Dr. Rathnakar U.P.

MD.DIH.PGDHM
Department of Pharmacology
Kasturba Medical College,
Mangalore
www.scribd.com
27
Why ionized drugs are not
absorbed?
The un-ionized form is usually lipid soluble
(lipophilic) and diffuses readily across cell
membranes.
The ionized form
1. Has low lipid solubility (but high water
solubilityie, hydrophilic) and
2. High electrical resistance and thus cannot
penetrate cell membranes easily.
METABOLISM
Chemical alteration of the drug in a living
organism is called bio-transformation
Where is metabolism mainly occurring?


Intestine epithelium, Kidney, lungs etc

Liver
Intestine
Portal
vein
Systemic
Portal
26
Outcome?????
Lipid soluble Water soluble
Active Inactive [Important]
Active Active [Codeine to morphine]
Active Toxic. [Eg. P.Mol NABQI]
Inactive Active, [ -Prodrug ]

25
Why and how drugs are
metabolized???
Foreign compounds-Lipid soluble

Most drugs are metabolized by many pathways,
simultaneously or sequentially producing a variety of
metabolites
2 sets of chemical reactions-Phase I & Phase II


24
Biotransformation
Administered drug
[Lipid soluble]
[Non-Polar]
Excreted
[water soluble]
[Polar]

By
Phase I and Phase II reactions
Catalyzed by enzymes
[Microsomal and Non-microsomal enzymes]
Oxidases & Transferases
23



Drug [if Polar]

Phase I [non-synthetic] [oxidation,
reduction, hydrolysis]

Metabolite [if Polar]

Phase II [Synthetic] [Conjugation]

Metabolite

Excreted

Drug metabolism is single
step or two step process
Reversal of order: INHAcetylated[Phase II] Hydrolyzed to isonicotinic acid [Phase I]
Non-polar
Non-polar
22
Metabolism:Phases: I & II
Most drugs are metabolized by many
pathways, simultaneously or sequentially
producing a variety of metabolites
Phase II
(Eg.INH)
Phase I Metabolite
21
Phase I (non-synthetic pathway)
1. Oxidation:
Addition of O
2
/ Removal of H
+
Eg. Phenytoin, Phenobarbitone, Propranolol

2. Reduction:
Opposite of Oxidation
Eg. Choramphenicol, Methadone

3. Hydrolysis:
Addition of water
Eg, Esters-Procaine, Succinylcholine
Amides: Procainamide, Lignocaine

4. Others-Cyclization and decyclization

End product active or inactive
20
Phase I Reactions
Use enzymes [Oxidases] to unmask/introduce polar groups [OHs, Os]
to drugs.
Enzymes belong to CYP450 family
[Cytochrome P450]
CYP3A4
3=Family
A=Sub family
4=Isozyme
Drug+O
2
+NADPH+HDrug
Modified
+ H
2
O+NADP
Alcohol dehydrogenase-Non P450 family
Grand mother!
Mother!
Individual!
19
Use enzymes [Transferases] to attach small
endogenous polar molecules to a drug
E.g. Glucuronate, glutathione, sulfate, acetate

Drug Drug acetate+Co-A
Phase II: Drug Conjugations
(Synthetic pathway)
Acetyl CoA
N-Acetyl transferase
18
Conjugation of a drug or phase I metabolite with
endogenous substrate e.g., glucuronic acid making it water
soluble for excretion.
End product usually inactive



Glucuronide conjugation
Acetylation
Eg. INH, Dapsone
Glycine conjugation
Eg. Salicylic acid, Nicotinic acid
Sulphate conjugation
Eg. Sex steroids
Glutathione conjugation
Eg. Paracetamol
Methylation
Eg. Adrenaline, DopamineEg. Morphine, Paracetamol

Phase II: Drug Conjugations
(Synthetic pathway)
17
Phase II enzymes




UDP- glucuronosyl transferase [Glucuronidation]
Glutathione-S-transferase [Glutathione conjugation]
N-acetyl transferase [Acetylation]
Sulfotransferfase [Sulfation]
16
Hofmann elimination
Drugs inactivated spontaneously without
enzymes

