Pharmacokinetics
Metabolism
Drug metabolism usually involves two types of biochemical reactions - phase I and
phase II reactions
Phase I reactions:
Oxidation, reduction, hydrolysis.
Mainly performed by the P450 enzymes but some drugs are metabolised by
specific enzymes, for example alcohol dehydrogenase and xanthine oxidase.
Products of phase I reactions are typically more active and potentially toxic
Phase II reactions:
Conjugation.
Products are typically inactive and excreted in urine or bile.
Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved
The majority of phase I and phase II reactions take place in the liver
First-pass metabolism
This is a phenomenon where the concentration of a drug is greatly reduced before it
reaches the systemic circulation due to hepatic metabolism.
As a consequence much larger doses are need orally than if given by other routes.
This effect is seen in many drugs, including:
1) aspirin
2) isosorbide dinitrate
3) glyceryl trinitrate GTN
4) lignocaine
5) propranolol
6) verapamil
7) isoprenaline
8) testosterone
9) hydrocortisone
Questions concerning zero-order kinetics and acetylator status are also common in the exam
Zero-order kinetics
Zero-order kinetics describes metabolism which is independent of the concentration
of the reactant.
This is due to metabolic pathways becoming saturated resulting in a constant
amount of drug being eliminated per unit time.
This explains why people may fail a breathalyser test in the morning if they have been
drinking the night before
Drugs exhibiting zero-order kinetics:
1) phenytoin
2) salicylates (e.g. high-dose aspirin)
3) heparin
4) ethanol
1
,Acetylator status
50% of the UK populations are deficient in hepatic N-acetyltransferase
Drugs affected by acetylator status
1) isoniazid
2) procainamide
3) hydralazine
4) dapsone
5) sulfasalazine
P450 enzyme system
Induction usually requires prolonged exposure to the inducing drug, as opposed to
P450 inhibitors, where effects are often seen rapidly
Inducers of the P450 system
1) smoking (affects CYP1A2, reason why smokers require more aminophylline)
2) chronic alcohol intake
3) phenytoin, carbamazepine (antiepileptics)
4) phenobarbitone (barbiturates)
5) rifampicin
6) St John's Wort
7) griseofulvin
Inhibitors of the P450 system
1) ciprofloxacin, erythromycin, quinupristin (antibiotics)
2) isoniazid
3) imidazoles: ketoconazole, fluconazole
4) ritonavir
5) cimetidine, omeprazole
6) amiodarone
7) allopurinol
8) SSRIs: fluoxetine, sertraline
9) sodium valproate
10) acute alcohol intake
2
,P450 drug interactions: more detail
Whilst you are expected to know in broad terms what are the main inhibitors and
inducers of the P450 system it is unlikely that you will be asked detailed questions about
the individual enzyme systems.
It is worthwhile noting that the most important and common reason for drug interactions
is the P450 CYP3A4 system.
The table below shows the main enzyme systems that are affected by common drugs.
There is clearly a lot of overlap within the various P450 enzymes.
P450
system Substrates Inhibitors Inducers
CYP3A4 Macrolides Macrolides Carbamazepine
Antiretrovirals Protease inhibitors Phenytoin
Calcium channel (including Phenobarbitone
blockers ritonavir) Rifampicin
Imidazoles St John's Wort
CYP2D6 Tricyclic SSRIs
antidepressants Ritonavir
Antipsychotics
CYP2C9 Warfarin Imidazoles Rifampicin
Sulfonylureas Amiodarone
Sodium valproate
CYP1A2 Theophylline Ciprofloxacin Smoking
Omeprazole
CYP2E1 Alcohol Chronic alcohol
Isoniazid
3
, Drugs which act on serotonin receptors
It should be noted that 5-HT receptor agonists are used in the acute treatment of
migraine whilst 5-HT receptor antagonists are used in prophylaxis
Agonists:
1) sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment of
migraine
2) ergotamine is a partial agonist of 5-HT1 receptors
Antagonists:
1) Pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine attacks.
2) Methysergide is another antagonist of the 5-HT2 receptor but is rarely used due to the
risk of retroperitoneal fibrosis
3) Cyproheptadine is a 5-HT2 receptor antagonist which is used to control diarrhoea in
patients with carcinoid syndrome
5-HT3 antagonists
5-HT3 antagonists are antiemetics used mainly in the management of chemotherapy
related nausea.
They mainly act in the chemoreceptor trigger zone CTZ area of the medulla
oblongata.
