2. Reading assignments: Katzung’s Basic & Clinical Pharmacology,……. 13 th Edi,Ch-2,p20-40; Lippincott Pharmacology,6 th Edi,Ch-2,p25-35;

3. Define terms associated with drug receptor interactions (such as affinity, intrinsic activity/efficacy, agonist/antagonist, partial agonist, drug potency etc) Describe in detail the dose-response relationship Explain drug combinations Describe therapeutic index of a drug Discuss the significance of therapeutic index Identify different types of drug actions Explain mechanisms of drug actions Describe the receptor theory of drug actions Determine the different factors modifying drug action Discuss tolerance and different kinds of receptor regulation (up- and down- regulations) Define Adverse Drug Reactions List different types Adverse Drug Reactions Explain Pharmacovigilance Learning objectives

4. PHARMACODYNAMICS SStudy of biochemical and physiological effects of drugs and mechanisms of actions DDDDose-Response Relationships: Relationship between receptor occupancy and drug effect 1:1 relationship between e ee effect & binding if spare receptors are not involved From: McGraw Hill’s AccessMedicine; Katzung; Figure 2.1 Effect Binding Note similarity to enzyme kinetics

5. Definitions to Know  Receptor:  Receptor: A molecule to which a drug binds to bring about a response  Agonist:  Agonist: A drug that activates its receptor upon binding  Pharmacological antagonist:  Pharmacological antagonist: A drug that binds without activating its receptor and, thus, prevents activation by an agonist  Competitive antagonist:  Competitive antagonist: A pharmacological antagonist that can be overcome by increasing agonist concentration  Irreversible antagonist:  Irreversible antagonist: A pharmacological antagonist that can not be overcome by increasing agonist concentration  Partial agonist:  Partial agonist: A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist  Graded dose-response curve:  Graded dose-response curve: A graph of increasing response to increasing dose  Quantal dose-response curve:  Quantal dose-response curve: A graph of the fraction of a population that shows a specified response at progressively increasing doses.

6.  Intensityproportional to number of receptors occupied  Intensity of response is proportional to number of receptors occupied or concentration of drug-receptor complexes (DR)  Mathematical descriptions and graphical representation of drug- receptor binding and substrate-enzyme complexes are similar inversely related to affinity  Dissociation constant (K D = k -1 /k 1 ) of drug-receptor complex is inversely related to affinity of drug for the receptor Dose-Response Relationships Usually expressed as log-dose response (LDR) curves

7. CCover a wide range of doses TTypically S-shaped or sigmoidal DDrugs acting by same mechanism usually have parallel LDR curves Properties of LDR Measures an increase in response in an individual as dose or concentration is increased  Log dose

8. Graded dose response and dose binding graphs. NBME

9. NNumber of individuals within group responding to a given dose; endpoint is set and an individual is either a r rr responder or a n nn non-responder EE xpressed as n nn normal histogram or c cc cumulative distribution profile; NNormal histogram is usually bell-shaped MMedian effective dose (ED 50 ): dose to which 50% of subjects respond TTherapeutic index and Margin of Safety are based on quantal responses (see next slide) All-or-None (quantal) Response Graded DRC Quantal DRC NBME

10. All-or-None (quantal) Response TI = LD 50 /ED 50 = 400/100 = 400/100 = 4 = 4 MS = LD 1 /ED 99 = 200/250 = 200/250 = 0.8 = 0.8 Measures responsiveness in a population of individuals as dose is increased What should be ideal TI & MS (CSF) with a safe drug? NBME

11. A new drug was studied in a large population of experimental subjects. Which of the following terms best expresses the variation in sensitivity to the drug of the subjects within the study? A. Drug potency B. Graded dose-response curve C. Margin of safety D. Quantal dose-response curve E. Therapeutic index Answer: D Quantal dose-response curves reflect the variance in drug responsiveness within a population

12. Calculate Therapeutic Index from the data below (A)20 (B)8 (C)4 (D)2 (E)0.8 Calculate Therapeutic Index from the data below What does ‘High’ or ‘Low’ TI signifies clinically ?

