2. GENERAL PHARMACO- DYNAMICS Assoc. Prof. I. Lambev E-mail: itlambev@mail.bg

3. 1. PHARMACO- DYNAMICS OF DRUGS  DEFINITION

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

5. The mechanism of action represents the interaction between drug molecules and biological structures of the organism.

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

7. 50 100 150 1 min (Effect or action?)... Blood pressure {mm Hg} ACh 2  g i.v. ACh 50  g Hypotensive effect of acetylcholine (ACh) ACh

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

9. osmotic diuretics Mannitol osmotic laxative drugs Duphalac MgSO 4 antiacids (antacids) NaHCO 3 Non-specific action have:

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

11. 3. MOLECULAR ASPECTS OF SPECIFIC DRUG ACTION How drugs act?

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

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

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

15. receptors (> 150 types with many subtypes) ion channels enzymes carrier molecules  Target macroproteins

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

17. A. Receptors are the regulatory macroproteins which mediate the action of endogenous and exogenous ligands (chemicals).

18. Receptors bind to Endogenous ligands: - neurotransmitters (mediators) - hormones - autacoids (tissue mediators) - grouth factors - inhibitory factors, etc. Exogenous ligands: - many (but not all) drugs - some other xenobiotics

19. Partial Agonist (unfull antagonist) The main receptor ligands are agonists - activate the receptors antagonists - block the receptors (Full)

20. The interaction between ligand and receptor involve weaker, reversible forces, such as: Ionic bonding Hydrogen bonding Hydrophobic bonding Van der Waals forces.

21. The numbers of receptors may be altered during chronic drug treatment, with either an increase in receptor numbers (up-regulation – e.g. beta-antagonists) or a decrease (down-regulation – desensitization: e.g. beta-2 agonists).

22. 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  -blockers develops slowly. This is probably related to adaptive regulation of receptor numbers.

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

24. Presynaptic receptors in adrenergic synapse and their role in the regulatory negative and positive feedback

25. 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.

26.  I onotropic 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.

27. Ligand-gated ion channel receptors Effector Coupling Time scale Examples ion channel (Ca 2+, Na +, K +, C – ) direct milliseconds nACh-receptors GABA A -receptors 5-HT 3 -receptors

28. N-receptor: 5 subunits

29. GABA A - receptors

30. Antiseizure drugs, induced reduction of current through T-type Ca 2+ channels. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006) (-)

31.  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.

32. The G-protein is a membrane protein comprising 3 subunits ( , ,  ). The alpha-subunit possesses GTP-activity. When the agonists occupy a receptor, the alpha-subunit dissociates and then activates a target (effector): - enzyme (AC, GC, PLC) - Ca 2+ ion channels

33. AC (adenylate cyclase) catalyses formation on the intracellular messenger (cAMP). cAMP activates 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.

34.  -ad- reno- ceptor 7 sub- units

35. Adrenaline (  1 &  2 ) Gs AC ATP cAMP PKA Effects Ex In (+)

36. PLC (phospholipase C) catalyses the formation of two intracellular messen- gers  InsP 3 and DAG, from memb- rane phospholipids. InsP 3 (inositol-triphosphate) increases free cytosolic calcium by releasing Ca 2+ from the endoplasmic reticulum. Free calcium initiates contractions, se- cretion, membrane hyperpolarization DAG activates protein kinase C (PKC).

37. Noradrenaline (  1 ) PLC PIP 2 IP 3 Ca 2+ DAG PKC ADP ATP Ex In (+) Gs

38. The regulation of intracelullular calcium is connected with ryonidine receptors.

39. Ryanodine receptors ( RyRs ) form a class of intracellular calcium channels in muscles and neurons. They regulate animal cells the releasing of Ca + in animal cells. There are multiple isoforms of RyRs : RyR1 is expressed in skeletal muscle RyR2: in myocardium (heart muscle) RyR3: in the brain.

