Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

1. Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology GENERAL PHARMACO- DYNAMICS Assoc. Prof. I. Lambev E-mail: itlambev@mail.bg

2. 1. PHARMACO- DYNAMICS OF DRUGS -DEFINITION

3. Pharmacodynamics: (1) How the drugs act on the body? (2) The mechanism of action of drug and its effects

4. The mechanism of action- the interaction between drug molecules and biological structures of organism.

5. The effect represents the final results from the drug action. • The effect can be • observed and measured, • but the action - not.

6. Hypotensive effect of acetylcholine (ACh) (Effect or action?) ... 1 min 150 Blood pressure {mm Hg} 100 50 ACh 2 mg i.v. ACh 50 mg ACh

7. 2. SITES OF DRUG ACTION • They can be divided into: • specific and • non-specific

8. Non-specific action have: • osmotic • diuretics Mannitol • osmotic • laxative drugs Duphalac MgSO4 • antiacids (antacids) NaHCO3

9. Specific action It is connected with interaction of the drug with specific site(s) on the cell membrane or inside the cell.

10. 3. MOLECUALAR ASPECTS OF SPECIFIC DRUG ACTION How drugs act?

11. Main specific targets for drug actions are:  DNA  microbial organelles  target macroproteins

12.  DNA Alkylating agents bind covalently to sites within DNA such as N7 of guanine and block DNA-replication.

13.  Microbial organelles Nystatin Doxy- cyclin Rifampicin Peni- cillins

14.  Target macroproteins • receptors (> 140 types • with many subtypes) • ion channels • enzymes • carrier molecules

15. P. Ehrilch (1854-1915) “Corpora non agunt nisi fixata” (a drug will not work unless it is bound).

16. A. Receptors are the regulatory macroproteins – sensitive elements in the system of chemical commu- nications that coordinates the function of the different cells in the body.

17. Receptors bind • endogenous ligands (such as the): • - neurotransmitters (mediators) • - hormones • - autacoids (tissue mediators) • - growth factors etc. • exogenous ligands: • many (but not all) drugs • some other xenobiotics

18. Main receptor ligands are: • agonists - activate the receptors • antagonists - block the receptors (Full) (Full) Partial Agonist (unfull antagonist)

19. The interaction between the ligand • and receptor does not involve cova- • lent bonds but weaker, reversible • forces, such as: • Ionic bonding • Hydrogen bonding • Hydrophobic bonding • Van der Waals forces

20. The receptors have a three-dimensional organization in space and require the different aspects of a ligand to be pre- sented in the correct 3-D configuration (like fitting a hand into the glove).

21. The numbers of receptors may be altered during chronic drug treatment, with either an increase in receptor numbers (up-regulation) or a decrease (down-regulation). The therapeutic effect of b-blockers develops slowly. This is probably related to adaptive regulation of receptor numbers.

22. There are pre- and postsynaptic receptors. Presynaptic receptors may inhibit or increase transmitter release (feedback mechanism: +/-)

23. Presynaptic autoreceptors- presynaptic regulation of transmitter release from noradrenergic terminals

24. There are 4 main types of recep- tors, according to their molecu- lar structure and the nature of receptor-effector linkage. The location of type 1, 2 and 3 receptors is on (into) the cell membranes; type 4 - into the cell nucleus.

25.  Ionotropic receptors (ligand-gated ion channel receptors) • These receptors are involved • mainly in fast synaptic transmission. • They are proteins containing several • transmembrane segments arranged • around a central channel. • Ligand binding and channel opening • occur on a millisecond time-scale.

26. Ligand-gated ion channel receptors Effector Coupling Time scale Examples ion channel(Ca2+, Na+, K+, Cl+) direct milliseconds nACh-receptors GABAA-receptors 5-HT3-receptors

27. N-receptor: 5 subunits

28. BDZ – benzo- diaze- pines

29. Ca2+ Ca2+ Valproates Succinimides (–) (–) Ca2+ Ca2+

30.  G-protein-coupled receptors All comprise 7 membrane-spanning segments. One of the intracellular loops is larger than the others and interacts with G-protein.

31. The G-protein is a membrane protein • comprising 3 subunits (a, b, g). The • alpha-subunit possessing GTP-activity. • When the agonists occupy receptor, • the alpha-subunit dissociates and • is than free to activate an target • (effector): • - enzyme (AC, GC, PLC) • - Ca2+ ion channels

32. AC (adenylate cyclase) catalyses • formation on the intracellular • messenger (cAMP). • cAMPactivates various protein • kinases (PKA and others) which • control cell function in many • different ways by causing phos- • phorylation of various enzymes, • carriers and other proteins.

33. b-ad- • reno- • ceptor • 7 sub- • units

34. Adrenaline (b1&b2) (+) Ex Gs AC In cAMP ATP PKA Effects

35. PLC (phospholipase C) catalyses the • formation of two intracellular messen- • gers - InsP3 and DAG, from memb- • rane phospholipids. • InsP3 (inositol-triphosphate) increases • free cytosolic calcium by releasing • Ca2+ from endoplasmic reticulum. • Free calcium initiates contractions, se- • cretion, membrane hyperpolarization • DAG activates protein kinase C (PKC).

36. Noradrenaline (a1) (+) Ex Gs PLC In PIP2 IP3 DAG ADP Ca2+ PKC ATP

37. Regulation of intracelullular calcium

38. Second messenger Protein- kinase Effector AC cAMP PKA PLC IP3 DAG PKC PKG GC cGMP

39. G-protein-coupled receptors Effector Coupling Time scale Examples Enzyme (AC, GC, PLC); Ca2+channels G-protein seconds AT1-receptors mACh-receptor Adrenoceptors (a, b) H1-H5-receptors Opioid receptors (m, k, d)

41.  Tyrosine-kinase receptors • Incorporate thyrosine kinase • in their intracellular domain. • These receptors are involved • mainly in events controlling • phosphorilation, cell growth • and differentiation.

42. Kinase-linked receptors Effector Coupling Time scale Examples thyrosine kinase etc direct minutes (to hours) Insulin receptor ANP receptor growth factors rec.

43.  Nuclear receptors • They are nuclear proteins, so • ligands must first enter cells. • Receptors have DNA-binding • domain. • Stimulation of these receptors • increase protein synthesis by • the activation of DNA transcription.

44. Nuclear (steroid/thyroid) receptors Effector Coupling Time scale Examples gene transcription via DNA hours steroid receptors thyroid receptors vitamin D receptors

45. a) Cytoplasmic receptors: Steroid hormones, Calcitriol Steroide hormonediffuse into the cell. When activated, the receptors translocate to the nucleus where they can upregulate gene transcription by action on specific DNA response elements and recruiting co-activator proteins.

46. b) Directly at nuclear receptors: Thyroid hormones (T3, T4) T3 or T4 penetrate the nucleus Combine with their receptors Alters DNA-RNA mediated protein synthesis

47. Types of receptor-effector linkage (R = receptor; G = G-protein; E = enzyme)

48. In Ex LAH+ (local anaesthetics) block Na+ channels. B. Ion channels

49. C. Enzymes Drug Action on enzyme Galantamine (-) ACh-esterase Digoxin (-) Na+/K+-ATP-ase Aspirin (-) COX-1/COX-2 (+) ACh-esterase Obidoxim

50. Ex In 3Na+ (–) Na+/K+ АТФ-аза DIGOXIN 2K+ 3Na+ Na+/Ca2+ обмен Ca2+