This slide explains the metabolism and excretion portion of Pharmacokinetics and related topics.
This slide is a work of Dr Anil Kumar Kasana, 2nd Year at All India Institute of Medical Sciences, Bathinda
7. WHAT?
•Drug metabolism is a process of chemical modification of a
drug and is carried out mostly by enzymes.
WHY?
•Drugs treated by the body as foreign substances, which body
tries to remove from the body by metabolism and excretion.
WHERE?
•The sites for drug metabolism include liver, kidney,
gastrointestinal tract, lungs and plasma
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8. The metabolism
generally results in
the conversion of a
drug to a less active,
less lipid soluble, less
toxic metabolite and
hence easily excreted
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10. BIO-TRANSFORMATION RESULTS IN:
Inactivation:
Active drug Inactive/less active metabolite
Ex- Ibuprofin, Paracetamol
Active metabolite from an Active Drug:
Active drug Active metabolite
Ex- Morphine Morphine-6-glucorinide
Diazepam Oxazepam
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11. Activation of Inactive Drug:
Inactive Drug (Prodrug) Active metabolite
Ex- Levodpa Dopamine
Enalapril Enalaprilat
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12. Present in the
smooth
endoplasmic
reticulum of the
liver, kidney
and GIT e.g.,
glucuronyl
Present in the
cytoplasm,
mitochondria of
different organs.
e.g., esterase,
amidase,
hydrolase.
MICROSOMAL
ENZYMES
NON-MICROSOMAL
ENZYMES
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13. Microsomal
Enzymes
Non-microsomal
Enzymes
Reactions Most of the Phase I
reactions,
Glucuronide
conjugation
Oxidation,
reduction,
hydrolysis.
All conjugation
except glucuronide
conjugation.
Inducibilty Inducible Not Inducible
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14. TYPES OF BIO-
TRANSFORMATION:
drug is converted to
more polar metabolite.
If this metabolite is
sufficiently water
soluble, then it will be
excreted in urine.
Phase-Il reactions:
Some metabolites
may not be
sufficiently polar to
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16. Oxidation
•Addition of oxygen/ removal
of hydrogen
•Ex- Phenytoin, Phenoarbitone
Reduction
•Removal of oxygen/ addition
of hydrogen
•Ex- Chloramphenicol,
methadone 25 August 2021 16
17. Hydrolysis
•Break down of compound by
addition of water.
• Ex- Esters – Procaine, Amides -
Lignocaine
Cyclization
•Conversion of straight chain
compound into ring structure.
• Ex- Proguanil
Decyclization
•Breaking up of the ring structure
of the drug.
• Ex- Phenoarbitone, Phenytoin
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18. CYTOCHROME P450 ENZYMES:
Oxidative reaction are carried by a group of enzymes called
Cytochrome (CYP) P450 enzymes.
There are more than 100 CYP P450 isoenzymes that differe
in affinity for substrates (drugs).
Most of the drugs (nearly 70%) are metabolised by
• CYP3A4/5 (50%)
• CYP2D6 (20%)
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22. FIRST PASS METABOLISM
•Process in which a drug administered by mouth is
absorbed from the gastrointestinal tract and
transported via the portal vein to the liver, where
it is metabolized.
•As a result, in some cases only a small proportion
of the active drug reaches the systemic circulation
and its intended target tissue.
•First-pass metabolism can be bypassed by giving
the drug via sublingual or buccal routes
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24. HOFMANN ELIMINATION:
Drugs can be inactivated without the need of
enzymes, this is known as Hofmann elimination.
Ex- Atrcurium, a skeletal muscle relaxant,
undergoes Hofmann elimination.
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26. DEFINITION:
Removal of the drugs and its metabolite
from the body is known as drug excretion.
Main excretory organs:
Kidney, Lungs, Faeces, Bile, Skin, Saliva, Milk
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27. KIDNEY:
•Glomerular Filtration: drugs with small
molecular size are more readily filtered.
•Extent of filtration is directly proportional to the
glomerular filtration rate (GFR).
•While GFR depend on: Plasma protein binding
,Concentration of free drug in the plasma,
Molecular weight
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28. Tubular Reabsorption:
•The tubular reabsorption depends on can occur in
both the ways inproximal and distal convoluted
tubules.
•The pH of the urine influences rate of passive
diffusion and hence excretion of certain weak acids
and weak bases.
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29. •Thus, weak acids are quickly eliminated in an
alkaline urine, e.g., barbiturates and salicylates;
•While weak bases are rapidly excreted in an
acidic urine, e.g., pethidine and amphetamine
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30. Tubular secretion:
• The tubular secretion can rapidly remove the plasma
protein bound drugs from the blood into tubular fluid
because the protein bound drugs have not been
eliminated by glomerular filtration.
• For example:
-- Acidic drugs include salicylates, chlorothiazide,
probenecid, penicillin;
-- Basic drugs include catecholamines, acetylcholine,
histamine, hexamethonium, morphine etc.
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32. LUNGS:
Alcohol and volatile general anaesthetics,
such as ether, halothane, isoflurane,
sevoflurane are excreted via lungs.
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33. FAECES:
Drugs that are not completely absorbed from the GIT
are excreted in faeces, e.g. purgatives like senna,
cascara, etc.
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34. BILE:
Some drugs are excreted via bile but after reaching the
intestine they are reabsorbed liver bile and the
cycle is repeated – such recycling is called
enterohepatic circulation.
It increases bioavailability, as well as duration of action.
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36. SALIVA:
Drugs like phenytoin, metronidazole and lithium
are excreted in saliva. Salivary estimation of
lithium may be used for non-invasive monitoring
of lithium therapy.
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37. MILK:
Drugs taken by lactating women may appear in
milk.
Ex- tetracyclin, chloramphenicol, morphine, etc.
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38. PLASMA HALF-LIFE (T 1/2 ):
It is the time required for the plasma concentration of a
drug decrease to 50% of its original value.
It is denoted by t1/2.
It helps in:
• determining duration of drug action.
• determine frequency of drug administration. 25 August 2021 38
39. LOADING DOSE:
This is a single or few quickly repeated dose given in the beginning to
attain target concentration rapidly. It may be calculated as—
Loading dose = target Cp * V / F
where V is Volume of Distribution, and F is serum concentration of
drug.
Thus, loading dose is governed only by V.
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40. MAINTENANCE DOSE
The dose of a drug which is repeated at fixed
intervals or given as a continuous infusion to
maintain target level in plasma or steady state
concentration.
The dose administered is equal to dose
eliminated in a dosing interval.
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41. CLEARANCE:
Clearance (CL) of a drug is defined as that volume
of plasma from which the drug is removed in unit
time.
Clearance = Rate of Elimination / Plasma Conc. Of
the drug
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42. ORDER OF KINETICS:
1st Order Kinetics Zero Order Kinetics
Type of reaction First order kinetics
refers to chemical
reactions whose rate
of reaction depends
on the molar
concentration of one
reactant
Zero order kinetics
refers to chemical
reactions whose rate
of reaction does not
depend on the
reactant
concentration
Slope of graph Curved Graph Linear Graph
t1/2 Half life is constant Half life decreases
with decreasing
concentration
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43. 1st Order Kinetics Zero Order Kinetics
Clearance Unchanged Inceases with
decreasing
concentration.
Competitive
inhibition
Rare Common due to
saturation of
enzymes
Examples Most of the drugs
i.e. common
Phenytoin, alcohol
i.e. few
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