40. RyRs are named after the plant alkaloid ryanodine, to which they show high affinity. Ryanodine is a poisonous alkaloid found in the South American plant Ryania speciosa. Ryanodine

41. Effector Second messenger Protein- kinase AC cAMPPKA PLC IP 3 DAG PKC GC cGMP PKG

42. Effector Coupling Time scale Examples Enzyme (AC, GC, PLC); Ca 2+ channels G-protein seconds AT 1 -receptors mACh-receptor Adrenoceptors (  ) H 1 – H 5 -receptors Opioid receptors (  ) G-protein-coupled receptors

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

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

46. 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.  Nuclear receptors

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

48. a) Indirect nuclear receptors: Steroid hormones and Calcitriol Steroid hormones and Calcitriol

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

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

51. B. Ion channels ExIn LAH + (local anaesthetics) block Na + channels.

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

53. Na + /K + АТФ-аза Na + /Ca 2+ обмен Ca 2+ 3Na + 2K+2K+ DIGOXIN ExIn (–)(–)

54. NA (noradrenaline) = NE (norepinephrine) D. Carrier molecules ( are transport proteins) Amitriptyline

55. 4. DOSE-RESPONSE RELATIONSHIPS (introduction)

56. Most drugs produce graded dose-related effects, which can be plotted as a dose response curve. Such curves are often hyperbolic (a), but they can be conveniently plotted on semi-logarithmic paper to give sigmoidal shape (b).

57. Plotted dose- response curves: (a) arith- metically (b) semi- logarith- mically Sigmoidal shape (b) Hyperbolic shape (a)

58. The method of plotting dose-response curves facilitates quantitative analysis of: full agonists, which produce graded responses up to maximum value; antagonists, which produce no response on their own but antagonize the response to an agonist; partial agonists, which produce some response but to a lower maximum than that of a full agonist and antagonize its effect.

59. The affinity of a drug is its ability to bind to the receptor. The intrinsic activity of a drug is its ability after binding to the receptor to produce effect. The efficacy of a drug is its ability to produce maximal response. The selectivity of a drug is the extent to which it acts preferentially on particular receptor types.

60. Affinity Intrinsic Efficacy Selec- activity tivity Agonists + + ++ + + (Morphine) Antagonists +   + (Naloxon) Partial agonists (Pentazocine) + +  + Drugs

61. Bisoprolol Metoprolol Nebivolol Propranol  1 /  2 -blocking activity  -blockers 50 25 293 1,9 S e l e c t i v i t y

62. Dose-response curve of two full agonists (A, B) of different potency, and a partial agonist (C).

63. In the clinical situation dose-response curves are influenced by many factors including genetic, as well as age, weight, nutrition; psychological and social factors (that strongly influence compliance and placebo effect).

64. 5. FACTORS, AFFECTINGDRUGCONCENTRATION AT THE SITE OF ITS ACTION. STRUCTUREACTIVITYRELATIONSHIP

65. Phenothiazines: Neuroleptic action in humans Sedative action in animals Benzodiazepines: Anxiolytic action in humans and animals

66. Penicillins: Antibacterial action in humans and animals

67. 6. Factors, influencing the drug kinetics and actions the drug kinetics and actions Drugs Age of patient Sex of patient Compliance of patient Environment Doctors Drugs Age of patient Sex of patient Compliance of patient Environment Doctors

68. 8. DIFFERENT TYPE OF DOSES The dose is the amount of drug administered to a patient. According to their size there are: dosis minima – the lowest dose, dosis optima (therapeutica) – best or therapeutic dose, dosis maxima – maximum tolerated dose, dosis toxica – poisonous dose, dosis letalis dosis letalis – lethal dose (LD). The latter can be: LD 05 LD 05 – minimum lethal dose that causes death in 5% of the animals, LD 50 LD 50 – lethal dose causing death in 50% of test animals, LD 100 LD 100 – absolutely lethal (deadly) dose.

69. According duration and schedule of treatment there are: dosis pro dosi – single dose, dosis pro die – daily dose (DD), dosis pro cura (cursu) – course dose, loading dose (representing a large initial dose), maintenance dose. Median effective dose (ED 50 ) Median effective dose (ED 50 ) is the dose at which a therapeutic effect is observed in 50% of cases. It is calculated graphically by using the dose-response curves.

70. The Therapeutic Index (TI) The Therapeutic Index (TI) is the ratio between the LD 50 and the ED 50 : TI = LD 50 /ED 50 It is calculated on the experimental animals and gives an idea of ​​ the therapeutic width. Drugs with low TI (e.g., Digitoxin) have a narrow therapeutic window and can easily be overdosed while drugs with a high TI (e.g., penicillins with TI > 100) have a large therapeutic window and very low toxicity. Index of Sure Safety Index of Sure Safety is determined in humans. Is the ratio between TD 1 (dose causing toxic effects in 1% of treated patients) and ED 99 (dose causing a curative effect in 99% of cases): ISS = TD 1 /ED 99