Pharmacokinetics
Content
•
Enzyme
induction and inhibition
•
Factors
affecting drug metabolism
•
First
and zero order kinetics
Intended Learning Outcomes
At the
end of this lecture, student will be able to
• Describe
enzyme induction and inhibition
• Give
examples for clinically significant enzyme induction and inhibition
• Explain
the factors affecting drug metabolism, differentiate between first and zero
order kinetics
Enzyme induction
• Repeated
administration of drug
• Stimulates
smooth ER
• Enhanced
microsomal activity
• Increase
metabolism
• Decreased
pharmacological response
• Prominent
in liver
Clinical relevance of Enzyme induction
• Clinical
consequences of increased drug metabolism
• Decreased
effect – if metabolite inactive
• Leads
to drug toxicity
– Ethanol
drinkers prone to liver toxicity
• Knowledge
can be used for therapeutic benefits
– Induction
of fetal hepatic glucuronyl transferase
Enzyme inducers
• CYP3A4:
Phenobarbitone, carbamazepine, phenytoin, pioglitazone
• CYP3A4:
CYP2C9: Rifampicin, Phenobarbitone
• CYP1A2:
Smoking, omeprazole, charcoal broiled meat
• CYP2E1:
Chronic ethanol intake, isoniazid
Enzyme inhibition
• Inhibition
of metabolism
• Increase
the concentration
• Rapid
process, usually reversible
• Sometimes
irreversible – secobarbital overdose
• Chloramphenicol,
erythromycin: hepatic MFOs – phenytoin, warfarin
• Disulfiram,
tolbutamide: Aldehyde dehydrogenase –Alcohol, phenytoin
Clinical relevance of Enzyme inhibition
Potentially adverse consequences:
• Severe
respiratory depression with morphine + MAOIs
• Enhanced
bleeding tendency with dicoumarol + cimetidine
Therapeutically beneficial consequences:
• Levodopa
+ carbidopa
• Aversion
of alcohol with disulfiram
• Reversal
of Skeletal muscle paralysis due to dtc by neostigmine
Factors affecting in drug metabolism
• Age
–
Low microsomal activity, GT activity, Above 60 yrs reduced hepatic blood flow
• Sex: Male rat – increased microsomal
activity
• Species: Rabbits – increased atropine
esterase activity
• Race: Chinese – headache, palpitation
after alcohol
• Drug – drug interactions
• Genetic variation
– Slow
acetylators + isoniazid – peripheral neuropathy
– Fast
acetylators + isoniazid – Hepatotoxicity
– Pseudocholine
esterase + succinyl choline – Prolonged apnoea
• Nutrition and diet
– Rich
in protein, low in CH – ↑metabolism
– Starvation
– Enzyme inhibition
• Disease
– Hepatitis,
cirrhosis, heavy metal poisoning – impaired metabolism
Drug Excretion
Kidneys
• Passive
Glomerular Filtration
– Unbound
fraction of ionized drugs
– Reabsorbed
by diffusion
– Small
amount appears in urine
– Molecular
weight < 20, 000 MW
• Active
tubular secretion
– Weak
acids and bases – actively secreted
– By
carrier mediated systems
– Transporters
such as P-gp & MRP2
– Secretion
of weak organic acid (Penicillin) – inhibited by probenecid
• Tubular
reabsorption
– Bidirectional
process
– Drugs
diffuse depending upon drug conc, lipid solubilty & pH
– Weak
acids quickly eliminated in alkaline urine (Salicylates)
– Weak
bases in acidic urine (Amphetamine, pethidine)
• Net
renal excretion = [GF + T. secretion] – T. Reabsorption
Lungs
• Volatile
general anesthetics
• Paraldehyde,
alcohol – partially excreted by lungs
Bile
• Hepatocytes
actively secrete drugs and their metabolites into bile
• Doxycycline,
cefaperazone – high conc in bile
• Enterohepatic
circulation
Intestine
• Enterocyte
transporters/ passive diffusion
• Drug/
metabolite secreted into lumen
• Cassia,
senna, heavymetals
Skin
• Small
quantity
• Arsenic,
mercury
Saliva
• Iodides
& metallic salts in saliva
• Lead
sulfide deposits in gum
Milk
• Passive
diffusion
• More
lipid soluble and less protein bound compound
Kinetics of Elimination
• Elimination:
Metabolic inactivation + excretion
• Clearance:
Theoretical volume of plasma from which the drug is removed in unit time
• CL
= Rate of elimination / Plasma conc.
• Loading
dose: single dose/ series of doses to achieve therapeutic drug conc.
• Maintenance
dose: to maintain the steady state conc.
• Zero order (Linear kinetics)
• Rate
of elimination remains constant
• Irrespective
of drug conc.
• First order (Exponential kinetics)
• Rate
of elimination ∝ drug conc.
• CL
remains constant (constant fraction)
Mixed order kinetics
• Saturation
kinetics/ Michaelis menton kinetics
• Phenytoin,
digoxin, warfarin, tolbutamide, aspirin
• Smaller
dose: 1st order
• Higher
dose: Zero order
• Metabolising
enzyme / elimination process – saturated
Kinetics of Elimination – Half life
• Plasma
half life
• Time
taken for its plasma conc. to be reduced to half of its original value
• Biological
half life
• Time
duration in which the principal pharmacological effect of drug decline by half
Methods of prolonging drug action
• By
retarding:
• Absorption
• Metabolism
in liver
• Renal
excretion
• Protein
binding
• Modifying
mol. structure
• By
retarding:
• Absorption
• Metabolism
in liver
• Renal
excretion
• Protein
binding
• Modifying
mol. structure
Summary
• Enzyme induction: slow irreversible process
• Enzyme inhibition: Rapid and mostly
reversible
• Enzyme inducers: Phenobarbitone,
phenytoin
• Enzyme inhibitors: chloramphenicol,
erythromycin
• Zero order (Linear kinetics): Rate of
elimination remains constant, Irrespective of drug conc.
• First order (Exponential kinetics):
Rate of elimination ∝ drug conc, CL remains constant (constant fraction)
