Pharmacodynamics 20 12-2013

1. Pharmacodynamics2012-2013 • According to: • H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed. • H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower: Pharmacology, 6th ed. • R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology, 3rd ed. • R.A.Harvey, P.C.Champe: Lippincott’s Illustrated Reviews: Pharmacology, 4th ed. • R.A.Harvey: Lippincott’s Illustrated Reviews: Pharmacology, 4th ed. • B.G.Katzung, S.B.Masters, A.J.Trevor: Basic and Clinical Pharmacology, 11th ed.

2. PHARMACOLOGY definition:Study of the manner in which the function of living systems is affected by chemical agents. General pharmacology:describes general actions which determine the action and activity of a drug Special pharmacology: description of individual drugs and therapeutic groups of drugs Pharmacodynamics (PD):mechanisms of the effects of drug on the body Pharmacokinetics (PK):the way the body affects the drug during time (absorption, distribution, metabolism, excretion)

3. Specialisation within pharmacology: • a wide field was divided in sub-forms of pharmacology, i.e.: • - molecular pharmacology concerns the effects of drugs from the • point of view of their molecular action • pharmacogenetics (genetic aspects of the action) • - pharmacoproteomics • - clinical pharmacology (clinical use and trial of drugs, TDM) • - toxicology (close to pharmacology) • Pharmacotherapy: very close to P – practical application of P • - causal (it is possible to treat the cause of disease: antimicrobial • therapy, substitution of some enzymes, hormones ..) • - symptomatic (headache...)

4. PHARMACODYNAMICS evaluates effect of the drug within the body – Phases of drug effects maximum onset diminish lag They depend on pharmacokinetics

5. ROUTES OF DRUG ADMINISTRATION • is determined primarily: • - by the properties of the drug (water or lipid solubility, ionization, etc.),- by the therapeutic objectives (e.g. the need of a rapid onset • of action, the need for long-term administration) • - factors associated with the patient • MAJOR ROUTES OF ADMINISTRATION: - enteral, - parenteral • MAJOR TYPES OF DRUG ADMINISTRATION: local and systemic

6. A) ENTERAL :1. O r a l :The most common route (though the most complicated pathway to the tissues). Some drug are absorbed from the stomach.Major site of absorption and of entry to the systemic circulation is duodenum (it provides a larger absorptive surface). Most drug, absorbed from the GIT, enter the hepatic portal circulation  to the liver before then distributed over body via the general circulation !Ingestion of drugs with food can influence absorption. Food in the stomach - delays gastric emptying  some drugs may be destroyed by acid  limited absorption. Enteric coated preparations - may protect the drug from stomach acid (e.g., omeprazole), or prevent gastric irritation (e.g., aspirin). Extended-release preparations- release is prolonged.

7. First-pass metabolism (presystemic metabolism)Most drug, absorbed from the GIT, enter the hepatic portal circulation  to the liver before then distributed over body via the general circulation !First-pass effect of the liver = high metabolism of the drug during its first passage via hepatic circulation  limits often the efficacy of many drugs when taken orally - e.g. propranolol, nitroglycerin. First-pass metabolism (presystemic metabolism) by the intestine or liver limits the efficacy of many drugs when taken orally.

8. 2. R e c t a l : 50% of the drainage of the rectal region bypasses the hepatic portal circulationbiotransformation of drugs that are metabolized by the liver is minimized. ! The rectal route has the additional advantage that it prevents the destruction of the drug by intestinal enzymes or by low pH in the stomach. It prevents also the damage of stomach and some other adverse effects of the drug in GIT !

9. B) PARENTERAL and OTHER: - For drug that are either poorly absorbed from the GIT or for agents (e.g. insulin) that are unstable in the GIT. - Treatment of unconscious patients. - The most frequent reason = the need of the rapid onset of action ! It provides the most control over the actual doseof drug delivered to the body.