13. Calculate margin of safety (MS) of this drug? (A)20 (B)8 (C)4 (D)2 (E)0.8

14. Which of the following facts are not true about Quantal dose response curve  (A)Used for Calculation of ED50, TD50, LD50, therapeutic index  (B)Used for Determination of dose, potency for a quantal effect  (C)Used for determining maximal efficacy of a drug  (D)Many lab animals or patients, in groups are taken for different doses  (E)Calculation of % of responders (showing quantal effect) to each dose

15. Note how each of the following alter the log dose response curve for agonist A: B = competitive inhibitor C = allosteric activator D = allosteric inhibitor NBME

16. Classical Terms Used to Describe Drug- Receptor Interactions Log-dose responses for drugs A, B & C 3 agonists

17. Terms  Affinity: propensity of drug to bind with a given inversely related to K D receptor and inversely related to K D ; drug with a K D of 10 ‑ 7 M has a higher affinity for receptor than drug with a K D of 10 ‑ 6 M  Potency: comparative expression relating the dose required to produce a particular effect of given intensity relative to a standard reference; a drug that exerts 50% 10 ‑ 7 Mpotent of its maximal response (ED 50 ) at 10 ‑ 7 M is more potent 10 ‑ 6 M than one with ED 50 of 10 ‑ 6 M maximum response  Efficacy: biological response resulting from binding of drug to its receptor (maximum response is usually assigned a value of 100%) efficacy  Intrinsic activity: often used interchangeably with efficacy (maximum response usually assigned value of 1.0)  Full agonist: stimulates a receptor, provoking a biological response (antonym of antagonist)  Partial agonist: provokes a maximal response somewhat less than a full agonist  Inverse agonist:  Inverse agonist: is based on the concept that there is ongoing basal signal transduction occurring which is reduced by the inverse agonist (this response is blocked by an antagonist) A & C more potent than B A & B have greater Efficacy or Intrinsic Activity than C A & B = Full Agonist; C = Partial Agonist NBME

18. A Model of Drug-Receptor Interaction Note the log dose-response curves for: F ull agonist Partial agonist Antagonist Inverse agonist

19. Competitive Antagonist Interaction of an antagonist with a receptor does not result in stimulus for biological response; but will block the effect of agonist binding at same receptor site  LDR for drug A

20. Properties of a Competitive Antagonist EEffects overcome by increasing dose of agonist (reversible effect) AAs the concentration of the antagonist increases, E EE Emax of agonist does not change IIntrinsic activity = 0 00 0.0 (zero) A fixed dose of a competitive antagonist will cause a parallel shift of the dose response curve for an agonist to the right NBME

21. Noncompetitive (Irreversible or Allosteric) Antagonists EEffect is n nn not completely overcome by increasing agonist concentration NNumber of functional r rr receptors is decreased AAs concentration of antagonist increases, E EE Emax decreases because fewer functional receptors are available AAAAllosteric or irreversible inhibitors A fixed dose of a noncompetitive antagonist will cause a nonparallel, downward shift of the dose-response curve for the agonist to the right.  NBME

22. 21 Determine affinity (when both binding to same Rc), potency and efficacy of agonists Determine safety or toxicity (from the shape of curve) Exercise 1 Uses of dose-response curves AB Efficacy Toxic effect Potency C D EF Therapeutic A > potent than B C > potent but < effective than A & B D < potent but as effective as A & B F > safer than E, although < potent 1234 Log dose 100 50 0 NBME

23.  To determine dose, potency and efficacy of antagonists  A. Dose response curve with an agonist alone  B. Dose response curve with same agonist in the presence of antagonist, (competitive antagonist)  C. Dose response curve with agonist in the presence of another antagonist (competitive antagonist)  D. Dose response curve with agonist in the presence of another antagonist (noncompetitive antagonist) AA & B Effect 12345 Log dose A & C A & D Non-competitive antagonist Competitive antagonists 100 50 0 C > potent than B Exercise 2 Uses of dose-response curves NBME

24. According to the figure, which of the following drugs have Q1.Highest efficacy? Q2.Highest potency? ( A)Drug A (B)Drug B (C)Drug C (D)Drug D (E)Drug E (F)Drug F

25. A vascular smooth muscle strip attached to a tension recording devise was bathed in an organ bath. A dose-response change in vascular tension to acetylcholine (ACh) was assessed. Pretreatment with which of the following would cause a parallel shift in the dose-response curve to ACh to the right? A. Atropine B. Nicotine C. Physostigmine D. Succinylcholine E. Tubocurarine Answer: A Atropine is a competetive antagonist of ACh at muscarinic receptors; thus shifts dose response curve parallel to the right

