Pharmacology notes

1. METABOLISM & EXCRETION
1

2. BIOTRANSFORMATION
(Metabolism)
 Chemical alteration of the drug in the body.
 Needed to render nonpolar (lipid soluble)
compounds polar (lipid insoluble) so that they
are not reabsorbed in the renal tubules &
they are excreted.
 Most hydrophilic drugs, e.g. streptomycin,
neostigmine, etc. are not metabolized & are
excreted unchanged.
 The primary site for drug metabolism is liver;
others are – kidney, intestine, lungs &
plasma.
2

3. BIOTRANSFORMATION
Biotransformation of drugs may lead to:
 Inactivation
 Active metabolite from an active
drug
 Activation of an inactive drug :
some drugs need conversion in the
body to an active metabolite. Such a
drug is called a prodrug.
3

4. BIOTRANSFORMATION
Active drug
Phenacetin
Primidone
Diazepam
Digitoxin
Imipramine
Amitriptyline
Codeine
Active metabolite
Paracetamol
Phenobarbitone
Oxazepam
Digoxin
Desipramine
Nortriptyline
Morphine
4

5. BIOTRANSFORMATION
Prodrug
Levodopa
Enalapril
Prednisone
Bacampicillin
Sulfasalazine
Active form
Dopamine
Enalaprilat
Prednisolone
Ampicillin
5-Aminosalicylic acid
5

6. BIOTRANSFORMATION
Biotransformation reaction can be
classified into :
 Nonsynthetic / Phase I reactions
-metabolite may be active or inactive
 Synthetic / Conjugation / Phase II
- metabolite mostly inactive
6

7. PHASE I REACTIONS
Phase I reactions include oxidation
(especially by the cytochromme P450
group of enzymes, also called mixed
function oxidases), reduction,
deamination, & hydrolysis.
7

8. PHASE II REACTIONS
Phase II reactions are synthetic reactions that
involve addition (conjugation) of subgroups
to –OH, -NH2 & -SH functions on the drug
molecule.The substances that are added
include glucuronate, acetate,
glutathione,glycine, sulfate, & methyl
groups. Most of these groups are relatively
polar & make the product less lipid soluble
than the original drug molecule.
8

9. SYNTHETIC (CONJUGATION)
REACTIONS
 Involve conjugation of the drug or its phase I
metabolite with an endogenous substrate,
derived from carbohydrate or amino acid, to
form a polar highly ionized organic acid,
easily excreted in urine or bile.
 Includes glucuronidation, acetylation,
methylation, glycine conjugation,
glutathione conjugation, sulfate
conjugation.
9

10. CONJUGATION REACTIONS
 Glucuronide conjugation. Most important
synthetic reaction. Compounds with hydroxyl
or carboxylic acid group are easily conjugated
with glucuronic acid which is derived from
glucose. E.g. chloramphenicol, morphine etc.
 Acetylation. Drugs with amino or hydrazine
residues are conjugated with the help of Ach.
CoA, e.g. sulfonamides, isoniazid. Multiple
genes control the acetyl transferases & rate
of acetylation shows genetic polymorphism
10

11. CONJUGATION REACTIONS
 Sulfate conjugation. Phenolic
compounds & steroids are sulfated by
sulfokinases, e.g. chloramphenicol,
adrenal & sex steroids.
 Glycine conjugation. Salicylates &
other drugs with carboxylic acid groups
are conjugated with glycine.
11

12. Allopurinol
Omeprazole
Erythromycin
Clarithromycin
Ketoconazole
Itraconazole
Ciprofloxacin
Isoniazid
Cimetidine
Quinidine
Metronidazole
Disulfiram
Verapamil
MAO inhibitors
Diltiazem
Amiodarone
DRUGS THAT INHIBIT DRUG
METABOLIZING ENZYMES
12

13. CONSEQUENCES OF MICROSOMAL
ENZYME INDUCTION
 Decreased intensity & / or duration of action
of drugs that are inactivated by metabolism,
e.g failure of contraception with oral
contraceptives
 Increased intensity of drugs that are
activated by metabolism. Acute paracetamol
toxicity is due to one of its metabolites –
toxicity occurs at lower doses in patients
receiving enzyme inducers.
13