Examples:
ondansetron
granisetron
Adverse effects:
constipation is common
4
Metabolism
Drug metabolism usually involves two types of biochemical reactions - phase I and
phase II reactions
Phase I reactions:
Oxidation, reduction, hydrolysis.
Mainly performed by the P450 enzymes but some drugs are metabolised by
specific enzymes, for example alcohol dehydrogenase and xanthine oxidase.
Products of phase I reactions are typically more active and potentially toxic
Phase II reactions:
Conjugation.
Products are typically inactive and excreted in urine or bile.
Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved
The majority of phase I and phase II reactions take place in the liver
First-pass metabolism
This is a phenomenon where the concentration of a drug is greatly reduced before it
reaches the systemic circulation due to hepatic metabolism.
As a consequence much larger doses are need orally than if given by other routes.
This effect is seen in many drugs, including:
1) aspirin
2) isosorbide dinitrate
3) glyceryl trinitrate GTN
4) lignocaine
5) propranolol
6) verapamil
7) isoprenaline
8) testosterone
9) hydrocortisone
Questions concerning zero-order kinetics and acetylator status are also common in the exam
Zero-order kinetics
Zero-order kinetics describes metabolism which is independent of the concentration
of the reactant.
This is due to metabolic pathways becoming saturated resulting in a constant
amount of drug being eliminated per unit time.
This explains why people may fail a breathalyser test in the morning if they have been
drinking the night before
Drugs exhibiting zero-order kinetics:
1) phenytoin
2) salicylates (e.g. high-dose aspirin)
3) heparin
4) ethanol
1
,Acetylator status
50% of the UK populations are deficient in hepatic N-acetyltransferase
Drugs affected by acetylator status
1) isoniazid
2) procainamide
3) hydralazine
4) dapsone
5) sulfasalazine
P450 enzyme system
Induction usually requires prolonged exposure to the inducing drug, as opposed to
P450 inhibitors, where effects are often seen rapidly
Inducers of the P450 system
1) smoking (affects CYP1A2, reason why smokers require more aminophylline)
2) chronic alcohol intake
3) phenytoin, carbamazepine (antiepileptics)
4) phenobarbitone (barbiturates)
5) rifampicin
6) St John's Wort
7) griseofulvin
Inhibitors of the P450 system
1) ciprofloxacin, erythromycin, quinupristin (antibiotics)
2) isoniazid
3) imidazoles: ketoconazole, fluconazole
4) ritonavir
5) cimetidine, omeprazole
6) amiodarone
7) allopurinol
8) SSRIs: fluoxetine, sertraline
9) sodium valproate
10) acute alcohol intake
2
,P450 drug interactions: more detail
Whilst you are expected to know in broad terms what are the main inhibitors and
inducers of the P450 system it is unlikely that you will be asked detailed questions about
the individual enzyme systems.
It is worthwhile noting that the most important and common reason for drug interactions
is the P450 CYP3A4 system.
The table below shows the main enzyme systems that are affected by common drugs.
There is clearly a lot of overlap within the various P450 enzymes.
P450
system Substrates Inhibitors Inducers
CYP3A4 Macrolides Macrolides Carbamazepine
Antiretrovirals Protease inhibitors Phenytoin
Calcium channel (including Phenobarbitone
blockers ritonavir) Rifampicin
Imidazoles St John's Wort
CYP2D6 Tricyclic SSRIs
antidepressants Ritonavir
Antipsychotics
CYP2C9 Warfarin Imidazoles Rifampicin
Sulfonylureas Amiodarone
Sodium valproate
CYP1A2 Theophylline Ciprofloxacin Smoking
Omeprazole
CYP2E1 Alcohol Chronic alcohol
Isoniazid
3
, Drugs which act on serotonin receptors
It should be noted that 5-HT receptor agonists are used in the acute treatment of
migraine whilst 5-HT receptor antagonists are used in prophylaxis
Agonists:
1) sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment of
migraine
2) ergotamine is a partial agonist of 5-HT1 receptors
Antagonists:
1) Pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine attacks.
2) Methysergide is another antagonist of the 5-HT2 receptor but is rarely used due to the
risk of retroperitoneal fibrosis
3) Cyproheptadine is a 5-HT2 receptor antagonist which is used to control diarrhoea in
patients with carcinoid syndrome
5-HT3 antagonists
5-HT3 antagonists are antiemetics used mainly in the management of chemotherapy
related nausea.
They mainly act in the chemoreceptor trigger zone CTZ area of the medulla
oblongata.
Examples:
ondansetron
granisetron
Adverse effects:
constipation is common
4
