Metabolism

Drug metabolism is the transformation of foreign compounds (xenobiotics ) into water soluble derivatives which can easily eleminate via renal route.

WHY STUDY METABOLISM?

Why Do Drug’s Get Metabolized?

•Metabolism is the process of preparing foreign chemicals for removal from the body

•Drug action is usually terminated by metabolic processes

•The rate of metabolism is one factor in determining the duration of action of drugs

•Metabolism often occurs in two steps

Metabolism = Anabolism + Catabolism

Factors affecting metabolism

Includes effect of: Gender Temperature Age Training Diet Exercise intensity & duration Pharmacodynamic factors(dose,

route ,frequency of adminstration) Drug interactions

Gender

Generally ♀ lower than male Sex hormones

Oestrogen & progesterone inhibit CHO metabolism Oestrogen stimulates fat metabolism and may

potentiate lipolytic effect of adrenaline (may overcome progesterone inhibits fat metabolism)

Men have higher levels of lean muscle mass. This means that women will generally have lower metabolisms than men.

Age

See reduced metabolism as age Both CHO and fat utilisation ↓

Age: with your age, your metabolism naturally slows down. This is because the body loses lean muscle mass over the years. Expect your metabolism to decline by about 2% every decade after the age of 20.

Chloramphenicol (in neonate).

Temperature

Higher oxygen consumption during exercise due to ↑core temp, energy sweating etc.

↓temp depends on body fat, clothing etc. ↑MR due to shivering

Effect of training status

Training greater use of fat and sparing of glycogen

It is important that you increase your total amount of lean muscle mass if you want to speed up metabolism. Focus on performing strength-training exercises to build your muscles.

Height: People who are taller have a greater

surface area for their bodies to fuel. Therefore taller people tend to have a more active metabolism and require more calories for energy production.

Family History Some families have a naturally high

metabolism, while others have a naturally low metabolism.

Eating Habits The more often you eat, the more active

your metabolism will be. If your body doesn't get a regular supply of calories, your metabolism will slow down This is why many people who are trying to lose weight suffer dieting syndrome.

Phases of metabolism•Phase I metabolism involves chemical

transformations, usually catalyzed by enzymes, including oxidations, reductions, hydrolyses, and other reactions that prepare the drug for elimination from the body. (functionalization reaction).

•Most often the products of phase I metabolism are more polar than the drug molecule.

In Phase II metabolism a very polar, highly hydrophilic molecule is added to the drug to make it water soluble, a process called conjugation.

•Most often these conjugates lose most or all of their biological activity.

•These conjugates are then excreted in the urine to remove the drug from the body.

(CYP450) Metabolism by cytochrome P450

enzyme systhem (CYP450)• Located in endoplasmatic reticulum

(liver and other cells)

N

NN

N

Fe3+

S

Cystein

HOH

Phase I (functionalization reactions)

Oxidations (electron removal, dehydrogenation and hydroxylation).

Reduction (electron donation , hydrogenation and removal of oxygen).

Hydrolytic reaction of amide and ester.

Oxidation reactions The main enzyme involved is mixed

function oxidases or monooxygenases found mainly in the liver and other tissues.

R-H +O2 + H+ NADPH ROH +H2O +NADP

Oxidation reactions 1-Carbon oxidation a-Hydroxylation at saturated carbons

b-Oxidation of unsaturated aliphatic

system. c- Hydroxylation of aromatic rings 2- N- oxygenation reactions 3-S – oxidation reactions

Hydroxylation of saturated aliphatic carbons

They are normally metabolized at ώ or ώ-1

CH3-CH2-CH2-CH(C3H7)COOH(valproic )Is converted to HOCH2-CH2-CH2-CH(C3H7)COOH or

(5hydroxy valproic)CH3-CH(OH)-CH2-CH(C3H7)COOH (4-

hydroxy valproic)

Enzymatic hydroxylation of cyclohexane occur at C3 or C4 as acetohexamide (hypoglycemic).