Different phases of Drug metabolism & elimination

1. Drugs Metabolism
DR. JAHID
Assistant Professor, PHARMACOLOGY
CUCMS.

3. ▪ These are chemical reactions that occur inside the body-
▪ To reduces the lipid solubility
▪ alter biological activity
▪ thereby converting the drug into water soluble
▪ so to facilitate excretion from the body……
▪ The main objective is therefore to facilitate drug
elimination.
Define drug metabolism

4. ▪ Organs of metabolism
▪Liver ( the main organ of metabolism)
▪Kidney
▪Intestine
▪Lungs
▪Skin
▪Adrenal gland and
▪Brain

5. Aims of drug metabolism
active drug inactive substances
active drug active metabolite
inactive drug (prodrug) active drug
toxic substances. Eg.
N-Acetyl Benzoquinone
Active Drug Active metabolite
• Codeine Morphine
• Diazepum Desmethyl diazepum, Oxazipum

6. Drug metabolite
Facilitate excretion
Loss of biological
activity
Drug
metabolite
Loss of lipophilicity

7. ▪ Plasma half life (t 1/2) of
drug:
▪ Half life (t1/2) is the time
taken by a drug to become
half of its initial concentration. 50mg/L
100 mg/L

8. ▪Time to decline conc. from 100 to 50: 2 hr
▪ So, t1/2 of this drug is 2 hr

9. ▪ Generally, a drug will be eliminated after 6 half
lives.
▪After 1 half-life the conc will be 50%
▪After 2 half-lives it will be 25%
▪After 3 half-lives 12.5% and
▪After 4 half-lives 6.25%
▪After 5 half-lives 3.125%
▪After 6 half-lives 1.56%

10. ▪ Drug metabolizing enzymes
1. Microsomal enzymes
▪They are mainly located on the smooth endoplasmic
reticulum of the liver, kidney, lungs and intestine.eg.
▪ Cytochrome P450
▪ Glucoronyl tranaferase
▪ Cytochrome P450 reductase
▪ Monooxygenase
▪They catalyze most of the oxidation, reduction, hydrolysis
and Glucoronide conjugation.

11. ▪Cytochrome system
▪The cytochrome system consists of more than 100 different
isoenzymes that are divided in families.
▪The families mostly significant for the human organism are
CYP1, CYP2 and CYP3.
▪These are themselves divided in subfamilies such as,
▪ CYP3A – causes about 50% biotransformation
▪ CYP2D - causes about 20% biotransformation
▪ CYP2C - causes about 15 % biotransformation

13. ▪ Non- microsomal enzymes
▪ Mostly present in cytoplasm and mitochondrica of
liver, plsama, brain and kidney.
▪ MAO (Mono amine oxidase) (present in brain)
▪ COMT (Catechol-o-Methyl tranferse) (Present in plasma)
▪ Amylase
▪ Hydroxylase
▪ Reductase

14. Phases of metabolism
There are 2 phases
▪ Phase I ( Non synthetic/ Functionalization reactions)
▪ Phase II ( also known as conjugation reactions).
▪ Most drugs proceed from phase I to phase II reactions.
▪ Some drugs may proceed directly to phase II.
▪ Some drugs are excreted in unchanged form.

15. Drug
Excretion
Drug
metabolite
Unchanged drug
Phase I
Phase II

17. ▪ Phases of metabolism:
▪ Phase 1 { Functionalization reactions }
▪These are metabolic reactions that convert lipophilic
molecules into polar substances by introducing or unmasking
functional groups on the parent compound.
▪ (-OH, -NH2, -SH, -COOH)
▪There are 3 reactions in phase 1
Oxidation (most important)
• Reduction
• Hydrolysis.
▪ Generally loss of pharmacological activity

19. 1.Oxidation: This reaction involves addition of O2 or (-)
charged radical or removal of H+ or (+) charged radical.
▪ It is two types:
▪ Microsomal oxidation: It occurs in most lipid soluble drugs
and steroid hormones.eg.
▪ Diazepum oxidized to Desmethyl diazepum.
▪ Non- Microsomal oxidation: Eg.
▪ Adrenaline deminated to dihydroxymandelic acid.

21. ▪ Reduction: opposite of hydrolysis
▪ It can take place in the drugs which contain disulphide
(S:S), azo (N:N), OR nitro (NO2).
▪ Prontosil is reduced to sulfonamide.
▪ Chlorumphenicol to arylamine
▪ Hydrolysis: Cleavage of drug molecule by taking
up a molecule of water.
▪Acetylcoline is hydrolyzed to choline and acetate.

23. Cytochrome P450 cycle in drug oxidations

24. ▪ Phase II (synthetic or conjugation reaction)
▪ Phase II reaction take place when a drug or phase I
metabolite contains a chemical group such as hydroxyl (-
OH), carboxyl (-COOH), amino (-NH2), Sulfhydryl (-SH).
▪Than they combining with a natural compound provided by
the body to form readily excreted water soluble polar
metabolites.
▪  in hydrophilicity

25. Phase II
Conjugations
• Glutathione (GSH) (GSH transferase)
• Sulfate (sulfotransferase)
• Glucuronide (UDPGT or UGT)
• Acetyl (N-acetyl transferase)
• Amino acids (acyl transferase)

27. The reactions are:
▪ Glucoronidation (morphine, paracetamol, diazepam)
▪ Acetylation (isoniazid, sulfonamides, dapsone)
▪ Methylation( adrenaline, noradrenaline, dopamine)
▪ Sulphation ( steroids, oestrogen)
▪ Glycine conjugation (salicylic acid)

28. Enzyme induction
It is the ability of a drug on administration to induce drug
metabolizing enzymes either by enhancing rate and extent
of enzyme synthesis or by decreasing the rate and extent of
degradation.
The inducer drug increases the metabolism of the induced
drug.

