Pharmacodynamics (updated 2011) - drdhriti

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An updated PowerPoint presentation on Pharmacodynamics suitable for UG MBBS level Medical students

An updated PowerPoint presentation on Pharmacodynamics suitable for UG MBBS level Medical students

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  • The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist activates the receptor (R), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates activity of an effector enzyme or ion channel (E). The signal is terminated by hydrolysis of GTP, (alppha subunit has GTPase activity) followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.) The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist activates the receptor (R), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates activity of an effector enzyme or ion channel (E). The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.) The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist activates the receptor (R), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates activity of an effector enzyme or ion channel (E). The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.)
  • PIP2 – phosphatidyl inositol 4,5-bisphosphate
  • Ligand gated channels – enclose ion selective channels – Na, K+, ca++ or Cl within their molecules. 4 domains in each of which amino acid chains traverse
  • Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (left) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently in the plane of the membrane. The cytoplasmic domains become phosphorylated ( P ) on specific tyrosine residues ( Y ) and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins ( S ). The receptor tyrosine kinase signaling pathway begins with ligand binding to the receptor's
  • In cytoplsm and In absence of any ligand, GR resides in association with HSP 90/HSP70 and immunophillins to prevent turning into active conformation. GR has a steroid binding domain and a DNA binding domain having 2 zinc fingers each made up of amino acids with chelated zinc. Binding or steroids detaches HSP90 and thus remove inhibitory influence and dimerization of the receptor occurs. The dimer receptor translocate into the nucleus and interacts with the specific DNA sequence called “responsive element”. Promotion or suppression of transcription -

Transcript

  • 1. Pharmacodynamics Department of Pharmacology NEIGRIHMS, Shillong
  • 2. Contents
    • PRINCIPLES AND MECHANISM OF DRUG ACTION
    • TRANSDUCE MECHANISMS
    • DOSE-RESPONSE RELATIONSHIP
    • COMBINED DRUG EFFECTS
  • 3. What is Pharmacodynamics?
    • What drugs do to the body when they enter?
    • Study of action-effect of drugs and dose-effect relationship
    • Defn.: It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level as well as cellular level
    • Also Modification of action of one drug by another drug
  • 4. PRINCIPLES OF DRUG ACTION
    • Do NOT impart new functions on any system, organ or cell
    • Only alter the PACE of ongoing activity
    • STIMULATION
    • DEPRESSION
    • IRRITATION
    • REPLACEMENT
    • CYTOTOXIC ACTION
  • 5. PRINCIPLE OF ACTION MODE EXAMPLE STIMULATION Selective Enhancement of level of activity of specialised cells - Excessive stimulation is often followed by depression of that function Adr stimulates Heart Pilocarpine stimulates salivary glands Picrotoxin – CNS stimulant  convulsions  coma  death DEPRESSION Selective Diminution of activity of specialised cells Certain drugs – stimulate one cell type and depress others Barbiturates depress CNS Quinidine depresses Heart Ach – stimulates smooth muscle but depresses SA node IRRITATION Non-selective often noxious effect – applied to less specialised cells (epithelium, connective tissue) -stimulate associated function Bitters – salivary and gastric secretion Counterirritants increase blood flow to a site REPLACEMENT Use of natural metabolites, hormones or their congeners in deficiency states Levodopa in parkinsonism Iron in anaemia CYTOTOXIC ACTION Selective cytotoxic action for invading parasites or cancer cells – for attenuating them without affecting the host cells Penicillin, chloroquine
  • 6. Drug Action by Physical/Chemical properties
    • Color – Tincture Card co.
