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Drug receptors in pharmacology
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Drug receptor interactions and types of receptor

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Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism

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Drug receptor interactions and types of receptor

  1. 1. DRUG RECEPTOR INTERACTIONS Dr. Siddhartha Dutta Mamc, New Delhi
  2. 2. CONTENTS Introduction Targets for drug binding Types of receptors Determinants of drug activity Receptor theories Drug receptor interactions Desensitisation and tachyphylaxis Conclusion
  3. 3. HISTORY  1878 – John Langley  1905 - Receptive substance on surface of skeletal muscle mediate drug action. Different in different species  Paul Ehrlich designated 'receptor‘ to be anchoring group of the protoplasmic molecule for the administered compound  “Corpora non agunt nisi fiata”
  4. 4.  1948 - Ahlquist showed the differential action of adrenaline & demonstrated its effects on two distinct receptor populations & the theory of receptor-mediated drug interactions gained acceptance  1970s - Pharmacology entered a new phase following the development of receptor-labelling techniques which made it possible to extract and purify the receptor material.
  6. 6. Drug is any substance or product that is used for diagnosis, prevention, treatment/cure of a disease or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the
  7. 7.  Cellular macromolecule, or an assembly of macromolecules, mainly protein in nature present on the surface of the cell membrane or inside the cell, concerned directly and specifically in chemical signaling between and within the cells
  8. 8. TYPES OF RECEPTORS  Ligand Gated Ion Channels  G-Protein Coupled receptors  Enzyme Linked receptors  Nuclear receptors
  9. 9. LIGAND GATED ION CHANNELS  Ionotropic Receptors  Typically receptors on which fast neurotransmitters act  Timescale: Milliseconds  Localization: Membrane  Effector: Ion Channel  Coupling: Direct  Gating mechanism: conformational change occurs in extracellular part of the receptor  Examples: Nicotinic Ach Receptor, GABA-A Receptor, Glutamate Receptor, Glycine receptor, 5–HT3, AMPA & kinate receptors
  10. 10. VOLTAGE OPERATED CHANNELS  These channels open when the cell membrane is depolarised. They underlie the mechanism of membrane excitability  Activation induced by membrane depolarisation is short lasting, even if the depolarisation is maintained  The most important channels in this group are selective sodium, potassium or calcium channels
  11. 11. G – PROTEIN – COUPLED RECEPTORS  Largest family  Metabotropic or 7–Transmembrane/Heptahelical (α- helices) receptors  Extracellular N-terminal domain and intracellular C- terminal domain  3rd cytoplasmic loop couples to the G- Protein  Timescale : Seconds  Location : Membrane  Effector : Channel or Enzyme  Coupling : G- Protein  Examples : adrenoceptors, Muscarinic Ach, histamine, serotonin, opioid, cannabinoid, amine, peptide, prostanoid
  12. 12. TARGETS FOR G-PROTEINS  Adenylate cyclase
  14. 14.  Ion Channels like K⁺ and Ca⁺⁺ channels are controlled by direct interaction between the βγ-subunit of G0 and the channel  Phospholipase A2(formation of arachidonic acid and eicosanoids)  Rho A/Rho kinase, a system that controls the activity of many signaling pathways controlling cell growth and proliferation, smooth muscle contraction, etc.  Mitogen-activated protein kinase (MAP kinase), activated by cytokines and growth factors acting on kinase-linked receptors and by GPCR ligands. Controls processes involved in cell division, apoptosis and tissue regeneration
  15. 15. KINASE LINKED AND RELATED RECEPTORS  Large, heterogenous group responding mainly to protein mediators.  Timescale : Hours  Location : Membrane  Effector : Protein Kinases  Coupling : Direct  Examples : Insulin, Growth Factors, Cytokine, ANF receptors
  16. 16. NUCLEAR RECEPTORS Two main categories: 1) Present in the cytoplasm, form homodimers and migrate to the nucleus. Their ligands are mainly endocrine in nature (e.g. steroid hormones) 2) constitutively present in the nucleus and form heterodimers with the retinoid X receptor. Their ligands are usually lipids (e.g. fatty acids).  A third subgroup transduce mainly endocrine signals but function as heterodimers with retinoid X receptor (e.g. thyroid hormone).  ligand-receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting co-activator or co-repressor factors
  17. 17. DRUG RECEPTOR INTERACTIONS  LIGAND: Any molecule which attaches selectively to particular receptor  AFFINITY: Capability of drug to bind to the receptor and form receptor complex  INTRINSIC ACTIVITY: Ability of the drug to trigger the pharmacological response after forming complex
  18. 18. DETERMINANTS OF DRUG ACTIVITY  Efficacy: The ‘strength’ of the agonist–receptor complex in evoking a response of the tissue  Potency: Amount of drug needed to produce an effect.