26. A vascular smooth muscle strip attached to a tension recording devise was bathed in an organ bath. A dose- response change in vascular tension to phenylephrine was assessed. An appropriate dose of phenoxybenzamine was added and the dose-response to phenylephrine was repeated. Which of the following is true with respect to the dose-response curve to phenylephrine obtained after phenoxybenzamine compared to that obtained before phenoxybenzamine was added to the bath? A. The curve was higher B. The curve was lower C. The curve was shifted downward and to the right D. The curve was shifted parallel to the left E. The curve was shifted parallel to the right Answer: C Phenoxybenzamine is an irrevesible antagonist; thus, a right, downward shift of the dose response curve

27. Partial Agonist as an Antagonist A partial agonist can act as inhibitor to a full agonist Acebutolol is a partial agonist at the β 1 -adrenoreceptor Airipiprazole is a partial agonist at the dopaminergic D 2 and at the serotonergic 5-HT 1A receptors NBME

28. Drug X when given in absence of Drug Y produces a submaximal response (in compare to full agonist for the Rcs of drug X) but in the presence of drug Y, it acts as an antagonist (on the same Rcs).Drug X is a a.Full agonist b.Partial agonist c.Competitive antagonist d.Non competitive antagonist e.Reverse agonist

29. EEffect of two drugs is greater than predicted from individual effects Physostigmine (an AChEI) potentiates the response to a aa acetylcholine (ACh) Cocaine (an uptake I blocker) potentiates the effects of n nn norepinephrine (NE) and e ee epinephrine (Epi) Potentiation With drug potentiation there is a shift of the dose response curve for the agonist to the left. NBME

30. A vascular smooth muscle strip attached to a tension recording devise was bathed in an organ bath. A dose-response change in vascular tension to norepinephrine (NE) was assessed. An appropriate dose of cocaine was added and the dose-response to NE was repeated. Which of the following is true with respect to the dose-response curve to NE obtained after cocaine compared to that obtained before cocaine was added to the bath? A. The curve was higher B. The curve was lower C. The curve was shifted downward and to the right D. The curve was shifted parallel to the left E. The curve was shifted parallel to the right Answer: D Cocaine potentiates NE by blocking its re-uptake; thus a parallel shift to the left

31. Learning objectives  Understand the following concepts for signaling mechanisms and drug action role of intracellular receptors that regulate gene expression role of ligand-regulated transmembrane enzymes (protein tyrosine kinases) role of ligand-gated channels role of G-proteins and second messengers mechanisms of receptor desensitization well-established second messengers: cAMP, calcium and phosphoinositide, cGMP interplay among signaling mechanism

32. Signal Coupling Mechanisms Steroids Insulin Growth factors IL-2Cytokines Nicotine Epinephrine hours min min msec sec

33. Ligand-Gated Channels millisecondsionotropic  Signals across the membrane due to changes in ion conductance alter electrical potential of cell; very fast response (milliseconds); ionotropic sodium channel  Nicotinic/ACh--sodium channel

34. GGGGABA--benzodiazepine--chloride channel Hyperpolarization Inhibitory GGGGlutamate/AMPA – s ss sodium channel Depolarization Excitatory GGGGlutamate/NMDA--calcium channel Depolarization Toxicity Excitotoxicity Other Ligand-Gated Channels NBME

35. G Protein-Coupled Receptors metabotropic  There are more than 100 members in the receptor superfamily (“serpentine” or “seven transmembrane” receptors); metabotropic: G- proteins: superfamily of diverse GTP- binding proteins that couple to “serpentine” receptors Agonists promote release of GDP, allowing attachment of GTP to nucleotide-binding site enzymeion channel When GTP is bound, G protein capable of regulating an enzyme or ion channel Signal terminated by hydrolysis of GTP to GDP; slow hydrolysis of GTP allows signal to persist long after ligand has dissociated from receptor G Proteins: G GG Gs stimulates adenylyl cyclase; Gi inhibits adenylyl cyclase & opens a K+ channel; Gq stimulates phospholipase C; Go closes a Ca2+ channel

36. Adenylyl Cyclase System Protein Kinase A  isoproterenol Clonidine 

37. Adenylyl Cyclase System Stimulatory agonist ACTH  agonists (isoproterenol) Glucagon FSH PGE 2 Thyrotropin Dopamine D 1 agonists Inhibitory agonists  2 agonists (clonidine) Muscarinic M 2 agonists Dopamine D 2 D 3 & D 4 agonists Know NBME

