i want 25 multiple choice qusetions with their model answer below each qusetion that covers different aspects of all of the following information : III) Metabolism (Biotransformation)
The aim of drug metabolism in most of the cases is to change lipid soluble drugs to water soluble metabolites to be easily excreted.
Site of Metabolism (Organs):
Liver (Hepatic) is the main site for biotransformation
The lungs have enzymes that can metabolize angiotensin I, prostaglandins and nicotine.
In the presence of UV light the skin converts provitamin D to pre-vitamin D.
The kidneys convert vitamin D to a more active form.
Plasma choline esterases inactivate acetylcholine and other similar compounds.
- G.I.T. & Gut flora metabolize Tyramine & Histamine
* Types of Metabolic reactions:
A) Phase-I (Non-Synthetic)→Oxidation, Reduction & Hydrolysis
1-Oxidation: - Alcohol Acetaldehyde Acetic acid → CO2 + H2O + Energy
2- Reduction:- Chloral hydrate (Active) Tri-chloro-ethanol (More active)
3- Hydrolysis: - Acetylcholine (Active) → Acetic acid + Choline (Inactive)
N.B) Results of Phase-I Metabolism:
1- Inactivation (the commonest fate): Active Drug Inactive Metabolite Adrenaline & Noradrenaline → Vanil Mandilic Acid (VMA)
2- Activation: Inactive Drug (Prodrug) →Active metabolite
- Cortisone (Inactive) >Hydrocortisone cortisol (Active)
3- Maintain Activation: Active Drug Active Metabolite
Diazepam (Active)→ Nor-diazepam (Active)
4- Toxification:
Drug Toxic metabolite
- Methyl alcohol Formaldehyde → Blindness
B) Phase-ll (Synthetic, Conjugation):
- Usually leads to inactivation
- May lead to activation e.g. Morphine Morphine-6-glucuronide (More active)
- Glucuronidation of paracetamol ==> inactivation-Acetylation of isoniazid ==> inactivation
- Methylation of adrenaline ==> active noradrenaline
Glycine conjugation of aspirin ==> inactivation
N.B) Most drugs undergo phase I then Phase II metabolism. Some drugs have reverse order e.g. Isoniazid Acetylation (Phase II) then Hydrolysis (Phase I).
Enzymes responsible for drug metabolism
1-Site
Microsomal enzymes
Smooth endoplasmic reticulum
2- Organs
Mainly Hepatic
3-Phase-l
Oxidation / Reduction
(Cytochrome P-450)
4- Phase-II
Glucuronidation ONLY
5-Induction
Inducible
6- Substrates
Usually lipophilic
Non-Microsomal enzymes
Cytoplasm, Mitochondria, etc.
All organs
Oxidation/Reduction & Hydrolysis
All Except Glucuronic acid
NOT inducible
Lipophilic & hydrophilic
Extrahepatic microsomal enzymes (oxidation, conjugation)
Hepatic microsomal enzymes (oxidation, conjugation)
Hepatic non-microsomal enzymes (acetylation, sulfation,GSH, alcohol faldehyde dehydrogenase, hydrolysis, oxired)
Factors affecting metabolizing enzyme activity:
1) Drugs: act on hepatic microsomal enzyme affecting drug metabolism.
A-Hepatic microsomal enzyme inducers (Activators):
Are drugs which increase the concentration of hepatic microsomal enzymes.
- Examples: Phenytoin, Carbamazepine, Rifampicin,
- Effect: They increase the metabolism of other drugs e.g. Oral anti-coagulants, Oral hypoglycemics & Oral contraceptives decrease in their duration of action.
N.B: They may also increase their own metabolism (Auto-induction) → Tolerance.
B-Hepatic microsomal enzyme inhibitors:
Are drugs which inhibit activity of hepatic microsomal enzymes.
Specific: Grapefruit juice, Sodium valproate, Erythromycin & Omeprazole.
-Effect. They & metabolism of other drugs (e.g. Theophylline→↑ its plasma level →Toxicity) & also their own metabolism.
Non-specific (General):
a- Hepato-toxic drugs.
b- Drugs Hepatic blood flow: Propranolol & Cimetidine.
2) Age: Lowering of drug metabolism occurs in extremes of age. So, drug doses should be reduced. e.g. Premature neonate can NOT conjugate chloramphenicol Fatal Grey Baby Syndrome
3) Sex: Androgen stimulates drug metabolism while estrogen inhibits drug metabolism.
4) Pathological conditions: In liver diseases, drug metabolism is reduced leading to increased susceptibility to drug toxicity e.g. Effect of diazepam is prolonged and it may cause coma when given in therapeutic dose to patients with liver impairment.
5) Starvation: Enzyme activity is decreased with inhibition of conjugation process e.g. depletion of glycine with inhibition of glycine conjugation.
6) Genetic factors: Genetic polymorphism is responsible for variation in response to drugs; e.g. Succinylcholine is metabolized by pseudo-cholinesterase, deficiency of this enzyme leads to succinylcholine apnea.