initiation &management of drug therapy

Therapeutic objectiveTherapeutic objective(prevention of DVT)

Choose drugChoose drug& dosing regimen& dosing regimen

(warfarin od)

Monitor therapeuticMonitor therapeuticand toxic responseand toxic response

(INR and bleeding)

PK PD

Initiation and management of drug therapyInitiation and management of drug therapy

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Interpatient variability - Pharmacodynamic factorsInterpatient 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. www.freelivedoctor.com

Interpatient Variability - Pharmacokinetic factors:Interpatient Variability - Pharmacokinetic factors:

AbsorptionAbsorption

Generally maximal in upper SBGenerally 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 unpredictableThe Effect of food often unpredictable - may (INH, rifampicin or captopril) - or (chloroquine)

Drugs with high first-pass (verapamil, propranolol) with food intakeSpecific effects of certain foods milk/antacids - tetracyclines

grapefruit juice -felodipine/terfenadine

First-pass metabolism *First-pass metabolism * (inactivation before entering the systemic circulation)

gut lumen insulin/benzylpenicillingut wall tyramine/salbutamolliver propranolol, verapamil, lignocaine

* Avoided by alternate route e.g. sl GTN, intranasal insulin, pr ergotamine


Interpatient Variability - Pharmacokinetic factors:Interpatient Variability - Pharmacokinetic factors:

EliminationElimination

Liver diseaseLiver disease (eg cirrhosis) affects first-pass by: (1) direct impairment of (eg cirrhosis) affects first-pass by: (1) direct impairment of hepatocellular function; (2) shunting drug directly into the systemic hepatocellular function; (2) shunting drug directly into the systemic circulationcirculation

- - 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 impairmentRenal impairment directly affects renal clearance as well as having indirect directly affects renal clearance as well as having indirect effects on protein binding and hepatic metabolism: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 plasmawww.freelivedoctor.com

Biotransformation of Drugs:1. Oxidation/Reduction by the P450 system1. 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) INDUCTIONINDUCTION by drugs or other environmental chemicals

- increased metabolism reduces availability of parent drugs (unless themetabolite is active when induction actually increases availability and toxicity)

- generally family specific

(2) INHIBITIONINHIBITION 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 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).

AgentAgent Isoform InducedIsoform Inducedpolycyclic aromatic hydrocarbons in cigarette smoke CYP1Aanticonvulsants CYP3Achronic EtOH, acetone and isoniazid CYP2E1


Clinical Implications of CYP2D6 variants:Clinical Implications of CYP2D6 variants:

Agents metabolized by CYP2D6Agents metabolized by CYP2D6

CardiovascularFlecainide MetoprololPropafenone TimololMexilitine Propranolol

PsychoactiveClozapine AmitriptylineHaloperidol ImipraminePerphenazine ClomipramineRemoxiprideThioridazine

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 therapyMonitoring drug therapy1. By Clinical Response

Indication result to result to toxic signs dose dose

FrusemideFrusemide Heart Failure Urea Oedema SevereDehydration hypotension

Carbidopa/DOPACarbidopa/DOPA Parkinson’s Dyskinesias Poor ConfusionBlepharospasm Control Depression

ThiopentoneThiopentone Induction Anaesthesia Insufficient RespiratoryToo Deep Anaesthesia Failure


Indication result to result to toxic signs dose dose

WarfarinWarfarin TE disease high INR low INR Bleeding

ThyroxineThyroxine Hypothyroidism low TSH high TSH Hyperthyroidism

StatinStatin Raised cholesterol AST/CK high TC Myopathy

Monitoring drug therapyMonitoring drug therapy2. By an in Vitro Test of Therapeutic Effect


Monitoring drug therapyMonitoring drug therapy3. By a target concentration strategy provided …

•Drug level quantitatively correlates with therapeutic & toxic effects.

•High risk of therapeutic failure (lack of response or toxicity)*

* Therapeutic failure usually arises if the drug has:

(1) A low therapeutic index

(2) Highly variable pharmacokinetics due to

- saturable elimination- genetic factors (poor metabolisers)- concurrent disease- multiple (and interacting) drug therapies

but remember to confirm compliance in all cases of therapeutic failure


TherapeuticTherapeuticRangeRange

Repeated Drug Dosing to Maintain SS LevelsRepeated Drug Dosing to Maintain SS LevelsWithin a Therapeutic RangeWithin a Therapeutic Range

•Lower limit set by the drug level giving perhaps 50% of the maximum therapeutic effect.

