The document discusses therapeutic drug monitoring (TDM), including choosing a drug and dosing regimen for a therapeutic objective, monitoring the therapeutic and toxic response, and managing drug therapy. It provides examples of TDM for various drugs, noting their therapeutic ranges, toxicity risks, and factors that influence pharmacokinetics and clearance. Close monitoring of drug levels is especially important for drugs with a low therapeutic index or highly variable pharmacokinetics.

1. Therapeutic objective (prevention of DVT) Choose drug & dosing regimen (warfarin od) Monitor therapeutic and toxic response (INR and bleeding) PK PD Initiation and management of drug therapy www.freelivedoctor.com

3. Interpatient Variability - Pharmacokinetic factors: Absorption Generally maximal in upper SB - gastric emptying often rate limiting hence …. AUC increased by metoclopramide/erythromycin and reduced by atropinics, phenthiazines and antihistamines The Effect of food often unpredictable - may  (INH, rifampicin or captopril) - or  (chloroquine) Drugs with high first-pass (verapamil, propranolol)  with food intake Specific effects of certain foods milk/antacids - tetracyclines grapefruit juice -felodipine/terfenadine First-pass metabolism * (inactivation before entering the systemic circulation) gut lumen insulin/benzylpenicillin gut wall tyramine/salbutamol liver propranolol, verapamil, lignocaine * Avoided by alternate route e.g. sl GTN, intranasal insulin, pr ergotamine www.freelivedoctor.com

4. Interpatient Variability - Pharmacokinetic factors: Elimination Liver disease (eg cirrhosis) affects first-pass by: (1) direct impairment of hepatocellular function; (2) shunting drug directly into the systemic circulation - increased bioavailability may be huge (eg 10-fold for chlormethiazole) - pro-drug activation may be severely impaired eg ACEIs - concomitant hypoalbuminaemia will complicate the picture if free fraction affects clearance - certain liver diseases have little PK impact eg acute viral hepatitis Renal impairment directly affects renal clearance as well as having indirect effects on protein binding and hepatic metabolism: - only binding of acidic drugs (eg warfarin/phenytoin) are affected HD does not restore reduced albumin binding but transplant does - reduced hepatic clearance (eg propranolol/nicardipine) depends on dialyzable factors in uraemic plasma www.freelivedoctor.com

6. Factors Affecting Metabolism by P450s: (1) INDUCTION by drugs or other environmental chemicals - increased metabolism reduces availability of parent drugs ( unless the metabolite is active when induction actually increases availability and toxicity) - generally family specific (2) INHIBITION by concommitant drugs - Competitive antagonism of specfic isoforms eg QUINIDINE (2D6) and FURAFYLLINE (1A2) - Haem-Fe binding eg CIMETIDINE, KETOCONAZOLE, ERYTHROMYCIN. - Suicide inhibitors eg OC (ethinyl oestradiol) and SECOBARB. (3) GENETIC POLYMORPHISMs within the CYP genes . - Subjects show extensive or poor metabolism of drugs transformed through specific P450s. Best characterized for CYP2D6 where PMs make up 10% of Caucasian subjects. Up to 20 alleles known and typable by PCR-RFLP (PHARMACOGENOTYPING). Agent Isoform Induced polycyclic aromatic hydrocarbons in cigarette smoke CYP1A anticonvulsants CYP3A chronic EtOH, acetone and isoniazid CYP2E1 www.freelivedoctor.com

8. Monitoring drug therapy 1. By Clinical Response Indication result to result to toxic signs  dose  dose Frusemide Heart Failure  Urea  Oedema Severe Dehydration hypotension Carbidopa/DOPA Parkinson’s Dyskinesias Poor Confusion Blepharospasm Control Depression Thiopentone Induction Anaesthesia Insufficient Respiratory Too Deep Anaesthesia Failure www.freelivedoctor.com

9. Indication result to result to toxic signs  dose  dose Warfarin TE disease high INR low INR Bleeding Thyroxine Hypothyroidism low TSH high TSH Hyperthyroidism Statin Raised cholesterol  AST/CK high TC Myopathy Monitoring drug therapy 2. By an in Vitro Test of Therapeutic Effect www.freelivedoctor.com

17. Enzyme Induction/inhibition by Anticonvulsants: Phenytoin, phenobarb, CBZ Lamotrigine Valproate Felbamate Ethosuximide Gabapentin Tiagabine Vigabatrine  * CYP/UGT  UGT (weak)  UGT/epoxidases/CYP2C  3A4  2C19 No Effect *  =inhibition;  /  =induction (+/++) www.freelivedoctor.com