Metabolism of Drugs
Session 3: Metabolism of Drugs
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe reactions involved in drug metabolism
Describe factors affecting drug metabolism
Describe first pass effect
Describe kinetics of metabolism
Explain clinical importance of drug metabolism
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD Projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
10 minutes
10 minutes
Presentation/
Reactions Involved in Metabolism
Reactions Involved in Metabolism
2
2
10 minutes
10 minutes
Buzzing
Reactions Involved in Metabolism
Reactions Involved in Metabolism
Buzzing
Presentation/
3
3
45 minutes
45 minutes
Small Group
Factors Affecting Metabolism
Factors Affecting Metabolism
Discussion
4
4
20 minutes
20 minutes
Presentation
First Pass Metabolism
First Pass Metabolism
5
5
20 munites
20 munites
Presentation
Kinetics of Metabolism
Kinetics of Metabolism
6
6
10 minutes
10 minutes
Presentation
Clinical Importance of Metabolism
Clinical Importance of Metabolism
7
7
05 minutes
05 minutes
Presentation
Key Points
Key Points
8
8
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 19 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Reactions Involved in Drug Metabolism (10 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
What are thereactions involved in drug biotransformation?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
There are several reactions involved in drug biotransformation.
These reactions are grouped into two major groups called Phase 1 and Phase 2.
Phase 1 Reaction
Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a process known as 'functionalisation'.
This group then serves as the point of attack for the conjugating system to attach a substituent such as glucuronide explaining why phase 1 reactions so often precede phase 2 reactions.
Phase 1 reactions take place mainly in the liver whereby many hepatic drug-metabolising enzymes, including CYP enzymes are involved.
In general phase 1 reactions include hydroxylation, dealkylation, deamination, desulfuration, dechlorination, hydrolysis and reductions reactions
PST 05104 Pharmacology & Therapeutics 20 NTA Level 5 Semester 1 Facilitator Guide
Phase 2 reactions
Most of phase 1 metabolites are more polar hence expected to be readily excreted.
However some drugs are not eliminated rapidly require a further reaction involving an addition of an endogenous glucuronic acid, sulfuric acid, amino acid or acetic acid to form a highly polar conjugate for elimination.
In general Phase 2 conjugation reactions involves glucuronidation, acetylation, conjugation, sulphation and methylation.
Rang and Dale pharmacology seventh
edition
STEP 3: Factors Affecting Metabolism of Drugs (45Minutes)
Activity: Small Group Discussion ( 30 minutes)
DIVIDE students into small manageable groups
ASK students to discuss on the following question
What are factors affecting metabolism of drugs?
ALLOW students to discuss for 15 minutes
ALLOW few groups to present and the rest to add points not mentioned
CLARIFY and SUMMARIZE by using the contents below
Drug metabolism is affected by the followings:
Genetic factors
o Genetic factors influence enzyme levels and expression of activity. There is a great variation in the population how individuals metabolize drugs.
o The greater part of this effect is due to Cytochrome P450 polymorphism.
PST 05104 Pharmacology & Therapeutics 21 NTA Level 5 Semester 1 Facilitator Guide
A few examples of variation on metabolism due to genetics include acetylation of isoniazid and hydroxylation where there are slow and fast metabolizers in the population for the drugs.
Diet and environmental factors
Cigarette smokers metabolize some drug faster than non-smokers because of enzyme
induction
Some foods and drinks also affect drug metabolism.
For example grape juice decrease metabolism of some drugs because of enzyme inhibition
Age and Sex
A decreased metabolism of drugs is observed in clinical practice in very young patients due to immature enzymes and very old patients due to deterioration of liver function
A variation in metabolism basing on sex difference in human is reported for ethanol, salicylates, some benzodiazepines, oestrogens and propranolol
Drug drug interactions
Drugs known to be enzyme inducers or enzyme inhibitors can affect metabolism of other drugs when administered concomitantly
Diseases
Some acute or chronic diseases/conditions decrease greatly hepatic metabolism.
Such conditions include alcoholic hepatitis, alcoholic cirrhosis and drug or viral induced hepatitis
STEP 4: First Pass Effect (20minutes)
Some drugs are extracted so efficiently by the liver or gut wall that the amount reaching the systemic circulation is considerably less than the amount absorbed.
This is known as first-pass or presystemic metabolism and reduces bioavailability even when a drug is well absorbed.
Presystemic metabolism is important for many therapeutic drugs and is a problem because:
o A much larger dose of the drug is needed when it is given orally than when it is given parenterally
o Marked individual variations occur in the extent of first-pass metabolism
Examples of drugs that undergoes first pass metabolism are as follows; o Aspirin
o Metoprolol
o Glyceryl trinitrate o Morphine
o Isosorbide dinitrate o Propranolol
o Levodopa o Salbutamol
PST 05104 Pharmacology & Therapeutics 22 NTA Level 5 Semester 1 Facilitator Guide
o Lidocaine o Verapamil
The first pass effect can be avoided greatly by the administration of drugs through Intraveous route, sublingual routeand the use transdermal patches.
STEP 5: Kinetics of Metabolism (20 Minute)
Drug metabolism involves:
First order kinetics
Zero order kinetics
First order kinetics (Linear Kinetics)
Most drugs are metabolized through first order kinetics and is observed in most clinical situations
In the first order kinetics the rate of metabolism of a drug is directly proportional to the concentration of free drug
That means a constant fraction of drug is cleared per unit time
Zero order kinetics (Non Linear kinetics)
Very few drugs exhibit this kinetics. A good examples are Aspirin, Phenytoin, Ethanol
In general zero order kinetics is observed in drugs when doses are high thus the enzyme is
saturated with a high free drug concentration.
In this situation the rate of metabolism is constant regardless drug concentration.
It remains constant all the time.
A constant amount of drug is metabolised per unit time
Drugs like Phenytoin that follows saturable kinetics may start showing first order kinetics initialy, but as more doses of a drug are added, the metabolising enzymes become saturated resulting to zero order/saturable kinetics as indicated in the graph below;
PST 05104 Pharmacology & Therapeutics 23 NTA Level 5 Semester 1 Facilitator Guide
Once the metabolising enzymes of phenytoin or any other drug with saturable kinetics are saturated, any small increment of the dose may result into marked increase of its plasma concentrations leading to drug toxixity
STEP 6: Clinical Importance of Drug Metabolism (10minutes)
Metabolism plays a pivotal role in the followings:
Lipophilic drugs when metabolised are converted to a more polar form which is easily eliminated through the kidney.
o This reduces drug accumulation and half-life.
Pro drugs are converted to their active inorder to produce their pharmacological action.
In some cases, metabolism of a drug may result into toxic metabolites in the body.
STEP 7: Key Points (5 minutes)
Metabolism of drugs mainly takes place in the liver through Phase I and Phase II reactions
Metabolism of drugs may either follow first or zero order kinetics
Metabolism makes a non-polar drug to be polar which will be readily excreted through kidneys
STEP 8: Evaluation (5 minutes)
What are organs involved in metabolism?
What are the factors affecting metabolism of drugs?
What types of enzymes are involved in phase 1 metabolism of drugs
PST 05104 Pharmacology & Therapeutics 24 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 25 NTA Level 5 Semester 1 Facilitator Guide
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