38. Clinical Correlates (interference of G-protein system)  1.Pertusis toxin in the respiratory epithelial cells- fuses all αi,ßi,γi subunits of G- protein by ADP Ribosylation→units fail to separate→fails to inhibit Adenylyl Cyclase→increase in c AMP→all respiratory manifestations  2.Cholera toxin in GI mucosa- causes ADP ribosylation of intrinsic GTPase of α stimulatory protein→GTP fails to convert into GDP→increase in α stimulatory activity→increase in c AMP in GI mucosal cells→ severe diarrhoea

39. The figure on the 2 preceding slides depict a signaling pathway for some types of drugs and hormones. Which of the following receptor subtypes is linked via a G i protein? A. Alpha-1 B. Beta-1 C. Beta-2 D. Dopamine-1 E. Muscarinic-2 Answer: E ACh acting on mucarinic-2 receptors signals via G i ; thus a decrease in cAMP or opening of potassium channels

40. Model of Desensitization Beta arrestin kinase pathway phosphorylation dephosphorylation Once receptor is Phosphorylated and binds β-arrestin it is inactive

41. Polyphosphoinositide Signaling System MMuscarinic receptors (M1, M; ex. pilocarpine)  1 -adrenoceptors (phenylephrine) VVasopressin receptors (V 1 ) AAngiotensin receptors (AT 1 ) SSerotonin receptors (5- HT 2 ) GqGqGqGq Phospholipase C Protein Kinase C   Know these examples!!!!! NBME

42. The figure on the preceding slide depicts a signaling pathway for some type of drugs and hormones. Which of the following agonists exerts its major pharmacological effects via this pathway? A. Dobutamine B. Glucagon C. Isoproterenol D. Pilocarpine E. Thyroxine Answer: D Pilocarpine is a M 1 & M 3 muscarinic agonist; thus signals via Gq

43. G-protein and second messenger control of cellular effector system NBME

44. Ligand-Regulated Transmembrane Enzymes (receptor tyrosine kinase) Protein Tyrosine Kinase Signaling: Insulin; Epidermal growth factor (EGF); Platelet derived growth factor (PDGF) Growth Factors Know these examples!!!!! NBME

45. Ligand-Regulated Transmembrane Enzymes (receptor tyrosine kinase) Cytokines Know these examples!!!!!

46. Signals via Gene Expression: Glucocorticoids; Mineralocorticoids; Sex steroid hormones; Vitamin D; Thyroid hormone; Retinoic acid Nuclear Receptors Ligand Responsive Transcription Factors (Nuclear Receptors) Know these examples!!!!! NBME

47. Cytoplasmic Guanylyl Cyclase  Nitric oxide guanylyl cyclase  Nitric oxide (NO, a gas) is formed in endothelial cells and diffuses through plasma membrane of smooth muscle cells activating guanylyl cyclase, converting GTP to cGMP  cGMPkinase G (EDRF)  cGMP activates protein kinase G, resulting in vasodilation; thus nitric oxide was first called endothelial derived relaxation factor (EDRF)  Nitric oxide: also involved in many other physiological and cytotoxic processes (see figure on next slide)

48. Cytoplasmic Guanylyl CyclaseProtein Kinase G  eNOS = endothelial nNOS = neuronal iNOS = inducible  Peroxynitrite ONO 2 - peroxynitrite

49. Which of the following will cause vasodilatation via the induction of nitric oxide synthase according to the pathway depicted in the preceding figure? A. Bradykinin B. Fenoldopam C. Hydralazine D. Isoproterenol E. Sodium Nitroprusside Answer: A Bradykinin,Acetycholine, & Histamine all act on endothealial cells to produce Nitric oxide

50. Other Intracellular Sites for Drug Action  Enzymes  Structural proteins  DNA  RNA Chemotherapy

51. Reprinted from “Rapid Review Series: Pharmacology,” by Pazdernik, Kerecsen, & Shaw, Table 2-1, p. 16, © 2003 Mosby, with permission from Elsevier. Summary Of Signaling Cross-talk Phosphorylation >> Dephosphorylation NBME

52. Which of the following most accurately describes the immediate signal transduction mechanism of insulin when used to treat hyperglycemia in a 15-year-old boy with type 1 diabetes mellitus? A. Activation of adenylyl cyclase B. Activation of gene transcription C. Activation of guanylyl cyclase D. Activation of phospholipase C E. Activation of tyrosine kinase Answer: E Insulin produces its biological affects first by activation a tyrosine kinase pathway resulting in phosphorylation of the internal domain of the receptor