10. 1. I n t r a v e n o u s (IV) : Common parenteral route. For drugs that are not absorbed orally often no other choice. The drug is not absorbed by the GIT 1st-pass metabolism by the liver is avoided. Rapid effects and maximal degree of control over the circulating levels of the drug. I.v. injection of some drugs may induce hemolysis or other adverse reaction (caused by the rapid delivery of high concentrations of drug to the plasma and tissues).The rate of infusion must be carefully controlled (similar to intra-arterial administration). ! Risk: the possibility of the most serious and highest adverse effects ! 2. I n t r a a r t e r i a l (IA) (e.g., RTG contrast drugs, anticancer drugs)

11. 3. I n t r a m u s c u l a r (IM) : Drugs can also be in specialized depot preparations - often a suspension of drug in a non-aqueous vehicle (e.g., ethylene glycol, oil). As the vehicle diffuses out of the muscle, the drug precipitates at the site of injection. The drug dissolves slowly  asustained dose over an extended period. E.g. sustained- release haloperidol decanoate - slow diffusion and extended effect. However, i.m. administration is also often used for rapid onset of action(epinephrine in anaphylaxis). 4. S u b c u t a n e o u s(SC) : Absorption is slower. It minimizes the risk of IV injection. Also solids may be used (e.g., capsules with the contraceptives - implanted for long-term activity; programmable mechanical pumps can be implanted to deliver insulin in diabetics).

12. 5. S u b l i n g u a l : Placement under the tongue  drug can diffuse into the capillary network  enter the systemic circulation directly (e.g., nitroglycerin). Drug bypasses the liver and is not inactivated by hepatic metabolism 6. I n h a l a t i o n : Used for gases (e.g., some anesthetics) or the drugs can be dispersed in an aerosol. Rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium actions can be almost as rapid as i.v. injection. E.g.: patients with asthma, chronic obstructive pulmonary disease - drug (beta2 agonists, corticosteroids) is delivered directly to the site of actionsystemic side effects are minimized.

13. 7. T o p i c a l : Used when a local effect of the drug is desired. E.g., the treatment of dermatophytosis - clotrimazole is applied as cream directly to the skin; ophthalmology - tropicamide for mydriasis ! It is necessary to take into consideration that a part of the drug used for topical applications may be absorbed (e.g. glucocorticoids) and then affect the whole organism (e.g., the mechanisms of the regulation of their secretion) ! 8. T r a n s d e r m a l : Itachieves systemic effects by applicationsof drug to the skin, usually via a transdermal patch. Used for the sustained delivery of drugs, (e.g., antimotion sickness - scopolamine; antianginal drug – nitroglycerin; once-a-week contraceptive patch) The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application.

14. 9. I n t r a n a s a l :- Desmopressin (treatment of diabetes insipidus; salmon calcitonin – treatment of osteoporosis – as a nasal spray)- Cocaine - the abused drug - by sniffing. 10. Intrathecal / Intraventricularinto cerebrospinal fluide.g. treatment of malignancies – e.g. methotrexate; amphotericin B - cryptococcal meningitis11. Special delivery systems- microspheres (to improve absorption)- pro-drugs (valaciclovir  aciclovir)- drug bound on the antibody (anticancer drugs)- liposomes (anthracyclines)

15. Changes in physiological functions Decrease Increase paralysis inhibition - + stimulation excitation nonspecific –phys.chem propert. (laxatives) specific - receptors

16. Specific vs. Non-specific mechanisms of drugs action • - non specific mechanisms of drug action (effect): • Not all drugs act via receptors- the mechanism of action is mediated by the chemical or physicochemical properties of a drugs • e.g., antacids chemically neutralize excess gastric acid, general anaesthetics, osmotic diuretics - act by virtue of their physico-chemical properties. • specific mechanisms of drug action (effect) • Drug interacts with specific target macromolecule (receptor) • - Interaction with various target sites -macromolecules(Na-K-ATPase, AChE, as false substrates or inhibitors for transport systems or enzymes).

17. HOW DRUGS ACT : MOLECULAR ASPECTS • TARGETS FOR DRUG ACTION • *Receptors (specialized proteins for perception chemical signals and their transduction to change in biological function) • * Ion channels • * Enzymes • * Carrier molecules

18. Targets for drug action • A drug is a chemical that affects physiological function in a specific way. • With few exceptions, drugs act on target proteins namely ― enzymes ― carriers ― ion channels ― receptors • Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognize only certain classes of drug. • 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.

