PHARMACODYNAMICS FOR BEGINNER IN ANAESTHESIA

PHARMACODYNAMICS

1. PHARMACODYNAMICS PRESENTER IZZATUL SUPERVISOR: DR THANESH

2. pharmacodynamics The study of the actions of drugs on living material at all levels, subcellular, cellular, tissue, organ and the whole organism

3. Mechanism of action How drugs change physiological, biochemical or pathological effect. Drug can interacts with following target sites in a cell Receptors Ion channels Enzymes Carrier molecules

4. Receptor mediated mechanism Receptor is a macromolecular complexes with recognition sites that selectively bind and interact with drugs to produce their characteristic biological effects Receptor functions: recognition of specific ligand molecule Transduction of signal into response

5. Clark’s Receptor Occupancy Theory The proportion of receptors occupied by drugs, is equal to the ratio of the effect produced to the maximal possible effect, E/ Emax Stephenson’s Receptor Theory The maximal effect can be produced by some agonist when only small proportion of the receptor is occupied

6. Drug receptor interaction: Selectivity: degree of complimentary co relation between drug and receptor Affinity: Ability of drug to get bound to the receptor Intrinsic activity/Efficacy: Ability of a drug to trigger pharmacological response after making drug receptor complex Four types of receptor binding Covalent- stable, essential irreversible; shared electrons Ionic electrostatic attraction between ions, strength diminishes as the square of the distance between ions Hydrogen- formed between hydrogen and two electronegative atoms Van der Waals forces

7. Types of receptors: Ligand-gated ion channels localized on cell membrane and coupled directly to an ion channel Enclose ion selective channels (Na, K, Ca, or Cl) within their molecules Eg : - nicotinic cholinergic receptor GABAa receptor NMDA receptor 5-HT3 receptors

8. G-Protein Coupled Receptors (GCPR) Large family of cell membrane receptors linked to the effector through GTP activated proteins (G-proteins) G-proteins: - heterotrimetric nucleotide regulatory proteins that translates a signal to a biological event inside cells. - Made up of 3 subunits designated α , β and γ When activated receptor bind to G-protein, it induce the G-protein to exchange GDP for GTP-> α -subunit to separate->second messengers

9. cAMP system

10. Inositol triphosphate (IP3) and (DAG) pathway

11. Enzyme Linked Receptor This class of receptors have subunit with enzymatic property (intrinsic) or bind a JAK enzyme on activation. The agonist binding site and the catalytic site lie respectively on the outer and inner face of the plasma membrane Intrinsic enzyme receptors: the intracellular domain is either a protein kinase or guanyl cyclase ( eg : Insulin, Epidermal growth factor), platelet derived growth factor. atrial natriuretic factor Cytokine receptors: Do not have intrinsic activity but agonist induced dimerization increases affinity for a cytoplasmic tyrosine protein kinase JAK. Eg : Growth hormone, erythropoietin, interferon)

12. Drug crosses the cellular membrane activates an intracellular receptor that regulates gene transcription. Eg : Glucorticoids , mineralcorticoids , adrogens , estrogen, thyroid hormone Cytoplasmic or Nuclear Receptor

13. DOSE- response RELATIONSHIP

14. Range of concentration over which drug produces increasing response EC 50 is directly proportional to the Kd but inversely propotional to the affinity potency

15. efficacy The ability of a drug bound to a receptor to produce an effect

16. slope Indicates the number of receptors that must be occupied before drug effect occurs

17. Spare receptor theory Exist when occupancy of only a few receptors by full agonist results in maximal response Allow explanation for agonist with low affinity for receptors to produce full response at low concentrations, to the extent that EC50 (Dose-response) is lower than KD (drug dissociation)

18. Quantal dose-effect curves Quantal response is an “either/or” event relates dose and frequency of response in a population of individuals Describe population rather than single individual esponse to drugs Based on plotting cumulative frequency distribution of responders against log drug dose

19. THERAPEUTIC INDEX Margin of safety Depend upon factor of dose producing desirable effect -> dose eliciting toxic effect Therapeutic window: plasma concentration that produce therapeutic effects in a large proportion of patients while producing adverse effects in few

20. AGONIST AND ANTAGONISM

21. Drugs that bind to physiological receptors causes the receptor to transduce a physiological response and mimic the effect of endogenous regulatory compounds. Both with high affinity and efficacy Full agonist is an agonist with maximal efficacy Partial Agonist – agents produce a lower response at full receptor occupancy Inverse agonist is a drug which act by same receptor as agonist but produce opposite effect Agonist

22. antagonism There are 4 types of antagonism:- Pharmacological Competitive Non competitive Physiological Chemical Pharmacokinetic

23. Competitive antagonism Compete with agonist for the receptor Can be overcome by increasing the agonist concentration Displace the agonist dose effect curve to the right Not affecting maximal efficacy

24. Non competitive antagonism Bind irreversibly to the receptor or an associated molecule Effects are not reversed by increasing concentration of the agonist Decrease maximal efficacy Eg : Phenoxybenzamine , organophosphate

25. ISOMERISM Occur when two or more compounds have same atomic formulae, but a different structural arrangement Structural isomerism Identical chemical formulae but different order of atomic bonds Same action or different actions

26. Tautomerism D ynamic interchange between two forms of a molecular structure, often precipitated by a change in the physical environment

27. STEReOISOMERISM 2 or more different substances that have the same molecular formula and chemical structure but different spatial arrangement 2 main types: Diasteromers : two or more chiral centers that are not mirror image of another Occur in drugs that have C=C and both C atoms have the same dissimilar substituents e g abC = Cba Cis- isomers->a and a, b and b are on the same side Trans-isomer->a and b are on opposite side Eg : Atracurium , mivacurium Optical: pairs of stereo-isomers that are mirror images of each other Dependant on the presence of chiral center Distinguished by the direction , in which when dissolved in solution rotate the plane of polarized light either to right or left

28. Advantages of steroisomerism Tramadol: racemix mixture of 2 enantiomers. One which is responsible for inhibition of noradrenaline uptake and the other is responsible for inhibition of 5-HT uptake and facilitation of its release Cisatracurium : less side effect (histamine release Ketamine S(+) is 2-3 times as potent as R(-) enantiomer and produce less cardiac depression Levobupivaciane cause less myocardial depression than bupivacaine and ropivaciane despite in higher concentration

29. THANK YOU