53.  Understand variation in drug responsiveness  idiosyncratic drug response  tachyphylactic response  hypersensitivity response  alteration in concentration of drug that reaches the receptor (pharmacokinetic effect)  variation in concentration of an endogenous receptor ligand  alteration in the number or function of receptors down-regulation up-regulation post-receptor responses Learning objectives

54. Physiological Compensations and Altered Responses DDecreased activity: Tolerance--response diminishes with time Pharmacokinetic tolerance: ○D○Due to the i ii induction of drug metabolizing enzymes ○C○Called metabolic tolerance or drug disposition tolerance ○W○W○W○Warfarin (oral anticoagulant) dose needs to be increased in patient taking barbiturates or phenytoin Pharmacodynamic tolerance: develops at the cellular level; referred to as cellular tolerance; due to c cc changes in receptor numbers or function; M MM Mechanisms: ○D○Desensitization: process occurs rapidly when continuous exposure to an agonist results in conversion of a channel to an altered state that remains closed or when a receptor-coupling element is phosphorylated to an inactive form ○D○Down-regulation: process of ligand-induced endocytosis and degradation of receptor; caused by agonists when administered at high doses for a prolonged period Agonists cause receptor down-regulation   NBME

55. Examples of Pharmacodynamic Tolerance CContinuous exposure to β ββ β-adrenergic agonists, such as occurs in the treatment of asthma with albuterol, results in a decreased responsiveness to the drug TTolerance to the analgesic effects of morphine upon continued use  Decreased sedation from continuous treatment with a b bb benzodiazepine such as diazepam

56. A 26-year-old heroin addict required 100 mg (normal dose =10 mg) of intravenous morphine to relieve severe pain from injuries attained in an automobile accident. Which term best explains why this individual required such a high dose of morphine to relieve pain? A. Pharmacodynamic tolerance B. Pharmacokinetic tolerance C. Potentiation D. Sensitization E. Tachyphylaxis Answer: A Opioid tolerance is due to down- regulation of receptors; thus requiring a large dose to produce an effect

57. Physiological Compensations and Altered Responses DDecreased activity: Tolerance--response diminishes with time Physiological antagonism: ○T○Two agents have o oo opposing physiological effects ○H○Histamine causes vasodilation and norepinephrine causes vasoconstriction ○W○When administered together these agents tend to counteract each other Competitive antagonism: r rr receptor antagonist administered with an agonist ○N○N○N○Naloxone: blocks effects of morphine. ○A○A○A○Atropine: blocks effects of ACh at muscarinic receptor ○P○P○P○Propranolol: blocks effects of isoproterenol at beta- adrenergic receptor  NBME

58. Physiological Compensations and Altered Responses  Increased activity: up-regulationabsence of ligand prolonged presence of antagonist Supersensitivity or hyperactivity: enhanced response to drug may be due to increase in number of receptors (up-regulation); during absence of ligand or prolonged presence of antagonist, ligand-induced receptor endocytosis and degradation decreases, and, therefore, the number of receptors per unit of tissue increases ○ Chemically induced supersensitivity: occurs after prolonged treatment with beta- blockers; some individuals become supersensitive to endogenous release of catecholamines ○ Denervation induced supersensitivity ○ Denervation induced supersensitivity: occurs at postsynaptic receptors when presynaptic nerve is surgically destroyed or lesioned Deficiency in degrading enzymes: usually genetic in nature; abnormal responses are referred to as pharmacogenetic effects succinylcholine ○ Patients with abnormal serum cholinesterase have increased sensitivity to succinylcholine primaquine ○ Individuals with glucose-6-phosphate dehydrogenase deficiency develop acute hemolytic anemia when given primaquine   Antagonists cause receptor up-regulation NBME

59. Physiological Compensations and Altered Responses  Increased activity: plasma albumin binding sites Competition for binding sites: Drugs may displace one another from plasma albumin binding sites, enhancing response to one or both agent(s). ○ If a drug is displaced from plasma protein-binding site, response is intensified and duration of action is shortened. Physiological synergism: Enhanced response may occur when two drugs produce the same or similar effects through different receptors or mechanisms; most CNS depressants act additively or synergistically; diazepam (Valium) plus ethanol produce severe, prolonged CNS depression ○ Terminology describing effects: Additive or summation Additive or summation: 5 + 5 = 10 Synergism Synergism: 5 + 5 = 15 Potentiation Potentiation: 0 + 5 = 20  NBME