19. RECEPTORS • Drug receptor = specialized macromolecule present on the cell surface or intracellularlythat binds a drug and mediates its pharmacological action. • Receptors = the sensing elements in the system of chemical communications that coordinates the function of different cells in the body, the chemical messengers being hormone or transmitter substances. • Drug + Receptor  Drug-receptor complex → Biologic effect The formation of the drug-receptor complex  biologic response; the magnitude of the response is proportional to the number of drug-receptor complexes.Receptor not only has the ability to recognize a ligand (drug), but can also couple or transduce this binding into a response by causing a conformational change or a biochemical effect.

20. RECEPTORS • they normally respond to endogenous chemicals in the body. • May mediate highly specific drug action • Two main types of receptor ligands are: • AGONISTS = Drugs that bind to the receptor and activatethem to produce a response • ANTAGONISTS =Drugs thatcombine with receptors, but do not • activate them. • Antagonists reduce the probability of the agonist combining with the receptor and so reduce or block its action.

21. Interaction of receptors with ligands • Formation of chemical bonds • mostly electrostatic and hydrogen bonds and van der Waals forces) – i.e., almost allways noncovalent bonds • covalent bonds are usually irreversible and therefore the effect is usually too high and poorly managable, more important for toxicology

22. The interaction between a drug and the receptordepends on the complementarity of "fit" of the two molecules (the key and the lock). • The precise fit of ligand and the key gives selectivity of interaction • this concerns also chiral properties (steroisomers) • The ability of a drug to combine with one particular type of receptor is calledspecifity (no drug is entirely specific but many have a relatively selective action on one type of receptor). • The „power“ that atract the ligand to the receptor is called affinity • The closer the fit and the greater the number of bonds - the stronger are attractive forces between them - the higher isaffinity • The "lock opening" reflects the activation of the receptor.

23. k+1 stimulus [R] + [A] [RA] EFECTOR EFFECT k-1 modify factors Basic principles The first step of drug action on specific receptors is the formation of a reversible drug-receptor complex, the reactions being governed by the Law of Mass Action – rate of chemical reaction is proportional to the concentrations of reactants R = receptor A = drug RA = drug-receptor complex k+1 = constant of association k-1 = constant of dissociation The activation of receptors is coupled to the physiological or biochemical effectors by means of several types of transduction mechanisms.

24. MAJOR RECEPTOR FAMILIES Mostly proteins that are responsible for transducing extracellular signals into intracellular responses. Four families: 1) ligand-gated ion channels 2) G protein-coupled receptors 3) enzyme-Iinked receptors 4) intracellular receptors. (Note: Pharmacology sometimes defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. I.e., enzymes and structural proteins can be considered to be „pharmacologic receptors“) .

25. Ligand-gated ion channels • Called ionotropic receptors. • Responsible for regulation of the flow of ions across cell membranes • Involved mainly in fast synaptic transmission. • Several structural families, the commonest -heteromeric assemblies of 4 - 5 subunits, with transmembrane helices arranged around a central aqueous channel. • Ligand binding and channel opening occur on milliseconds. Response to these receptors is very rapid. • Examples: nicotinic acetylcholine, gamma-aminobutyric acid type A (GABAA) and 5-hydroxytryptamine type 3 (5-HT 3) receptors.

26. G-protein-coupled receptors • Also calledmetabotropic receptors. • Single peptidewithseven membrane-spanning regions, these receptors are linked to a G protein. One of the intracellular loops is larger than the others and interacts with the G-protein. • The G-protein = membrane protein comprising three subunits (α,,γ), the α-subunit binds GTP,possessing GTPase activity. Binding of the ligand to the extracellular region of the receptor activates the G protein GTP replaces GDP on the α-subunit. • Dissociation of the G protein  both the α-GTP subunit and the ,γsubunit interact with other cellular effectors – so called second messengers (responsible for further actions in the cell). • There are several types of G-protein, which interact with different receptors and control different effectors - Gs, Gi, Go, Gq. • Examples: muscarinic acetylcholine receptor, adrenoceptors and neuropeptide receptors. Responses:several seconds to minutes.

27. Second messengers: A common pathway turned on by Gs - activation of adenylyl cyclase by a-GTP subunits  production of cAMP that regulates protein phosphorylation. G proteins also activate phospholipase C - responsible for the generation of 2 other second messengers - IP3 and diacylglycerol. These effectors are responsible for the regulation of free calcium concentrations within the cell.