    • Physical mass – Ispaghula
    • Physical form – Dimethicone (antifoaming)
    • Smell - Volatile Oils
    • Taste - Bitters
    • Osmotic action – Mannitol, Magsulf
    • Adsorption – Activated Charcoal
    • Soothing-demulcent – Soothing agents like calamine
    • Oxidizing property – Pot. Permanganate
    • Chelation – EDTA, dimercaprol
    • Radioactivity - Iodine and others
    • Radio-opacity – Barium sulfate
    • Chemical properties – Chelating agents (EDTA, dimercaprol)
    • Scavenging effect – Mesna (with cyclophosphamide)
  • 7. MECHANISM OF DRUG ACTION
  • 8. MECHANISM OF DRUG ACTION
    • MAJORITY OF DRUGS INTERACT WITH TARGET BIOMOLECULES:
    • Usually a Protein
    • ENZYMES
    • ION CHANNELS
    • TRANSPORTERS
    • RECEPTORS
  • 9. 1. Enzymes – drug targets
    • All Biological reactions are carried out under catalytic influence of enzymes – major drug target
    • Drugs – increases/decreases enzyme mediated reactions
    • In physiological system enzyme activities are optimally set
    • Enzyme stimulation is less common by drugs – common by endogenous substrates
      • Pyridoxine (cofactor in decarboxylase activity)
      • Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia)
    • Enzyme inhibition – common mode of DRUG action
  • 10. Effect of Enzyme stimulation Vmax (s) _ Vmax _ ½ Vmax (s) - ½ Vmax - kM(s) kM Substrate conc. Reaction velocity Enz. Stm Enz Ind Normal
  • 11. Enzymes – contd.
    • Nonspecific inhibition: Denaturation of proteins – strong acids, heavy metals, alkalies, alcohol, phenols etc.
    • Specific Inhibition:
    • Competitive Noncompetitive
    • equilibrium
    • nonequilibrium
  • 12. What is specific enzyme inhibition?
    • A drug may inhibit a particular enzyme without affecting others and influence that particular substrate-enzyme reaction ultimately to influence in the product formation
    Normal Drug + Enzyme
  • 13. Competitive Inhibition
  • 14. Enzyme Inhibition - Examples
    • Equilibrium:
      • Physostigmine Vs Acetylcholine (cholinesterase)
      • Sulfonamides Vs PABA (folate synthetase)
      • Moclobemide Vs Catecholamines (MAO-A)
      • Captopril Vs Angiotensin 1 (ACE)
    • Nonequilibrium:
      • Orgnophosphorous compounds/Nerve gases (cholinesterase)
    • Non-competitive:
      • Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) , Aspirin (cyclooxygenase), Digoxin (Na+ K+ ATPase)
  • 15. Effects of enzyme inhibition: Normal Competitive (equilibrium)
  • 16. 2. Ion Channnel
    • Proteins take part in transmembrane signaling and regulates ionic composition
    • Drugs also target these channels: mainly on 3 types
      • Ligand gated channels
      • G-protein operated channels
      • Direct action on channels
    • Examples: BZD opens ligand gated GABA A Cl- channel, Histamine binds GPCR and activates G-protein, local anesthetics – directly blocks channel
    • Many drugs modulate opening and closing of channels: Phenytoin, Ethosuximide, Nifedepine, Quinidine and Nicorandil etc.
  • 17. + + - - + + -- - - + + + + - - Na + + + + + - - - - Resting (Closed**) Open (brief) inactivated Very slow repolarization in presence of LA LA receptor LA have highest affinity for the inactivated form Refractory period LA acting on Na+ receptors
  • 18. 3. Transporters
    • Substrates are translocated across membrane by binding to specific transporters (carriers) – Solute Carrier Proteins (SLC)
    • Pump the metabolites/ions in the direction of concentration gradient or against it.