  20. 20. OCCUPATION THEORY, CLARK’S (1926)  Drugs act on independent binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor complex formed.  D + R  DR  RESPONSE  Intensity of pharmacological effect is directly proportional to number of receptors occupied  The response ceases when this complex dissociates  Maximal response occurs when all the receptors are occupied at equilibrium  Limitations ??
  21. 21. THE INDUCED-FIT THEORY, DANIEL KOSHLAND (1958)  States that the morphology of the binding site is not necessarily complementary to the preferred conformation of the ligand  Binding produces a mutual plastic molding of both the ligand and the receptor as a dynamic process.  The conformational change produced by the mutually induced fit in the receptor macromolecule is then translated into the biological effect, eliminating the rigid and obsolete “ key and lock” concept  Agonist induces conformational change – response  Antagonist does not induce conformational change – no response
  22. 22. PATON’S RATE THEORY (1961)  The response is proportional to the rate of drug-Receptor complex formation  Effect is produced by the drug molecules based on the rates of association and dissociation of drugs to and from the receptors  Antagonists act much more slowly than agonists do and hence the rate of dissociation is inversely proportional to the potencies of antagonists while is directly proportional to the agonists  Type of effect is independent of number of receptors rather rate of binding and release from the receptor.
  23. 23. THE TWO-STATE (MULTISTATE) RECEPTOR MODEL  Developed on the basis of the kinetics of competitive and allosteric inhibition  It postulates that a receptor, regardless of the presence or absence of a ligand, exists in two distinct states: the R(active) and R* (inactive) states  R and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor  Occupied receptor can switch from its ‘resting’ (R) state to an activated (R*) state, R* being favored by binding of an agonist but not an antagonist
  24. 24.  Added drug encounters an equilibrium mixture of R and R*  If it has a higher affinity for R* than for R, the drug will cause a shift of the equilibrium towards R* (i.e. it will promote activation and be classed as an agonist)  If its preference for R* is very large, nearly all the occupied receptors will adopt the R* conformation and the drug will be a full agonist (positive efficacy)  Shows only a modest degree of selectivity for R*, a smaller proportion of occupied receptors will adopt the R* conformation(partial agonist  Shows no preference, the prevailing R:R* equilibrium will not be disturbed and the drug will be a neutral antagonist(zero efficacy)  Shows selectivity for R it will shift the equilibrium towards R and be an inverse agonist (negative efficacy)
  25. 25. AGONIST  A drug that binds to physiological receptor and mimic the regulatory effects of endogenous substance.  It has high affinity and high intrinsic activity
  26. 26. TYPES OF AGONISM  Summation :- Two drugs eliciting same response, but with different mechanism and their combined effect is equal to their summation. Aspirin Codiene PG Opiods receptor Analgesic+ Analgesic+ ++
  27. 27.  Additive: combined effect of two drugs acting by same mechanism Aspirin NSAIDS PG PG Analgesic+ Analgesic+ + +
  28. 28. SYNERGISM (SUPRA ADDITIVE):- The combined effect of two drug effect is higher than either individual effect.  1.Sulfamethaxazole+ Trimethoprim  2. Levodopa + Carbidopa.