28. Effectors controlled by G-proteins • Two key pathways are controlled by receptors, via G-proteins. Both can be activated or inhibited by pharmacological ligands. • Adenylate cyclase (AC)/cAMP: • ― AC catalyses formation of the intracellular messenger cAMP • ― cAMP activates various protein kinases, which control cell function in many different • ways by causing phosphorylation of various enzymes, carriers and other proteins. • Phospholipase C/inositol trisphosphate (IP3)/diacylglycerol (DAG) • ― catalyses the formation of two intracellular messengers, IP3 and DAG, from • membrane phospholipid • ― IP3 increases free cytosolic Ca2+ by releasing Ca2+ from intracellular compartments • ― increased free Ca2+ initiates many events, incl. contraction, secretion, enzyme • activation and membrane hyperpolarisation • ― DAG activates protein kinase C control of many cellular functions by • phosphorylating of proteins. • Receptor-linked G-proteins also control: ― phospholipase A ( formation of arachidonic acid and eicosanoids) • ― ion channels (e.g. K and Ca channels  affect membrane excitability, transmitter release, contractility, etc.).

29. Enzyme-Iinked receptors (Kinase-linked receptors) • Cytosolic enzyme activity is an integral component of their structure or function. • Binding of a ligand to an extracellular domain activation or inhibition of this cytosolic enzyme activity. • Duration of responses - minutes to hours. • The most common - with a tyrosine kinase activity as part of their structure. Binding of a ligand activates the kinase  phosphorylation of tyrosine residues of specific proteins. • E.g., when insulin binds two receptor molecules, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates target molecules-insulin-receptor substrate peptides-that subsequently activate other important cellular signals (e.g., IP3, and the mitogen-activated protein kinase system).

30. Receptors for various hormones (e.g. insulin) and growth factors incorporate tyrosine kinase in their intracellular domain. • Cytokine receptors have an intracellular domain that binds and activates cytosolic kinases when the receptor is occupied. • Common architecture - with a large extracellular ligand- binding domain connected via a single -helix to the intracellular domain. • Signal transduction generally involves dimerisation of receptors, followed by autophosphorylation of tyrosine residues. The phosphotyrosine residues act as acceptors for the SH2 domains of a variety of intracellular proteins, thereby allowing control of many cell functions. • Two important pathways are: • ― the Ras/Raf/MAP kinase pathway, which is important in cell division, growth and • differentiation • ― the Jak/Stat pathway - is activated by many cytokines; it controls the synthesis and release of many inflammatory mediators. • A few hormone receptors (e.g. atrial natriuretic factor) have a similar architecture and are linked to guanylatecyclase.

31. Protein phosphorylation in signal transduction • Many receptor-mediated events involve protein phosphorylation, which controls the functioning and binding properties of intracellular proteins. • „Kinasecascades“ mechanisms that leads to amplification of receptor-mediated events involes: • Receptor-linked tyrosine kinases • Cyclic nucleotide-activated tyrosine kinases • Intracellular serine/threonine kinases • There are many kinases, with differing substrate specificities, allowing specificity in the pathways activated by different hormones or cytokins . • Desensitisation of G-protein-coupled receptors occurs as a result of phosphorylation by specific receptor kinases, causing the receptor to become non-functional and to be internalised. • There is a large family of phosphatases that act to reverse the effects of kinases.

32. Intracellular receptors (nuclear receptors) regulate gene transcription The receptor is intracellular ligand must diffuse into the cell to interact with the receptor. (some are actually located in the cytosol rather than the nuclear compartment) E.g., steroid and thyroid hormones, vitamin D. Receptor becomes activated because of the dissociation of a small repressor peptide. Activated ligand-receptor complex migrates to the nucleus, where it binds to DNA sequences regulation of gene expression. The time course of activation and response of these receptors is much longer, cellular responses delayed (30 minutes or more), and the duration of the response (hours to days) is much greater than in other receptors.