    • Drugs can interact with these transport system
    • Examples: Probenecid (penicillin and uric acid), Furosmide (Na+K+2Cl- cotransport), Hemicholinium (choline uptake) and Vesamicol (active transport of Ach to vesicles), Thiazides block Na+Cl- symporter, Aphetamine (blocks Dopamine reuptake), Reserpine (blocks grannular reuptake of NA)
  • 19. 4. Receptors
    • Drugs usually do not bind directly with enzymes, channels, transporters or structural proteins, but act through specific macromolecules – RECEPTORS
    • Definition: It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. G-protein coupled receptor
  • 20. Evidences of Drug action via receptors
    • Drugs exhibit structural specificity of action
    • Competitive Antagonism
    • Acetylcholine 1/6000 th of cardiac cells – maximal effect
    1. 2. Piperidine side chain
  • 21. Some Common Terms
    • Agonist: An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine
    • Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine
    • Inverse agonist: an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM in BDZ receptors
    • Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. opioids
    • Ligand: any molecule which attaches selectively to particular receptors or sites (only binding or affinity but no functional change)
  • 22. Drug – Receptor occupation theory – Clark`s equation
    • Drugs can alter cellular function by interacting with receptors
    • D + R DR E (direct
    • function of D + R)
      • But, affinity and intrinsic activity (IA) are different
      • Competitive antagonist – occupy receptor but no IA
    • D + R DR S E
    K 1 K 2 K 1 K 2
  • 23. Some Definitions – contd.
    • Affinity: Ability of a substrate to bind with receptor
    • Intrinsic activity (IA): Capacity to induce functional change in the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy
    • If explained in terms of affinity and IA:
    • Agonist: Affinity + IA (1)
    • Antagonist: Affinity + IA (0)
    • Partial agonist: Affinity + IA (0-1)
    • Inverse agonist: Affinity + IA (0 to -1)
  • 24. Drug-receptor binding and agonism
    • Drug- Receptor:
    D Ri DRa D Ri DRa D Ri DRa D DRi DRa Full agonist Partial agonist Neutral Inverse agonist
  • 25. Receptors – contd.
    • Two essential functions:
      • Recognition of specific ligand molecule
      • Transduction of signal into response
    • Two Domains:
      • Ligand binding domain
      • Effectors Domain – undergoes functional conformational change
  • 26. Two State Receptor Model
  • 27. Nature of Receptors – contd.
    • No hypothesis anymore
    • Cell surface receptors remain floated in cell membrane lipids
    • Functions are determined by the interaction of lipophillic or hydrophillic domains of the peptide chain with the drug molecule
    • Non-polar hydrophobic portion of the amino acid remain buried in membrane while polar hydrophilic remain on cell surface
    • Hydrophilic drugs cannot cross the membrane and has to bind with the polar hydrophilic portion of the peptide chain
    • Binding of polar drugs in ligand binding domain induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain
    • All four major families have common properties but individual receptors have different amino acid sequencing
  • 28. Receptors – contd.
    • Drugs act on Physiological receptors and mediate responses of transmitters, hormones, autacoids and others – cholinergic, adrenergic or histaminergic etc.
    • Drugs may act on true drug receptors - Benzodiazepine receptors
  • 29. Receptor Subtypes
    • Example Acetylcholine - Muscarinic and Nicotinic
      • M 1 , M 2 , M 3 etc.
      • N M and N N
    • Criteria of Classification:
      • Pharmacological criteria – potencies of selective agonist and antagonists – Muscarinic, nicotinic, alpha and beta adrenergic etc.
      • Tissue distribution – beta 1 and beta 2
      • Ligand binding
      • Transducer pathway
      • Molecular cloning
  • 30. The Transducer mechanism
    • Most transmembrane signaling is accomplished by a small number of different molecular mechanisms (transducer mechanisms)
    • Large number of receptors share these handful of transducer mechanisms to generate an integrated response
    • Mainly 4 (four) major categories:
      • GPCR
      • Receptors with intrinsic ion channel
      • Enzyme linked receptors
      • Transcription factors (receptors for gene expression)
  • 31.  
  • 32. G-protein Coupled Receptors
    • Large family of cell membrane receptors linked to the effector enzyme/channel/carrier proteins through one or more GTP activated proteins (G-proteins)
    • All receptors has common pattern of structural organization
    • The molecule has 7 α -helical membrane spanning hydrophobic amino acid segments – 3 extra and 3 intracellular loops
  • 33. GPCR
  • 34. GPCR – contd.