•The upper limit is defined by toxicity NOT therapeutic effect and is the level causing toxicity in <5-10% patients.


TDM: AminoglycosidesTDM: AminoglycosidesTDM: AminoglycosidesTDM: Aminoglycosides

• Monitoring is mandatory in ALL patients

AG accumulate in the renal cortex to levels 100-fold > plasma

>95% of AG are cleared by glomerular filtration

•Toxicity manifests as:

•NEPHROTOXICITY (Proximal tubule)

•OTOTOXICITY (Hair cells)

Targets for IV GENTAMICINTargets for IV GENTAMICINpeak 30-60 min post-dose = 5-10 mg/L ) BUT toxicity can emerge below these levelsTrough before next dose < 2 mg/L ) if loop diuretics co-administered

If impaired renal function either REDUCE DOSE or INCREASE DOSE INTERVAL(in anephric patients creatinine clearance = 0 : adjustment, knr/kr = 1/20 so …dose reduced to 0.25mg/kg/d or interval increased to 160h)

cochlear (hearing deficits)- neomycin/amikacin

vestibular (disturbed balance)- streptomycin/gentamicin


TDM: Anticonvulsants (PHENYTOIN)TDM: Anticonvulsants (PHENYTOIN)TDM: Anticonvulsants (PHENYTOIN)TDM: Anticonvulsants (PHENYTOIN)

•Therapeutic range - 40-80mol/L (NB total drug) 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 1st order elimination within the TR - ‘apparent’ t1/2 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.


Alteration in ClearanceAlteration in Clearance increased decreased

rifampicin erythromycinanticonvulsants ciprofloxacinsmoking (>10cigs/d) verapamil

propranolol

TDM: TheophyllineTDM: Theophylline

• Therapeutic range - 5-20g/ml (28-110mol/L)

• 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 if in doubt do not give bolus loading dose.


TDM: LithiumTDM: Lithium

Therapeutic range 0.6-1.2 mmol/L NB at plateau (pre-dose) & avoid Li-heparin tubes!

Toxicity - signs as a guide - TR: fine tremor especially at dosing peak- moderate intox (1.5-3): coarse tremor, ataxia & diarrhoea- severe intoxication (>3): confusion & fits

PK problems Complete absorption - SR formulations to reduce peak levels.>95% excreted by the kidney - initial t1/2 12h but terminal t1/2 much longer

70-80% reabsorbed in PCT with no distalreabsorption (unlike Na) PCT retention (hence toxicity risk ) is by:• reduced exchangeable Na from any cause• loop or thiazide diuretics• NSAIDs or ACEIs.

Special problems Pregnancy - Dose requirements increase due to renal clearance. Li is also teratogenic and excreted in breast milkSevere intoxication - usually requires dialysis but because of

slow clearance from some compartments rebound rises in Li levels may necessitate repeated HD.www.freelivedoctor.com

TDM: DigoxinTDM: Digoxin• 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 Mechanism Condition/Drug(s)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 diureticsof the Na pump


Enzyme Induction/inhibition by Anticonvulsants:Enzyme Induction/inhibition by Anticonvulsants:

Phenytoin, phenobarb, CBZPhenytoin, phenobarb, CBZLamotrigineLamotrigineValproateValproateFelbamateFelbamate

EthosuximideEthosuximideGabapentinGabapentinTiagabineTiagabineVigabatrineVigabatrine

** CYP/UGT CYP/UGT UGT (weak)UGT (weak) UGT/epoxidases/CYP2CUGT/epoxidases/CYP2C 3A43A4 2C19 2C19

No EffectNo Effect

* * =inhibition; =inhibition; / / =induction =induction (+/++)


initiation &management of drug therapy

Documents

shunting drug

drug tolerance

poor metabolism of drugs

inductionby drugs

chloroquine drugs

acidic drugs

biotransformation of

management of drug therapy