33. Receptors that control gene transcription (nuclear receptors) - intracellular receptors • Ligands: e.g., steroid hormones, thyroid hormones, vitamin D and retinoic acid, certain lipid-Iowering and antidiabetic drugs. • Receptors are intracellular proteins, so ligands must first enter cells. • Receptors consist of a conserved DNA-binding domain attached to variable ligand-binding and transcriptional control domains. • DNA-binding domain recognises specific base sequences, thus promoting or repressing particular genes. • Pattern of gene activation depends on both cell type and nature of ligand, so effects are highly diverse. • Effects are produced as a result of altered protein synthesis therefore, theyare slow in onset (min 30 min delay); actiondurationis long (hours to days)

34. Terminological note: Transmitter substances - chemicals released from nerve terminals; they bind to the receptors  sequence of post-synaptic events  effects (e.g., muscle contraction or glandular secretion). Inactivation by enzymic degradation or reuptake. Hormones - chemicals released into the bloodstream physiological effects on tissues - specific hormone receptors. Drugs may interact with the endocrine system by  or hormone release or by activation (e.g.steroidal anti-inflammatory drugs), or blockade (e.g., oestrogen antagonists) of the receptors. Local hormones(autacoids) - histamine, serotonin, kinins, prostaglandins - released in pathological processes. Enzymes Catalytic proteins that increase the rate of chemical reactions in the body. Some drugs act by inhibiting enzymes (anticholinesterases, MAO inhibitors, inhibitors of COX).

35. SECOND MESSENGERS • Chemicals whose intracellular concentration increases or, more rarely, • decreases response to receptor activation by agonists and trigger • processes that eventually result in a cellular response. • The most studied second messengers: • - Ca ions, • - cAMP, • - inositol-1,4,5-triphosphate (IP3), • - diacylglycerol (DG) • cAMP - from ATP by adenyl cyclase (e.g. when -adrenoceptors • are stimulated). cAMP activates protein kinase A which phosphorylates • a protein (enzyme or ion channel) leading toa physiological effect. • IP3 and DG- formed from membrane phosphatidylinositol • 4,5-biphosphate by activation of a phospholipase C. Both messengers • can, like cAMP, activate kinases, but IP3 does this indirectly by • mobilizing intracellular calcium stores. Some muscarinic effects • of acetylcholine and alpha1-adrenergic affects involve this mechanism.

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

37. Graded dose-response curve (DRC) • (or concentration-response curve (CRC) • Quantitative– evaluating magnitude in change of action • As the concentration of a drug increases, the magnitude of its effect also increases. • The relationship between dose and response is continuous, and can be described for many systems by application of the law of mass action. • The response is a graded effect, meaning that the response is continuous and gradual. • Relationship between dose and response(effect). • A graph of the relationship = a graded dose-response curve is given by plotting the magnitude of the effect (ordinate) against the log of the drug dose or concentration (abscissa) -a rectangular hyperbola. • (Few exceptions: a quantal response - all-or-nothingresponse).

38. Two important properties of drugs can be determined by graded DRC: 1/ Potency (affinity),a measure of the amount of drug necessary to produce an effect of a given magnitude. 2/ Efficacy(intrinsic activity)of the drug. Agonist =a drug capable of fully activating the effectors when it binds to the receptor.

39. effect 50% EC50 c 10-8 10-7 10-6 10-5 10-4 Log-concentration-effect curve (graded DRC) (results are displayed as CRC/DRC) potency (affinity) efficacy (intrinsic act.) slope of the curve

40. AFFINITY (POTENCY): • This is a measure of how avidly a drug binds to its receptor. • Measure of how much drug is required to elicit a response (the lower the dose, the more potent the drug) • It is characterized by the equilibrium dissociation constant (KD)- the ratio of rate constants for the reverse (k-1) and forward (k+1)reaction between the drug and the receptor. • The concentration producing an effect that is 50 % of the maximum is used to determine potency -commonly designated as the EC50. • EC50, ED50 or pD2 =parameters of affinity of a drug • EC50 or ED50 = the concentration or dose needed to produce a 50% maximalresponse;  the lower EC50 or ED50 , the higher affinity • pD2= negative decade logarithm of the concentration of drug that produces 50% of the maximum response (e.g., drug with pD2 = 7 induces 50% of the maximum response in the concentration 10-7, if pD2 = 5, the concentration is 10-5¨)  the higher pD2, the higher affinity !