  • 35. G-proteins and Effectors
    • Large number can be distinguished by their α -subunits
    G protein Effectors pathway Substrates Gs Adenylyl cyclase Beta-receptors, H2, D1 Gi Adenylyl cyclase Muscarinic M2 D2, alpha-2 Gq Phospholipase C Alph-1, H1, M1, M3 Go Ca++ channel K+ channel in heart, sm
  • 36. GPCR - 3 Major Pathways
    • Adenylyl cyclase:cAMP pathway
    • Phospholipase C: IP3-DAG pathway
    • Channel regulation
  • 37. 1. Adenylyl cyclase: cAMP pathway PKa Phospholambin Increased Interaction with Faster relaxation Ca++ Troponin Cardiac contractility Other Functional proteins
  • 38. Adenylyl cyclase: cAMP pathway
    • Main Results:
      • Increased contractility of heart/impulse generation
      • Relaxation of smooth muscles
      • Lipolysis
      • Glycogenolysis
      • Lipolysis
      • Modulation of junctional transmission
      • Hormone synthesis
      • Opens specific type of Ca++ channel – Cyclic nucleotide gated channel (CNG) - - -heart, brain and kidney
      • Responses are opposite in case of AC inhibition
  • 39. 2. Phospholipase C:IP3-DAG pathway PKc
  • 40. IP 3 -DAG pathway
    • Main Results:
      • Mediates /modulates contraction
      • Secretion/transmitter release
      • Neuronal excitability
      • Intracellular movements
      • Eicosanoid synthesis
      • Cell Proliferation
      • Responses are opposite in case of PLc inhibition
  • 41. 3. Channel regulation
    • Activated G-proteins can open or close ion channels – Ca++, Na+ or K+ etc.
    • These effects may be without intervention of any of above mentioned 2 nd messengers – cAMP or IP/DAG
    • Bring about depolarization, hyperpolrization or Ca ++ changes etc.
    • Gs – Ca++ channels in myocardium and skeletal muscles
    • Go and Gi – open K+ channel in heart and muscle and close Ca+ in neurones
  • 42. Intrinsic Ion Channel Receptors
  • 43. Intrinsic Ion Channel Receptors
    • Most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels
    • The natural ligands include acetylcholine, serotonin, aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate)
  • 44. Enzyme Linked Receptors
    • 2 (two) types of receptors:
      • Intrinsic enzyme linked receptors
        • Protein kinase or guanyl cyclase domain
      • JAK-STAT-kinase binding receptor
  • 45. A. Enzyme linked receptors
    • Extracellular hormone-binding domain and a cytoplasmic enzyme domain (mainly protein tyrosine kinase or serine kinase)
    • Upon binding the receptor converts from its inactive monomeric state to an active dimeric state
    • Cytoplasmic domains become phosphorylated on specific tyrosine residues
    • Enzymatic activities are activated, catalyzing phosphorylation of substrate proteins
  • 46. Enzyme linked receptors – contd.
  • 47. Enzyme linked receptors – contd.
    • Activated receptors catalyze phosphorylation of tyrosine residues on different target signaling proteins, thereby allowing a single type of activated receptor to modulate a number of biochemical processes
    • Examples:
      • Insulin - uptake of glucose and amino acids and regulate metabolism of glycogen and triglycerides
      • Trastuzumab , antagonist of a such type receptor – used in breast cancer
  • 48. B. JAK-STAT-kinase Binding Receptor
    • Mechanism closely resembles that of receptor tyrosine kinases
    • Only difference - protein tyrosine kinase activity is not intrinsic to the receptor molecule
    • Uses Janus-kinase (JAK) family
    • Also uses STAT (signal transducers and activators of transcription)
    • Examples – cytokines, growth hormones, interferones etc.
