Therapeutic objective

1
Initiation and management of drug therapy
Therapeutic objective (prevention of DVT)
Choose drug dosing regimen (warfarin od)
PK
PD
Monitor therapeutic and toxic response (INR and
bleeding)
2
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.

3
Interpatient Variability - Pharmacokinetic
factors Absorption Generally maximal in upper
SB - gastric emptying often rate limiting hence
. AUC increased by metoclopramide/erythro
mycin 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-p
ass 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
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
5
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
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
Agent Isoform Induced polycyclic aromatic
hydrocarbons in cigarette smoke CYP1A anticonvulsa
nts 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).
7
Clinical Implications of CYP2D6 variants
Agents metabolized by CYP2D6 Cardiovascular Fleca
inide Metoprolol Propafenone Timolol Mexilitine Pr
opranolol Psychoactive Clozapine Amitriptyline Ha
loperidol Imipramine Perphenazine Clomipramine Rem
oxipride 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.

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 Parkinsons Dyskinesi
as Poor Confusion Blepharospasm Control Depr
ession Thiopentone Induction Anaesthesia Insuffi
cient Respiratory Too Deep Anaesthesia Failur
e
9
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
10

• 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

11
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 lt5-10 patients.

12
TDM Aminoglycosides

• Monitoring is mandatory in ALL patients
• AG accumulate in the renal cortex to levels
  100-fold gt plasma
• gt95 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 ) BUT
  toxicity can emerge below these levels
• Trough before next dose lt 2 mg/L ) if
  loop diuretics co-administered

cochlear (hearing deficits) - neomycin/amikacin
vestibular (disturbed balance) -
streptomycin/gentamicin
13
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 gt150h
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.
14
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 r
ifampicin erythromycin anticonvulsants ciprof
loxacin smoking (gt10cigs/d) verapamil pro
pranolol
15
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 (gt3) confusion fits
• PK problems Complete absorption - SR
  formulations to reduce peak levels.
• gt95 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.

16
TDM Digoxin

• Therapeutic range 1-2ng/L (taken gt6h
  post-dosing 1ng/L1.3nmol/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 Erythromyci
n, omeprazole ? absorption Exchange resins,
kaolin ? GFR Any cause of renal
impairment/Cyclosporine PD increase
block Hypokalaemia/Kaluretic diuretics of the Na
pump
17
Enzyme Induction/inhibition by Anticonvulsants
Phenytoin, phenobarb, CBZ Lamotrigine Valproate Fe
lbamate Ethosuximide Gabapentin Tiagabine Vigaba
trine
? CYP/UGT ? UGT (weak) ? UGT/epoxidases/CYP2C ?
3A4 ? 2C19
No Effect
?inhibition ?/ ? induction (/)