Initiation and management of drug therapy
Therapeutic objective
(prevention of DVT)
PK
Choose drug
& dosing regimen
(warfarin od)
Monitor therapeutic
and toxic response
(INR and bleeding)
PD
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
polycyclic aromatic hydrocarbons in cigarette smoke
anticonvulsants
chronic EtOH, acetone and isoniazid
Isoform Induced
CYP1A
CYP3A
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
Propafenone
Mexilitine
Psychoactive
Clozapine
Haloperidol
Perphenazine
Remoxipride
Thioridazine
Metoprolol
Timolol
Propranolol
Amitriptyline
Imipramine
Clomipramine
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
 dose
result to
 dose
toxic signs
Heart Failure
Urea
Dehydration
Oedema
Severe
hypotension
Carbidopa/DOPA Parkinson’s
Dyskinesias
Blepharospasm
Poor
Control
Confusion
Depression
Thiopentone
Anaesthesia
Too Deep
Insufficient
Anaesthesia
Respiratory
Failure
Frusemide
Induction
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
Thyroxine
Hypothyroidism
low TSH
high TSH Hyperthyroidism
Statin
Raised cholesterol
AST/CK high TC
Bleeding
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 <510% 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)
•OTOTOXICITY (Hair cells)
Targets for IV GENTAMICIN
peak 30-60 min post-dose = 5-10 mg/L )
Trough before next dose < 2 mg/L
)
cochlear (hearing deficits)
- neomycin/amikacin
vestibular (disturbed balance)
- streptomycin/gentamicin
BUT toxicity can emerge below these levels
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
anticonvulsants
smoking (>10cigs/d)
erythromycin
ciprofloxacin
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 t 1/2 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





Thyrotoxicosis/T4
Verapamil, amiodarone, propafenone
Erythromycin, omeprazole
Exchange resins, kaolin
Any cause of renal impairment/Cyclosporine
PD
increase block
of the Na pump
Vd and CL
Vd and/or CL
absorption
absorption
GFR
Hypokalaemia/Kaluretic diuretics
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 (+/++)