  • 49. JAK-STAT-kinase Receptors
  • 50. Receptors regulating gene expression
    • Lipid soluble biological signals cross the plasma membrane and act on intracellular receptors – NO acts by stimulating cGMP
    • Receptors for corticosteroids, mineralocorticoids, thyroid hormones, sex hormones and Vit. D etc. stimulate the transcription of genes in the nucleus by binding with specific DNA sequence – called - “Responsive elements”
  • 51. Receptors regulating gene expression – Clinical implication
    • Hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins – gene active hormonal drugs take time to be active (Bronchial asthma)
    • Beneficial or toxic effects persists even after withdrawal
  • 52. Receptors regulating gene expression
  • 53. Summary of Transducers
  • 54. Functions of Receptors
    • To Regulate signals from outside the cell to inside the effector cell – signals not permeable to cell membrane
    • To amplify the signal
    • To integrate various intracellular and extracellular signals
    • To adapt to short term and long term changes and maintain homeostasis.
  • 55. Non-receptor mediated drug action
    • Physical and chemical means - Antacids, chelating agents and cholestyramine
    • Enzymes, Ion channels and transporters
    • Alkylating agents: binding with nucleic acid and render cytotoxic activity – Mechlorethamine, cyclophosphamide etc.
    • Antimetabolites: purine and pyrimidine analogues – 6 MP and 5 FU
  • 56. Receptor Regulation
    • Up regulation of receptors:
      • In tonically active systems, prolonged deprivation of agonist (by denervation or antagonist) results in supersensitivity of the receptor as well as to effector system to the agonist. Sudden discontinuation of Propranolol, Clonidine etc.
      • Unmasking of receptors or proliferation or accentuation of signal amplification
  • 57. Receptor Regulation
    • Continued exposure to an agonist or intense receptor stimulation causes desensitization or refractoriness: receptor become less sensitive to the agonist
    • Examples – beta adrenergic agonist and levodopa
    • Causes:
      • Masking or internalization of the receptors
      • Decreased synthesis or increased destruction of the receptors (down regulation)
  • 58. Desensitization
    • Sometimes response to all agonists which act through different receptors but produce the same overt effect is decreased by exposure to anyone of these agonists – heterologous desensitization
    • Homologous – when limited to the agonist which is repeatedly activated
    R+ Transducer Homologous Ach Hist Heterologous
  • 59. Mechanism of desensitization ßARK (beta-adrenergic receptor kinase) Beta-arrestin
  • 60. Dose-Response Relationship
    • Drug administered – 2 components of dose- response
      • Dose-plasma concentration
      • Plasma concentration (dose)-response relationship
    • E =
    E max X [D] Kd + [D] E is observed effect of drug dose [D], E max = maximum response, K D = dissociation constant of drug receptor complex E max
  • 61. Dose-Response Curve dose Log dose % response % response 100% - 50% - 100% - 50% - E = E max X [D] Kd + [D]
  • 62. Dose-Response Curve
    • Advantages:
      • A wide range of drug doses can easily be displayed on a graph
      • Potency and efficacy can be compared
      • Comparison of study of agonists and antagonists become easier
  • 63. How we get DRC in vitro Practically??
    • Example: Frog rectus muscle and Acetylcholine response – in millimeters
      • Can compare with a drug being studied for having skeletal muscle contracting property.