60. Learning objectives  Understand dose dependent toxicity  Understand drug allergies  Understand drug idiosyncrasies  Understand Benefit to Risk Ratio  Understand the concept of over extension of the pharmacological response  Understand organ directed toxicity  Know the four major classes of drug allergies Type I Type II Type III Type IV

61. ADVERSE EFFECTS (TOXICOLOGY) TToxicity: Dose related adverse effects of drugs: Benefit-to-risk ratio: This expression of adverse effects; more useful clinically than therapeutic index Overextension of the pharmacological response: Responsible for mild, annoying side effects as well as severe side effects: ○A○A○A○Atropine-induced dry mouth; ○P○P○P○Propranolol-induced heart block; ○D○D○D○Diazepam-induced drowsiness Organ-directed toxicities: toxicity associated with particular organ or organ system: ○A○A○A○Aspirin-induced gastrointestinal toxicity ○A○A○A○Aminoglycoside-induced renal toxicity ○A○A○A○Acetaminophen-induced hepatotoxicity ○D○D○D○Doxorubicin-induced cardiac toxicity NBME

62. ADVERSE EFFECTS (TOXICOLOGY) FFFFetal Toxicity: some drugs are directly toxic whereas others are teratogenic: Directly toxic effects: ○S○S○S○Sulfonamide-induced kernicterus ○C○C○C○Chloramphenicol-induced Gray baby syndrome ○T○T○T○Tetracycline-induced teeth discoloration and retardation of bone growth Teratogenic effects: causes physical defects in developing fetus; effect most pronounced during organogenesis (day 20 of gestation to end of first trimester in human) Human Teratogens: Thalidomide; Antifolates; Phenytoin; Warfarin; Isotretinoin; Lithium; Valproic acid; Fetal alcohol syndrome KNOW this list NBME

63. DDrug Allergies (Hypersensitivity): abnormal response resulting from previous sensitizing exposure activating immunologic mechanism; differs from drug toxicity in: Principle: ○A○Altered reaction occurs only in fraction of population ○D○Dose-response is unusual: minute amount of otherwise safe drug elicits severe reaction ○M○Manifestations of reaction are different from usual pharmacological and toxicological effects of drug ○P○Primary sensitization period before individual experiences response ○B○Being small molecules, most drugs by themselves are not immunogenic; they bind covalently to self-macromolecule or alter structure of self-macromolecule to become immunogenic Types: See Table on next slide ADVERSE EFFECTS (TOXICOLOGY)

64. Types of Drug-Induced Hypersensitivities TypeTarget Organ Clinical Manifestations Mechanism I. Anaphylactic (immediate) Gastrointestinal tract Skin Lung Vasculature Gastrointestinal allergy Urticaria Asthma Anaphylactic shock IgE II. Cytotoxic (autoimmune) Circulating Blood Cells Leukopenia Thrombocytopenia Hemolytic anemia Granulocytopenia IgM, IgG III. Arthus (immune complex) Blood vessels Skin Joints Kidney Serum sickness Vasculitis Arthritis Glomerular nephritis Ag-Ab Complexes IV. Cell- mediated (delayed) Skin Lungs Central nervous system Contact nephritis Tuberculosis Allergic encephalitis Sensitized T-cells Know NBME

65. Hypersensitivity Reactions  Type I: Mediated by synthesis of IgE antibody directed towards allergen IgE molecules bind to blood basophils and tissue mast cells via Fc receptors for antibody When offending drug introduced into body, immediately binds to IgE bound to sensitized cells, resulting in release of mediators (histamine, leukotrienes, prostaglandins) Mediators initiate skin and smooth muscle responses, cause tissue injury and provoke inflammatory response Include anaphylaxis, urticaria and angioedema

66. Hypersensitivity Reactions  Type II:Cytotoxicity  Type II: Cytotoxicity Reactions are usually mediated by IgM or IgG binding to cells or tissue Resulting in the activation of complement and lysis of the cell Destruction of circulating cells  Type III: Mediated by immune complexes: Symptoms of immune-complex induced serum sickness: ○ Urticarial skin eruptions ○ Arthralgia or arthritis ○ Lymphadenopathy ○ Fever Stevens-Johnson syndrome, such as that induced by sulfonamides, is a severe form of immune vasculitis

