Metabolism & Elimination

- The kidney cannot efficiently eliminate lipophilic (Non-Polar) drugs that readily cross cell
membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are
first metabolized into more polar (hydrophilic) substances.
- The liver is the main site of drug metabolism.
- Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation,condensation, or isomerization.

Metabolism

Definition:-

-(biotransformation) usually conversion of drug from non-polar (active) to Polar (less active) 

more polar (not active)  to facilitate excretion.

Classification:-

Phase I

Reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar

functional group, such as-OH or -NH.

Phase I Reactions:

1: Oxidation

2: Reduction

3: Hydrolysis

Phase II

This phase consists of conjugation reactions.

Conjugation may be with :

1: Acetic acid (Acetylation) 3: Sulfate

2: Methylation 4: Glycine 5: Glucuronic acid

Metabolism Enzymes:-

Microsomal Enzymes Non-Microsomal Enzymes

Majority Majority of drug biotransformation reaction Some of drug biotransformation reaction

Site Smooth endoplasmic reticulum. Cytoplasm and mitochondria.

Organs Mainly in liver then kidney, lungs,

intestinal mucosa.

Hepatic cells as well as in other

tissues including plasma.

Phase I - Catalyse oxidative(CYP450)

reductive) & hydrolytic reactions

Catalyse few oxidative , reductive &

hydrolytic reactions.

Phase II Glucuronidation reactions only Also conjugation reaction other than

glucuronidation.

Activity Can be induced and inhibited. Can't be induced and inhibited.

Results of metabolism:-

1-Inactivation e.g. Acetylcholine (Active) Choline + Acetic acid (Inactive).

2- Activation e.g. L-dopa(Inactive) Dopamine (Active).

3- Maintain activation e.g. Diazepam (Active) Nor-Diazepam (Active) .

4- Toxification e.g. Methyl alcohol (Non-toxic) Formaldehyde (Toxic-Blindness)

Factors Affecting Metabolism:-

Age:

Deficiency of liver microsomal enzyme especially child prolonged action of drug lead to increase

toxicity e.g. Chloramphenicol when used in babies cause Grey baby syndrome.

Sex differences:

hormonal activity might affect the activity of certain oxidation Sex differences: Metabolic difference

between sexes have been noted for a number of enzymes.

Genetic factor:

Absence of specific gene responsible for synthesis of special enzyme

State of health:

Presence of disease (liver disease) - Alters in the normal metabolism. which essential for normal metabolism

Inhibition of microsomal enzymes:

Certain drugs inhibits the activity of microsomal enzyme (decrease metabolism rate) leading to prolongation the action of other drugs > increase (drug) activity and may leading to toxicity.

Induction of microsomal enzymes:

Certain drugs increase the activity of microsomal enzyme leading to increase metabolism rate decrease activity of drug other drugs.

- Hepatic microsomal enzyme (HME) inducers 

E.g. Carbamazepine, Phenobarbital, phenotoin and Rifampicin.

- Hepatic microsomal enzyme (HME) inhibitors

E.g. Cimetidine, Chloramphenicol, Omeprazole ,Erythromycin and Ketoconazole

Elimination

Def. The process which involve excretion of drug outside of the body.

Routes of drug excretion (elimination):

1-Kidney:-

Through: 1: Glomerular filtration: For water soluble non bound drugs (Most).

2: Proximal (Active) tubular secretion: e.g. Penicillin.

3: Distal (Passive) tubular reabsorption: For lipid soluble drugs.

Reabsorption may affected by pH:-

- Acidification of urine (Vit. C) Increase excretion of basic drugs.

-Alkalization of urine (NaHCo3) Increase excretion of acidic drugs.

2-GIT :- through Saliva and Bile.

3-Skin :- through sweat gland(Rifampecin) and Breast (milk) Nicotine and Morphine.

4-Lung:- e.g. Anesthetic Gases e.g Nitrous oxide & Halothane .

Method used to prolong duration of action of drugs

Decrease Absorption

1) Add Vasoconstrictor(Adrenaline + local anesthesia).

2) Use sparingly soluble complex.

3) Use of drug in oil (Vasopressin in oil).

4) Use of sustand release (slow release) tablets.

5) Use SC pellet implantation.

Decrease Metabolism Use HME inhibitors .

Decrease Excretion  Probenecid with Penicillin .

Increase protein binding Add methoxy group to sulfonamide

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