complex → Biologic effect • As the concentration of free drug increases, the ratio of the concentrations of bound receptors to total receptors approaches unity

24. Concept of drug receptor binding & agonists A receptor can exist in at least two conformational states, active (Ra), and inactive (Ri). These states are in equilibrium, & the inactive state Ri predominates in absence of agonist drug, thus basal activity will be low or absent. • If a drug that has a higher affinity for Ra than R iis given, it will drive the equilibrium in favor of active state and thus activate more receptors. Such drug will be an agonist. A full or strong agonist is sufficiently selective for the active conformation that at a high concentration it will drive the receptors completely to the active state.

25. If a different but structurally similar compound binds to the same site on R but with only slightly or moderately greater affinity for Ra than for Ri, its effect will be less, even at high concentrations. Such a drug that has intermediate or low efficacy is referred to as a partial agonist

26. If a drug binds with equal affinity to either conformation of receptor but does not change the activation equilibrium, then it will act as a competitive antagonist. • A drug with preferential affinity for Ri actually will produce an effect opposite to that of an agonist, and thus named inverse agonist. It further reduces the resting level and effect of receptor activity.

27. ANTAGONISTS • They are of 3 main types : 1. Chemical antagonist : This combines with agonist and inactivates it away from tissues or receptors Examples: a. Alkaline antacids neutralize HCl in stomach of peptic ulcer patients; b. protamine (basic) neutralizes the anti-coagulant heparin (acidic) in plasma c. Chelating agents bind with higher affinity to heavy metals (e.g. lead, mercury, arsenic ) in plasma and tissues, preventing their tissue toxicity

28. 2. Physiological antagonist : • This is actually an agonist on the same tissue but produces opposite effect to that of the specific agonist; it acts by mechanisms or receptors that are different from those of the specific agonist . • Physiological antagonists quickly reverse the action of the specific agoniston the same tissue. • Examples: • Adrenaline, given IM, is a quick acting physiologic antagonist to histamine (that is released from mast cells or basophils) in anaphylactic shock; it is a life-saving drug in this condition

29. 3. Pharmacological antagonist : Pharmacological receptor antagonists have affinity for the receptors but have no intrinsic activity or efficacy There are three main types : A. Competitive reversibleantagonist : This antagonist , because of similarity in its chemical structure to agonist, competes with agonist for binding to its specific receptors in tissue, and thus decreases or prevents binding of agonist and its effect on tissue. The antagonist molecules bind to the agonist receptors withreversible ionic bonds, so that it can be displaced competitively from receptorsby increasing the concentration or dose of agonist , and thusresponse of tissue to agonistis restored.

30. agonist (A) and antagonist (I) • The DR curve of agonist is shifted to the right, and the maximal response can be restored by increasing dose of agonist. The more is the concentration of antagonist, the greater is this shift of DR curve of agonist to the right. Examples: • atropine is a competitive reversible antagonist to Ach at muscarinic receptors; • Beta-blockers are competitive antagonists to adrenaline at beta –adrenergic receptors.

31. B.Non-competitive antagonist : There are two subtypes: 1. Irreversible antagonist : Here, the antagonist molecules either bind to agonist receptors by strong irreversible covalent bonds or dissociate very slowly from the receptors, so that the effect of antagonist can not be overcome fully by increasing concentration of agonist.

32. The dose response curve of agonist is shifted slightly to the right , but the maximal height or response of curve is depressedand can NOT be restored by increasing the dose of agonist . This is due to decrease in number of receptors remaining available to bind to agonist. • The more is the concentration of antagonist, the more is depression of maximal response

33. 2. Allosteric antagonism : Here, the antagonist binds to allosteric site on receptor that is different from the site that binds agonist molecules, leading to change in receptor binding or affinity to agonist with subsequent antagonism. The dose response curve of antagonist is similar to that of irreversible non-competitive antagonist. Note :Allosteric enhancement : with some receptors, a drug can bind to another allosteric site on agonist receptor leading to increase in binding of agonist to its receptor and thus allosteric enhancement of agonist effect . e.g. Binding of benzodiazepines to GABA-A receptors can enhance the depressant GABA effect on brain neurons.

35. C. Uncompetitive antagonist: Here antagonist bind to a receptor different from that of agonist, and is located more distally in the effector mechanism so that the effect of agonist is blocked as well as that of other agonists that produce similar effect by acting on a different receptor i.e. it lacks specificity.The dose-response curve is similar to that of irreversible non-competitive antagonist. A + RA Depolarization → Increases free calcium B + RU Y Uncompetitive antagonist Contraction

36. Receptor regulation 1. Receptor up-regulation : This means increase in number of receptors and/or affinity of specific receptors ( receptor supersensitivity). It may occur with : A. Prolonged use of receptor antagonist :here, there is lack of binding of receptor to agonist for long period of time B. Disease : e.g. hyperthyroidism : here excess thyroxine hormone in blood stimulate proliferation of beta-adrenergic receptors in heart which increases risk of cardiac arrhythmia from adrenaline or use of beta-adrenoceptor agonists .

37. B. Receptor down-regulation (Receptor tolerance): This means a decrease in number and/or affinity of available specific receptors due to their prolonged occupation by agonist . • It occurs with continued use (for days or weeks) of receptor agonist , and is evident as decrease in response to agonist . • In order to restore the intensity of response, the dose of agonist must be increased. Tachyphylaxis :it is a rapidly developing receptor tolerance • It is not due to receptor down-regulation • It is associated with repeated use of large doses of direct receptor agonist, usually at short dose intervals , OR with continuous IV infusion of agonist.