E.g. atracurium
15
Microsomal and non-microsomal
enzymes
Microsomal Non-Microsomal
In endoplasmic
reticulum
Most of Phase I and
some Phase II
[Glucuronide
conjugation]
Inducible
CYP450
Eg. CYP2D6




Cytoplasm, Mitochondria
of liver cells and plasma
Most of Phase II and
some Phase I [Some
oxidation, most
reduction and hydrolysis]
Not inducible
Genetic polymorphism
E.g.transferases
14
Prodrug
Inactive drug
Converted to active form by metabolism
Improved bioavailability: L-Dopa & Dopamine
Prolongs duration of action: Fluphenazine
Improves taste: Clindamycin palmitate
Reduces adverse reactions: Bacampicillin
Methenamine release Formaldehyde in acidic
urine
13
Factors affecting Biotransformation
1. Age: Extremes of age enzymes may be deficient
Chloramphenicol in premature babies causes Gray baby
syndrome.
2. Malnutrition
metabolism due to enzyme proteins
3. Liver disease
metabolism dose of drug
4. Genetic
Genetically determined variation in metabolism
Slow and fast acetylators: INH
Succinylcholine
12
Enzyme induction and Inhibition
Induction Inhibition
Inducers: Rifampicin,
Phenytoin, Barbiturate,
Carbamazapine
Increase synthesis of
microsomal enzymes
Accelerate metabolism of
substrate
Rifampicin & OCP
Reduced efficacy
Increased toxicity: paracetamol
& alcoholics
Beneficial: Phenobarbitone in
newborn jaundice
Long time
Inhibitors: Chloramphenicol,
Ciprofloxacin, Erythromycin
Warfarin & Erythromycin
Increased incidence of
bleeding
Quick process
11
Consequences of induction
Decreased intensity/duration of action
Toxicity
Tolerance-self inducers
Intermittent porphyria
Difficulty in adjustment of dosage
10
Microsomal Enzyme induction
Drug A
Metabolism[24hrs] Enzyme
Drug B
[Inducer]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Effect
=No drug effect
OCP
Metabolism[24hrs] Enzyme
Drug B
[Rifampicin]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Prevents pregnancy
=Pregnancy!
+
+
9
Microsomal Enzyme inhibition
Drug A
[Toxic]
Metabolism[24hrs] Enzyme
Drug B
[Inhibitor]
Metabolism[72hrs]
Effect
=Drug accumulates
Warfarin
Metabolism[24hrs] Enzyme
Drug B
[Erythrymycin]
Enzyme
Metabolism[72hrs]
Anticogulant
=Bleeding
+
+
Enzyme
Drug A
[Toxicity]
Warfarin
[Toxicity]
8
Non-microsomal enzymes
Genetic polymorphism
INH
Long duration of action=Lower dose
Non-microsomal Enzyme
Slow acetylators
[40% of polpulation]
INH
Short duration of action=Higher dose
Non-microsomal Enzyme
Fast acetylators
[40% of polpulation]
7
Genetic variation in drug metabolism
Succinylcholine, isoniazid, primaquine etc show
genetically determined variation in metabolism

Succinylcholine apnoea - paralysis of respiratory
muscles and diaphragm

Isoniazid:
slow acetylators
rapid acetylators

Primaquine: Hemolysis in G6PD deficiency
5
MOA of some drugs is enzyme
inhibition!!!!
6
First Pass Metabolism
Drug metabolism that occurs before reaching systemic
circulation is described as first pass metabolism.

Extensive First pass metabolism seen for:
Lignocaine
Propranolol
Insulin
Catecholamines

Prodrugs activated
4
First Pass Metabolism
3
First pass metabolism
Not given orally
Lignocaine
Hydrocortisone
Testosterone
High oral dose
Propranolol
Verapamil
Morphine
2