67.  Type II Reactions: Penicillin-induced hemolytic anemia; Methyldopa-induced autoimmune hemolytic anemia Quinidine-induced thrombocytopenia Sulfonamide-induced granulocytopenia Clozapine-induced granulocytopenia  Type III Immune Vasculitis: Sulfonamides Penicillins Thiouracils Anticonvulsants (especially lamotrigine) Iodides Examples of Type II & III Reactions

68. Hypersensitivity Reactions  Type IV: Cell-mediated or delayed hypersensitivity Often occurs when drugs applied topically Mediated by sensitized T-cells Many drugs and plants (Poison ivy) can induce a contact dermatitis

69. AAbnormal response not immunologically mediated; often caused by g gg genetic abnormalities in enzymes or receptors; referred to as pharmacogenetic disorders. CClassical idiosyncracies: Patients with a aa abnormal serum cholinesterase develop apnea when given normal doses of s ss succinylcholine. "Fast" and "slow" acetylation of i ii isoniazid: ○G○Genetic studies identify individuals as "fast" or "slow" acetylators with bimodal distribution in general population ○"○"Slow" acetylators have low hepatic N-acetyltransferase (NAT) activity and are homozygous for autosomal recessive gene ○"○"Slow" acetylators: more prone to isoniazid-induced vitamin B6 deficiency (may produce anemia and various neuropathies) Drug Idiosyncrasies   Pharmacogenomics Know NBME

70. CClassical idiosyncracies (cont): Hemolytic anemia elicited by p pp primaquine in patients whose red cells are deficient in g gg glucose-6-phosphate dehydrogenase: ○N○Normal erythrocytes have several mechanisms that protect against oxidative insults such as from metabolic derivatives of primaquine ○A○About 10% of black males in the U. S. develop acute hemolytic anemia when given normal therapeutic doses of primaquine Barbiturate-induced p pp porphyria occurs in individuals with abnormal heme biosynthesis: ○M○May induce acute attacks of porphyria ○G○Genetic abnormality is in the pathway of heme biosynthesis ○B○Barbiturate acid moiety mimics part of heme structure, occupying portion of heme site on protein that regulates production of ALA synthetase ○H○Heme is a repressor, inhibiting production of ALA synthetase and reducing porphyrin production Drug Idiosyncrasies Hemolytic anemia in G-6-PDH Deficiency: Primaquine Sulfonamides Nitrofurantoin  Know NBME

71. A 21-year-old woman experiences an asthmatic attack after taking 2 aspirin for a severe headache. Which of the following terms best describes the adverse effect of aspirin in this patient? A. Drug allergy B. Drug idiosyncrasy C. Drug toxicity D. Placebo response E. Tachyphylactic response Answer: B An asthmatic attack produced by NSAIDs in some people is due to a shunt of arrachidonic acid to the lipooxygenase pathway when cyclooxygenase is inhibited; an Idiosyncratic reaction

76. Learning objectives Pharmacotherapeutics:  Understand how the use of drugs are related to pharmacokinetics, pharmacodynamics and adverse effects  Understand the placebo response  Understand the importance of drug interactions  Understand special aspects of Geriatric Pharmacology

77. PHARMACOTHERAPEUTICS  Application of the principles of pharmacokinetics, pharmacodynamics and adverse effects to the treatment of patients  Selection of therapeutic regimen: Accurate diagnosis Knowledge of pathophysiology Knowledge of pharmacokinetics and metabolites in normal and diseased patients Transfer of knowledge to effective bedside action Plan to make specific measurements that will reveal efficacy and toxicity, and determine course for continued therapy  Pharmacogenomics Personalized Medicine Personalized Medicine

78. Placebo Response  Most patients perceive any therapeutic intervention by caring, interested and enthusiastic health care professionals as a positive measure; a factor in alternative medicines and therapies Manifestation in patient may involve objective physiological and biochemical changes and changes in subjective complaints associated with disease 20 and 40% Incidence of a placebo response is constant between 20 and 40% in clinical trials

79. PowerPoint Slides  Several of the PowerPoint slides are Copyright © 2002-04, the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved.  Some of slides in this session are from the above mentioned format and are free for use by members of ASPET.  Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology,MUA), Dr. S. Kacker (co-professor, Clinical Pharmacology & Therapeutics, MUA)  Core concepts of various USMLE High yield review series like Kaplan,BRS etc. are thoroughly explored & integrated whenever necessary