41. EFFICACY (intrinsic activity) The maximal response produced by a drug (Emax), depends on the number of drug-receptor complexes and the efficiency with which the activated receptor produces a cellular action. A drug with greater efficacy is more therapeutically beneficial than one that is more potent.

42. Slope of DRCThe slope of the mid portion of DRC varies from drug to drug. A steep slope= a small increase in drug dosage produces a large change in responses. It indicates how much increase in drug dosage produces a desirable change in response.

43. Agonists: Drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand agonist. E.g., phenylephrine is an agonist at a1 adrenoceptors, because it produces effects that resemble the action of norepinephrine. Agonist may have many effects that can be measured, including actions on intracellular molecules, cells, tissues, and intact organisms. All of these actions are attributable to interaction of the drug molecule with the receptor molecule.

44. Types of agonists: F u l l agonists- induce a maximal response when all receptors are occupied P a r t i a l agonists produce less than the full effects, even when all receptors are occupied (The partial agonist may be more, less, or equally potent. Potency is an independent factor) In the presence of a full agonist, a partial agonist acts like a competitive inhibitor. Inverse agonist – it stabilizes receptor in its inactive conformation (effects are opposite to those of agonist; e.g. in G-protein coupled receptors - famotidine, losartan, metoprolole)

45. Agonists effect 100% EC50 = 10-6 β = 1 EC50 = 10-8 α = 1 50% EC50 = 10-8 γ = 0,5 c 10-10 10-9 10-8 10-7 10-6 10-5 10-4

46. Partial agonist • efficacy (intrinsic activity) > than zero but < than efficacy of a full agonist. • It cannot produce as high (max.) response as full agonist even inthe case that all the receptors are occupied! • Note: partial agonist may have affinity higher, lower or equivalent to that of a full agonist. • It may act as an antagonist of a full agonist (as the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist). • The potential of partial agonists to act both agonistically and antagonistically may be used therapeutically . • E.g., aripiperazole (atypical neuroleptic) = a partial agonist at selected D receptors overactive dopaminergic pathways are inhibited, underactive pathways may be stimulated  ability to improve many of the symptoms of schizophrenia, with a small risk of extrapyramidal adverse effects.

47. DRUG ANTAGONISM • The effect of one drug is diminished or abolished in the presence of • another drug. • /1/ Chemical antagonism • Interaction of two substance based on their chemical properties  aloss • of all effects of a drug (e.g., chelators bind the metal ionsto form an • inactive complex, protamine - ionically binds to heparin). • /2/ Pharmacokinetic antagonism • "Antagonist" reduces the concentration of active drug at its site of action • in various ways: e.g., an increase of the biotransformation of the • anticoagulants during the use of phenobarbitone (enzyme induction), • decrease or increase in the excretion ...

48. /3/ Antagonism by receptor block • Antagonists in this sense are drugs that bind to receptors but do not • activate them and thereby it decrease the effect of an agonist • A) competitive (reversible) antagonism: • Competitive antagonists bind reversibly with receptors at the same site as the agonist but induce no action – they block the receptor for agonist • The response can be returned to normal by increasing • the dose of agonist as this increases the probability of agonist-receptor • collisions at the expense of antagonist receptor collisions. • The ability of higher doses of agonist to overcome the effects of the • antagonist  aparallel shift of the dose-response curve to the right • The maximum response is not depressed • ! Competitive antagonist has no intrinsic efficacy !

49. B) Non-competitive antagonism: • There is a decrease in the maximum response present without a DRC shift • Two main mechanisms for absence of true competition: • a) Irreversible antagonism: • Antagonist binds with the same site as the agonist but dissociates very • slowly, or not at all, from thereceptors(due to the covalent bond) •  no change (or nearlyno change) in the antagonist occupancy when • the agonistis applied. • Irreversible competitive antagonism occurs with drugs that • form covalent bonds with receptors (e.g., phenoxybenzamine ...) • b )Antagonism due negative allosteric modulation • Antagonist binds to receptor at the site different from the agonist binding • site • either prevents binding of the agonist or • preventsthe agonist from activating the receptor

50. Antagonist interrupts receptor-effector linkage. (e.g., Ca blockers prevent influx of Ca ions through the membrane block the contraction of smooth muscle produced by other drugs). There is the reduction of the slope and maximum agonist DRC !