  • 64. Practically log1 = 0 log10 = 1 Log20 =1.30 Log40 = 1.60 Log 80 = 1.90 Log160 = 2.20
  • 65. Potency and efficacy
    • Potency: It is the amount of drug required to produce a certain response
    • Efficacy: Maximal response that can be elicited by a drug
    Response Drug in log conc. 1 2 3 4
  • 66. Potency and efficacy - Examples
    • Aspirin is less potent as well as less efficacious than Morphine
    • Pethidine is less potent analgesic than Morphine but eually efficacious
    • Diazepam is more potent but less efficacious than phenobarbitone
    • Furosemide is less potent but more efficacious than metozolone
    • Potency and efficacy are indicators only in different clinical settings e.g. Diazepam Vs phenobarbitone (overdose) and furosemide vs thaizide (renal failure)
  • 67. Slope of DRC
    • Slope of DRC is also important
    • Steep slope – moderate increase in dose markedly increase the response (individualization)
    • Flat DRC – little increase in response occurs in wide range of doses (standard dose can be given to most ptients)
    • Example: Hydralazine and Hydrochlorothiazide DRC in Hypertension
    Hydralazine Thiazide Fall in BP
  • 68. Therapeutic index (TI)
    • Therapeutic Index =
    Median Lethal Dose (LD50) Median Effective dose (ED50) Idea of margin of safety Margin of Safety
  • 69. Therapeutic index (TI)
    • It is defined as the gap between therapeutic effect DRC and adverse effect DRC (also called margin of safety)
  • 70. Combined Effects of Drugs
    • Drug Synergism:
      • Additive effect (1 + 1 = 2)
        • Aspirin + paracetamol, amlodipine + atenolol, nitrous oxide + halothane
      • Supra-additive effect (1 + 1 = 4)
        • Sulfamethoxazole + trimethoprim, levodopa + carbidopa, acetylcholine + physostigmine
    • PABA DHFA THFA
    • Sulfamethoxazole Trimethoprim
    Folate synthase Dihydrofolate reductase
  • 71. Drug Antagonism
    • Physical: Charcoal
    • Chemical: KMnO 4 , Chelating agent
    • Physiological antagonism: Histamine and adrenaline in bronchial asthma, Glucagon and Insulin
    • Receptor antagonism:
      • Competitive antagonism (equilibrium)
      • Non-competitive
      • Non-equilibrium (competitive)
  • 72. Receptor antagonism - curves
    • Competitive:
      • Antagonist is chemically similar to agonist and binds to same receptor molecules
      • Affinity (1) but IA (0), Result – no response
      • Log DRC shifts to the right
      • But, antagonism is reversible – increase in concentration of agonist overcomes the block
      • Parallel shift of curve to the right side
    • Non-competitive:
      • Allosteric site binding altering receptor not to bind with agonist
      • No competition between them – no change of effect even agonist conc. .is increased
      • Flattening of DRC
  • 73. Receptor antagonism - curves
    • Non – equilibrium:
      • Antagonists Binds receptor with strong bond
      • Dissociation is slow and agonists cannot displace antagonists (receptor occupancy is unchanged)
      • Irreversible antagonism developes
      • DRC shifts to the right and Maximal response lowered
  • 74. Drug antagonism DRC
  • 75. Drug antagonism DRC – non-competitive antagonism Response Shift to the right and lowered response Drug in log conc. Agonist Agonist + CA (NE)
  • 76. Spare Receptor
    • When only a fraction of the total population of receptors in a system, are needed to produce maximal effect, then the particular system is said to have spare receptors
    • Example – Adrenaline (90%)
  • 77. Competitive Vs NC antagonism
    • Competitive
    • Binds to same receptor
    • Resembles chemically
    • Parallel right shift of DRC in increasing dose of agonist
    • Intensity depends on the conc. Of agonist and antagonist
    • Example – Ach and atropine, Morphine and Naloxon e
    • Noncompetitive
    • Binds to other site
    • No resemblance
    • Maximal response is suppressed
    • Depends only on concentration of antagonist
    • Diazepam - Bicuculline
  • 78. Summary
    • Basic Principles of Pharmacodynamics
    • Mechanisms of drug action – Enzymes, Ion channels, Transporters and Receptors with examples
    • Definitions of affinity, efficacy, agonist and antagonists etc.
    • Drug transducer mechanisms
    • GPCR and different GPCR transducing mechanisms – cAMP, Protein kinase etc.
    • Up regulation and down regulation of receptors and desensitization
    • Principles of dose response curves and curves in relation to agonist, competitive antagonist etc.
    • Therapeutic index, margin of safety and risk-benefit ratio concepts
    • Combined effects of drugs – synergism etc.
    • Dose response curve (DRC) – agonist and antagonist
  • 79. Thank you