14. CONSEQUENCES OF MICROSOMAL
ENZYME INDUCTION
 Tolerance – if the drug induces its own
metabolism (autoinduction) e.g.
carbamazepine, rifampicin
 Precipitation of acute intermittent
porphyria: enzyme induction increases
porphyrin synthesis by derepressing
δ-aminolevulenic acid synthetase
14

15. FIRST PASS (PRESYSTEMIC)
METABOLISM
 Metabolism of a drug during its passage from
the site of absorption into the systemic
circulation.
 Orally administered drugs are exposed to
drug metabolizing enzymes in the intestinal
wall & liver
 The extent of first pass metabolism differs for
different drugs & is an important determinant
of oral bioavailability
15

16. DRUGS WITH HIGH FIRST
PASS METABOLISM
Not given orally
Isoprenaline
Lignocaine
Hydrocortisone
Testosterone
High oral dose
Propranolol
Verapamil
Salbutamol
Nitroglycerine
Morphine
Pethidine
Propoxyphene
16

17. ATTRIBUTES OF DRUGS WITH
HIGH FIRST PASS METABOLISM
 Oral dose is considerably higher than
sublingual or parenteral dose
 There is marked individual variation in
the oral dose due to differences in the
extent of first pass metabolism.
 Oral bioavailability is increased in
patients with severe liver disease.
17

18. DRUG EXCRETION
Drugs & their metabolites are excreted in:
- Urine. Most impotant channel of excretion.
- Faeces. Apart from unabsorbed fraction,
most of drug present in faeces is derived
from bile.
- Exhaled air
- Saliva & sweat
- Milk
18

19. RENAL EXCRETION
The kidney is responsible for excreting all
water soluble substances. The amount of
drug or its metabolites present in urine is
The sum of total glomerular filtration,
Tubular reabsorption, & tubular secretion.
19

20. GLOMERULAR
FILTRATION
All nonprotein bound drug presented to
the glomerulus is filtered. Glomerular
filtration of a drug depends on its
plasma protein binding & renal blood
flow. Glomerular filtration rate declines
with age.
20

21. TUBULAR REABSORPTION
Depends on lipid solubility & ionization of the
drug at the existing urinary pH.
- Lipid soluble drugs filtered at the
glomerulus back diffuse in the tubules
because 99% of glomerular filtrate is
reabsorbed.
- Nonlipid soluble & highly ionized drugs are
not reabsorbed.
21

22. TUBULAR REABSORPTION
Changes in urinary pH affect tubular reabsorption of
drugs that are partially ionized:
- Weak bases ionize more & are less absorbed in
acidic urine.
- Weak acids ionize more & are less reabsorbed in
alkaline urine.
This principle is used to facilitate drug elimination in
poisoning, i.e. urine is alkalinized in barbiturate &
salicylate poisoining while it’s acidified in morphine &
amphetamine poisoning.
22

23. TUBULAR SECRETION
This is the active transfer of organic acids
& bases by two separate nonspecific
mechanisms which operate in the
proximal tubule.
- Active transport of a drug across
tubules reduces concentration of its
free form in the tubular vessels & promotes
dissociation of protein – bound drug which is
secreted.
23

24. TUBULAR SECRETION
 Organic acid transport. Penicillins,
probenecid, uric acid, salicylates,
sulfinpyrazone, nitrofurantoin,
methotrexate, drug glucuronides etc.
 Organic base transport. Thiazides,
quinine, procainamide, choline,
cimetidine, amiloride etc.
24

25. KINETICS OF DRUG
ELIMINATION
 Clearance (CL). The CL is the
theoretical volume of plasma from
which the drug is completely removed
in unit time.
CL = rate of elimination/C
where C is the plasma concentration.
25

26. KINETICS OF DRUG
ELIMINATION
 First order (exponential) kinetics.
The rate of elimination is directly
proportional to drug concentration.
- CL remains constant; or a constant
fraction of the drug present in the
body is eliminated in unit time.
26

27. KINETICS OF DRUG
ELIMINATION
 Zero order (linear) kinetics. The
rate of elimination remains constant
irrespective of of drug concentration.
- CL decreases with increase in
concentration ; or a constant amount
of the drug is eliminated in unit time
e.g ethanol, phenytoin, warfarin
27

28. THE END
GOD BLESS
28