38. It may be due to : 1. Desensitization of receptors : Change in the receptor: where the agonist-induced changes in receptor conformation result in receptor phosphorylation, which diminishes the ability of the receptor to interact with G proteins 2. Depletion of intra-cellular stores of transmitter e.g. depletion of noradrenaline stores in vesicles inside sympathetic nerve ending resulting from repeated use of indirect sympathomimetic amphetamine • In order to restore the response, the agonist drug must be stopped for short time to allow for recovery of receptors or stores of transmitter.

39. causes of variation in pharmacologic responsiveness Individuals usually show variation in intensity of response to drugs due to : 1. Variation in concentration of drug that reaches the tissue receptors : due to pharmacokinetic factors 2. Abnormality in receptor number or function : either genetically-determined or acquired due to up-regulation or down-regulation 3.Post-receptor defect inside cells : This is an important cause of response variation 4. Variation in Concentration of an Endogenous Receptor Ligand contributes greatly to variability in responses to pharmacologic antagonists.

40. Individuals usually show variation in intensity of response to drugs due to : 1. Variation in concentration of drug that reaches the tissue receptors : due to pharmacokinetic factors 2. Abnormality in receptor number or function : either genetically-determined or acquired due to up-regulation or down-regulation 3.Post-receptor defect inside cells : This is an important cause of response variation 4. Variation in Concentration of an Endogenous Receptor Ligand contributes greatly to variability in responses to pharmacologic antagonists.

41. B. QUANTAL DOSE–RESPONSE RELATIONSHIPS the influence of the magnitude of the dose on the proportion of a population that responds. • These responses are known as quantal responses, because, for any individual, the effect either occurs or it does not. The desired response is either : A. Specified in amount or magnitude : e.g. increase in heart rate of 20 beats/min by a drug that stimulates heart. If the recorded response in any individual shows this amount or more, then this is regarded as positive response; otherwise, the response is negative

42. Determines minimum dose at which each patient responded with the desired outcome. The results have been plotted as a histogram, and fit with a gaussian curve. μ = mean response; σ = standard deviation. B. All-or-none response : e.g. death; prevention of epileptic seizures; prevention of cardiac arrhythmias • For most drugs, the doses required to produce a specified quantal effect in individuals are lognormally distributed; ie, a frequency distribution of such responses plotted against the log of the dose produces a gaussian normal curve of variation

43. Example: • At 1.25mg/L, 2% respond, and 2.5mg/L 3% respond, • Then at 5mg/L plot 2%, and at 7mg/L plot (2+3 = 5% etc.) • When these responses are summated, the resulting cumulative frequency distribution constitutes a quantal dose-effect curve of the proportion or percentage of individuals who exhibit the effect plotted as a function of log dose

44. The quantal dose-effect curve is often characterized by: 1. median effective dose (ED50): the dose at which 50% of individuals exhibit the specified quantal effect. 2. median toxic dose (TD50): the dose required to produce a particular toxic effect in 50% of Animals. 3. Median lethal dose (LD50): the dose required to produce a death in 50% of Animals.

45. Summation and Potentiation • Potentiation requires that the drugs act at different receptors or effector systems. • Example of potentiation would be the increase in beneficial effects noted in the treatment of AIDS by combination therapy with AZT (a nucleoside analog that inhibits HIV reverse transcriptase) and a protease inhibitor (protease activity is important for viral replication). Two common types of “agonistic” drug interactions are : 1. Summation: When two drugs with similar mechanisms are given together, they typically produce additive effects. 2. Potentiation or synergism : if the effect of two drugs exceeds the sum of their individual effects.

46. Prediction of drug safety in man • This may be obtained from knowledge of Therapeutic Index (TI) of drug. the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals TI = TD50 / ED50 where : TD50 = the drug dose that produces a toxic effect in half the population ED50 = the drug dose that produces a therapeutic effect in half the population. • A larger value indicates a wide margin between doses that are effective and doses that are toxic.

47. TI is determined by measuring the frequency of desired response, and toxic response, at various doses of drug. • In humans, the therapeutic index of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses. • The concentration range over which a drug produces its therapeutic effect is known as its therapeutic window

48. when the therapeutic index is low, it is possible to have a range of concentrations where the effective and toxic responses overlap • Agents with a low therapeutic index are those drugs for which bioavailability critically alters the therapeutic effects • When therapeutic index is large, it is safe and common to give doses in excess (often about ten-fold excess) of that which is minimally required to achieve a desired response. In this case, bioavailability does not critically alter the therapeutic effects.

49. Specificity vs. Selectivity • Specificity : If a drug has one effect, and only one effect on all biological systems it possesses the property of specificity. a drug that has a particular effect and not another. • Selectivity: refers to a drug's ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors. a drug that acts on a particular target (receptor) and not another • For example, a drug binds on a particular receptor-target (so its selective), but that target may be expressed in different tissues and thus may exert different biological effects (so no-specific).

50. ADVERSE EFFECTS OF DRUGS These are unwanted and/or harmful effects I. Predictable or dose-related or type A effects : A. Side effects : These occur at therapeutic doses of a drug. They are usually minor, and decrease or disappear on reducing dose or sometimes with continued use of drug B. Toxic effects : These are due to large toxic doses . They are usually serious, and need stopping drug use, and sometimes supportive treatment to save life. They may be : 1. Functional e.g. respiratory depression OR 2. Structural : causing tissue damage e.g. damage to liver or kidney or heart or nerves