Initiation and management of drug therapy

Therapeutic objective
(prevention of DVT)

Choose drug
PK & dosing regimen PD
(warfarin od)

Monitor therapeutic
and toxic response
(INR and bleeding)
 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

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
 Biotransformation of Drugs:
1. Oxidation/Reduction by the P450 system

•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.

Relative contribution of the major P450

isoforms to human drug metabolism
 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 Agent Isoform Induced

polycyclic aromatic hydrocarbons in cigarette smoke CYP1A
anticonvulsants CYP3A
chronic EtOH, acetone and isoniazid CYP2E1

(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).
 Clinical Implications of CYP2D6 variants:

Agents metabolized by CYP2D6

Cardiovascular
Flecainide Metoprolol
Propafenone Timolol
Mexilitine Propranolol

Psychoactive
Clozapine Amitriptyline
Haloperidol Imipramine
Perphenazine Clomipramine
PMs show large increases in AUC compared to EMs. The high plasma
Remoxipride levels increase the frequency of adverse drug reactions (type I) and
Thioridazine 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
Monitoring drug therapy
2. By an in Vitro Test of Therapeutic Effect

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
3. 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

Repeated Drug Dosing to Maintain SS Levels
Within a Therapeutic Range

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: 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)

cochlear (hearing deficits)
•OTOTOXICITY (Hair cells) - neomycin/amikacin

vestibular (disturbed balance)

- streptomycin/gentamicin
Targets for IV GENTAMICIN
peak 30-60 min post-dose = 5-10 mg/L ) BUT toxicity can emerge below these levels
Trough 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)
TDM: Anticonvulsants (PHENYTOIN)
•Therapeutic range - 40-80mol/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.
 TDM: Theophylline
• Therapeutic range - 5-20g/ml (28-110mol/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.

Alteration in Clearance increased decreased

rifampicin erythromycin
anticonvulsants ciprofloxacin
smoking (>10cigs/d) verapamil
propranolol
TDM: 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 distal

reabsorption (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 milk
Severe intoxication - usually requires dialysis but because of
slow clearance from some compartments rebound rises in Li
levels may necessitate repeated HD.
 TDM: 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 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
 Enzyme Induction/inhibition by Anticonvulsants:

Phenytoin, phenobarb, CBZ * CYP/UGT

Lamotrigine  UGT (weak)
Valproate  UGT/epoxidases/CYP2C
Felbamate  3A4  2C19

Ethosuximide
Gabapentin No Effect
Tiagabine
Vigabatrine

* =inhibition; /  =induction (+/++)