  29. 29. PARTIAL AGONIST  Full affinity + low intrinsic activity  Partly as effective as agonist  Greater affinity for RA than RI  Cannot produce a full biological response at any concentration ex: Pentazocine
  30. 30. INVERSE AGONIST:  Full affinity & intrinsic activity<0(0 to-1)  Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity).  Eg. Beta carbolines on BZD receptor  Chlorpheneramine on H1,  Risperidone/clozapine/chlorpromazine on 5-HT2a  Ziprasidone/olanzapine on 5-HT2c
  31. 31. ANTAGONIST  A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has no activity. Types of Antagonism 1. Chemical antagonism 2. Physiological /Functional antagonism 3. Pharmacokinetic antagonism 4. Pharmacological antagonism  Competitive ( Reversible/irreversible)  Non competitive (Irreversible)
  32. 32. PHARMACOKINETIC ANTAGONISM  Antagonist effectively reduces the concentration of the active drug at its site of action  Either by increased metabolic degradation, decreased absorption or increased excretion  A- Calcium & tetracycline, Cholestyramine & warfarin/digoxin  D- Phenylbutazone & warfarin  M- ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP ↓ ciprofloxacin/chloramphenicol/erythromycin & theophylline  E- ↓ Probencid/aspirin/sulfonamides/thiazides/indomethacin & penicillin/zidovudine, NSAIDS & methotrexate/ furosemide
  33. 33. PHARMACOLOGICAL ANTAGONISM Competitive antagonism- Reversible - Irreversible 1) Reversible antagonism  Antagonists that bind reversibly to the same receptor site as that of an agonist  Surmountable  Shift of the agonist log concentration–effect curve to the right, without change of slope or maximum effect  Linear relationship between agonist dose ratio and antagonist concentration
  34. 34.  Shift is expressed as a dose ratio, r, (the ratio by which the agonist concentration has to be increased in the presence of the antagonist in order to restore a given level of response)  Agonist reduces the rate of association of the antagonist molecules  Consequently, the rate of dissociation temporarily exceeds that of association, and the overall antagonist occupancy falls.
  35. 35. IRREVERSIBLE ANTAGONISM  It occurs when the antagonist dissociates very slow or not at all from the receptors results no change when the agonist applied.  Antagonist effect cannot be overcome even after increasing the concentration of agonist  Occurs with drugs that possess reactive groups that form covalent bonds with the receptor  Aspirin, omeprazole and MAO inhibitors
  36. 36. SPARE RECEPTORS  Receptors are said to be spare when, the maximal response can be elicited by an agonist at a concentration that does not result in 100% occupancy of available receptors  Agonist has to bind only a portion of receptors for full effect- increase sensitivity of the system  Many full agonists are capable of eliciting maximal responses at very low occupancies, often less than 1%  Spare receptors, or a receptor reserve denotes that the pool is larger than the number needed to evoke a full response  For a biological response economy of hormone or transmitter secretion is thus achieved at the expense of providing more receptors
  37. 37. DESENSITISATION & TACHYPHYLAXIS  TACHYPHYLAXIS  The effect of a drug gradually diminishes when it is given continuously or repeatedly, which often develops in the course of minutes  Tolerance- Gradual decrease in responsiveness to a drug, taking days or weeks to develop.  Refractoriness is used to indicate loss of therapeutic efficacy  Drug resistance is used to indicate loss of effectiveness
  38. 38. MECHANISM OF DESENSITISATION  Change in receptors- Ion channels  Translocation of receptors- beta adrenoreceptor  Exhaustion of mediators-amphetamines  Increased metabolic degradation- alcohol/nitrates  Physiological adaptation-thiazide
  39. 39. BIASED AGONISM  Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a “biased” agonist compared to a “balanced” agonist  The ability of some ligands to selectively activate some signaling pathways while blocking others  Peptides PACAP1-27 and PACAP1-38 activate PACAP (pituitary cyclase-activating polypeptide type 1) receptors to elevate cyclic AMP and increase production of IP3  The receptor is not the minimal unit of control of agonism, it is the agonist-receptor complex that controls the ultimate signaling event  Nature of the receptor-active state and the interaction of the activated receptor with the multiple cytosolic signaling
  40. 40.  Molecular dynamics predicts that when proteins such as receptors change conformation, different regions of the receptor change independently (i.e., the protein does not form uniform global conformation)  Signaling protein s interact with different regions of the receptor  Unique receptor conformations stabilized by agonists most likely will result in differential (biased) activation of cell signaling pathways  Activation of a receptor that interacts with multiple signaling components in a cell most likely will never produce equal activation of all pathways  Functionally selective agonists are defined as having a signaling bias different from that of the natural agonist
  41. 41. CONCLUSION
  42. 42. THANK YOU
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Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism


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