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
Interpatient variability - Pharmacodynamic factors Drug effects in vitro may confirm to simplified schemes.
The concentration-effect seen clinically rarely conforms to these schemes but have 4 characteristic variables:
Potency affects dosage but is relatively unimportant.
Maximal effect is NOT equivalent to efficacy and is usually more important than potency. BUT may not be achieved due to concentration-related adverse effects.
Slope is relevant to dose range.
Individual responsiveness (variability) will depend on genetic, age, disease and drug effects on receptor function.
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
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
Biotransformation of Drugs: 1. Oxidation/Reduction by the P450 system Relative contribution of the major P450 isoforms to human drug metabolism
Haem-containing proteins within the smooth ER responsible for most PHASE I biotransformations
Large superfamily of enzymes - 12 gene families expressed in humans.
Diverse range of xenobiotics are substrates for the P450 system - but all show high lipid solubility.
CYP3A4 is the major isoform in humans with substantial extrahepatic expression especially in the gut wall.
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
Clinical Implications of CYP2D6 variants: Agents metabolized by CYP2D6 Cardiovascular Flecainide Metoprolol Propafenone Timolol Mexilitine Propranolol Psychoactive Clozapine Amitriptyline Haloperidol Imipramine Perphenazine Clomipramine Remoxipride Thioridazine PMs show large increases in AUC compared to EMs. The high plasma levels increase the frequency of adverse drug reactions (type I) and reduces drug tolerance in PMs. In the Case of METOTPROLOL, PMs are at high risk of hypotension and bradycardia even at normal ‘therapeutic’ doses.
As well as ‘loss-of-function’ variants, ultrarapid metabolizers have been identified with duplicated or amplified 2D6 genes. These may explain some incidences of apparent therapeutic ‘failure’ with 2D6 metabolized drugs.
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
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
Hypoalbuminaemia and urea both the free fraction
Toxicity - manifests as nystagmus, ataxia and confusion
(dose-dependent in that order)
Extensive but saturable hydroxylation in the liver I.e. switches from zero to 1 st order elimination within the TR - ‘apparent’ t 1/2 may rise from 10-15h to >150h * * dose increments within the TR should be no more than 25-50mg Mild P450 inducer and will increase clearance of: warfarin, OCP, dexamethasone, cyA and pethidine. www.freelivedoctor.com
Toxicity - manifest as tachyarrythmias, vomiting & convulsions.
PK problems - Bioavailability varies widely between preparations and lower in MR formulations given PM vs. AM. Non-linear CL : 90% eliminated by the liver & 10% unchanged in the urine (reversed ratio in neonates) I.e.No adjustment for renal failure required but dose in presence of impaired hepatocellular function.
Whenever possible establish drug level before administering IV and
Therapeutic range 1-2ng/L (taken >6h post-dosing; 1ng/L=1.3nmol/L) for inotropic effect not AF.
Toxicity - may be nonspecific eg nausea, vomiting, abdo pain & confusion but remember bradycardia with increasing of heart block especially with AV junctional escape rhythms and visual disturbance (xanthochromia).
PK problems - 10% population have enteric bacterium (E. lentum) that can metabolize digoxin. Large volume of distribution ( 5L/kg lean BW) and predomin excreted unchanged in the urine with CL GFR.
Large of number of interactions -
Mechanism Condition/Drug(s) PK Vd and CL Thyrotoxicosis/T4 Vd and/or CL Verapamil, amiodarone, propafenone absorption Erythromycin, omeprazole absorption Exchange resins, kaolin GFR Any cause of renal impairment/Cyclosporine PD increase block Hypokalaemia/Kaluretic diuretics of the Na pump www.freelivedoctor.com