Connecting Pharmacology with Therapeutics

1. Connecting Pharmacology with Therapeutics Clive Roberts

2. Become wise!

7. What can be predicted from a drug’s pharmacological profile • Pharmacological actions • Some adverse effects • Some contraindications • Some drug interactions • Acute toxicity risk • Mode of administration possibilities

8. What can NOT be predicted? • Therapeutic effect • Appropriate usage in comparison with other drugs • Some adverse effects • Some drug interactions

10. What does the pharmacological profile consist of • Pharmacodynamic data • Pharmacokinetic data • Physicochemical properties • Potential to induce or inhibit hepatic enzymes • Acute toxicity information • “The therapeutic ratio” • Usage history • Cost

11. Pharmacodynamic information • What receptors does it block or stimulate • Or what ionic channels or enzymes etc does it affect • What is the hypersensitivity risk • What unrelated toxicity occurs, how serious and how often • What happens in acute overdose

12. Pharmacokinetic information • How is it cleared from the blood – liver/kidney/lung etc • First order / zero order process • If liver, how high is the clearance rate • What is the bioavailability • If low is it due to pre-systemic hepatic clearance or poor absorption

17. Pharmacokinetic info. continued • How is the drug distributed in the body • What is the volume of distribution • What is the extent of plasma protein binding • What is the plasma half life

21. Patient groups at risk • Liver disease • Renal disease • Heart disease • Lung disease • Elderly • Those taking other drugs • Pregnancy

22. So let’s take the example ofPhenytoin

26. ?? Digoxin

31. Mrs Y.Y. Born 1912 • Admitted late Feb with general deterioration in health, nausea, anorexia, constipation • At her EPH there had been an outbreak of D+V 4 weeks previous. She had never really got better. • Dehydrated, hypotensive, pale, slow reg pulse

32. Drugs – perindopril, digoxin, frusemide, aspirin, Isosorbide mononitrate • Urea 31, creatinine 223 • ECG ……………

34. Digoxin level 3.5 • What went wrong?

35. What is it about the patient with hepatic failure that puts them at risk • Pharmacokinetic disturbance - • Decreased clearance of some drugs • Increased bioavailability of some drugs • Altered distribution volume • Decreased protein binding • CNS sensitivity • Electrolyte abnormality

36. What is it about the patient with hepatic failure that puts them at risk - continued • Fluid retention • Risk of bleeding – generally and specifically in gut • Metabolic disturbance • Encephalopathy risk

37. And the renal patient ? • Pharmacokinetic disturbance • Mainly affecting drug clearance • Also protein binding • Increased sensitivity • Poor tolerance of adverse effects • Decreased effectiveness of some drugs

38. Drugs in the elderly • Multiple indications leads to polypharmacy • Pharmacokinetic disturbance of metabolism, excretion, protein binding and drug distribution • Increased sensitivity to the actions of drugs on CVS, CNS, GIT • Poor tolerance of adverse effect

39. Drug interaction • Pharmacodynamic mechanisms usually easy to predict • Pharmacokinetic mechanisms – need to know / look up.

40. Le Fin

41. Profile of new drug for reflux oesophagitis • Phenothiazine drug with powerful antigastric secretory action at low doses. • Acts on both h2 receptors and the proton pump • Also blocks muscarinic receptors throughout the body • Inhibits some hepatic enzymes • Causes a rise in transaminases in some patients • Limited experience in overdose

42. Profile of new drug for reflux oesophagitis • High hepatic clearance with extraction ratio of 65% • Widely distributed in tissues • Plasma half life of 48 h

43. What might you predict about the adverse effects?Who might be at greatest risk?What drug interactions might occur?What about self harm doses?