29. ▪Enzyme inducers are
▪Rifampicin
▪Phenobarbital
▪Phenytoin
▪Carabamazepine
• Clinical relevance of induction:
• Decreased pharmacological effects
• Development of tolerance
• Risk of adverse effects

30. Enzyme inhibition
It is the ability of drugs to inhibit drug metabolizing
enzymes thereby decreasing the metabolism of drugs.
The inhibitor drug decreases the metabolism and increase
the duration of action inhibited drug

31. ▪Enzyme inhibitors are
▪Cimetidine
▪Metronidazole
▪Isoniszide (INH)
▪Ketoconazole
• Clinical relevance of inhibition:
• Increased pharmacological effects
• Risk of adverse effects

32. ▪ Factors affecting drug metabolism
▪ Genetic factors
▪ Diseases
▪ Gender
▪ Age

33. Genetic variation in drug metabolism:
The first is the debrisoquinsparteine oxidation type of
polymorphism, which apparently occurs in 3–10% of
Caucasians and is inherited as an autosomal recessive trait.
In affected individuals, the CYP2D6 –dependent oxidations
The second well-studied genetic drug polymorphism
involves the stereoselective aromatic (4)-hydroxylation
of the anticonvulsant mephenytoin, catalyzed by CYP2C19.
The third relatively well-characterized genetic
polymorphism is that of CYP2C9

34. ▪ Genetic variation in drug metabolism:
▪In Acetyl transferase enzyme deficiency If INH given & in
that person there will be chance of slow acetylation or rapid
acetylation occur.
▪Glucose-6-PO4 deficiency : If primaquine , aspirin,
sulfonamides are given - there will be severe haemolysis .
▪Pseudocholinestaerase : BreaksAch & also degrades succinyl
cholin causes Muscle relaxant .
▪ Chlorumphenicol can causes aplastic anaemia
B. Phase II Enzyme Polymorphisms

35. induce CYP1A enzymes

37. converted
to metabolites unchanged form

38. ▪Water soluble
▪Ionized
▪And in more polar form
▪Pharmacologically inactive

39. the lung excluded

40. • Major routes are-
▪Renal ( the most important)
• Minor routes are-

41. ▪ Glomerular filtration.
▪ Active tubular secretion
▪ Tubular reabsorption

42. ▪Glomerular filtration:
▪ Depends on-
▪ GFR
▪ Only free drugs can pass through this
process.
▪ Drugs that are bound to plasma protein
can’t filtrate by this process. (Warfarin
98% bound to plasma.)
▪ Drug size < 20,000 MW
▪ Driving force for GF is hydrostatic
pressure of blood flowing in capillaries.

43. ▪Active Tubular secretion
▪ Active process (blood to tubular lumen)
▪ This mainly occurs in proximal tubule.
▪ Requires energy for transportation of compound against
concentration gradient.
▪ Proximal tubule cells transfers charged molecules from
plasma to the tubular fluid.
▪ Eg. Acidic drugs:Penicillin, Probinacids, salicylic acid
▪ Basic drugs: Morphine, Thiazide, Histamine.

45. ▪Tubular reabsorption
▪ Drug lipid solubility > reabsorption
▪ Degree of drug ionization
▪ Drug molecular size
increase in the half life

46. ▪ActiveTubular Reabsorption:
electrolytes, glucose,
vitamins.
PassiveTubular Reabsorption:
Primary determinant: Lipid solubility.

47. Tubular Reabsorption
URINARY ACIDIFIERS URINARY ALKALINIZERS
Sodium bicarbonate
Potassium Citrate

48. ▪Excretion through lungs:
▪ Gaseous and volatile substances such as general
anesthetics (Halothane) are absorbed & excrete through
lungs by simple diffusion.
▪ It depends on-
1. Pulmonary blood flow
2. Rate of respiration and
3. Solubility of substance

49. BILIARY EXCRETION
• Drugs / metabolites excreted in feces
Liver  bile  duodenum  feces
• Unabsorbed orally ingested drugs
• Metabolites excreted in the bile can be blocked their
reabsorbed from the intestinal tract.e,g: Mercury
poisoning
Transporter in apical border of gi  feces

50. Drugs excreted through breast milk
slightly acidic (pH=6.5)
weak basic drugs

52. ▪Urine pH
▪It varies between 4.5 to 7.5
▪ It depends upon diet, drug intake and
pathophysiology of the patient .
▪ Acetazolamide and antacids produce alkaline
urine, while ascorbic acid makes it acidic.
▪ In acidic drug poisoning (eg.Paracetamol)
alkalization of urine done to promoto
excretion.
▪ In alkaline drug poisoning (e.g.Diazepum)
acidification of urine done to promoto
excretion.

53. ▪RENAL DYSFUNCTION