Download Sites of drug metabolism

Medicinal chemistry
Third stage
Lecture 2
Dr. Narmin Hussen
B.Sc. In Pharmacy
M.Sc. In Ph.chemistry
Drug Metabolism
 Drug metabolism is the term used to describe the
biotransformation of pharmaceutical substances in the body
so that they can be eliminated more easily.
 Drug metabolism often converts lipophilic chemical
compound into more readily excreted polar products.
Sites of drug metabolism
 The most important organ for drug metabolism is the liver
because it is relatively rich in a large variety of metabolizing
enzymes.
 Metabolism by organs other than liver (called as extra-hepatic
metabolism) is of lesser importance because lower level of
metabolising enzymes is present in such tissues.
Example :
 kidney ,lungs , skin (epithelial cells); plasma. nervous tissue
(brain); intestines
Drugs are metabolized through various reactions including:
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Oxidation
Reduction
Hydrolysis
Hydration
Conjugation
Condensation
Isomerization
Phases of metabolism reactions
First pass effect
 It happens most commonly when the drug is administered
orally. Before the drugs reaches the systemic circulation the
drug can be metabolized in the liver. As a result, concentration
of the drug in the systemic circulation will be reduced.
Tocainide is a lidocaine analog, that does not have
significant 1st pass metabolism
Sulindac
 Sulindac sulfoxide is inactive parent drug .
 Sulindac sulfoxide is converted to an active metabolite
(Sulfide) include the nonsteroidal anti inflammatory agent .
Azothioprine
 Immunosuppressant azothioprine being cleaved to the purine
antimetabolite 6-mercaptopurine .
 Both the parent drug and its metabolite are active
Phenacetin and acetaminophen
Excretion
 The main route of excretion of a drug and its metabolites is
through the kidney( renal excretion).
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Non renal excretion
Biliary excretion
Pulmonary excretion
Salivary excretion
Mammary excretion
Skin / Dermal excretion
Urine pH
 The pH normally is within the range of 5.5 to 7 with an average
of 6.2
 It depends upon diet, drug intake and physiology of the patient .
 In alkaline urine( antacids ) , acidic drugs( ascorbic acid) are
more readily ionized.
 In acidic urine, alkaline drugs are more readily ionized. Ionized
substances (also referred to as polar) are more soluble in water
so dissolve in the body fluids more readily for excretion.
 In aspirin poisoning, making the urine more alkaline with
sodium bicarbonate increases ionization of the salicylic acid
(aspirin metabolite) and increases excretion from the body.
Receptor
 A Receptor is a protein molecule usually found on the surface
of a cell (or inside a cell) that receives chemical signals from
outside the cells and when such chemical signals bind to a
receptor , they cause some form of cellular /tissue response .
Many drug receptors are the same as those used by endogenously
produced ligands :
 Cholinergic agents interact with the same receptors as the
neurotransmitter acetylcholine.
 Synthetic corticosteroids bind to the same receptors as
cortisone and hydrocortisone .
Receptors for the same ligand are found in various
throughout the body:
tissues
 Non steroidal anti-inflammatory drugs combine with the
desired cyclooxygenase
receptors at the site of the
inflammation and the undesired cyclooxygenase receptors in
the gastrointestinal mucosa , causing severe discomfort and
sometimes ulceration.
 One of the second generation antihistamines , Fexofenadine is
claimed to cause less sedation.
 In contrast, some antihistamines are used for their CNS
depressant activity because a significant proportion of the
administrated dose is crossing the blood-brain barrier binding
to the histamine H1 receptors in the periphery.
Receptor and signal as “Lock and key”
 A hormone or neurotransmitter (the key) affects target cells
by binding to specific receptor molecule ( the lock ) , which
are often located in the cell membrane.
Agonist and antagonist
Tamoxifen and raloxifene
 They cannot be classified simply as agonists or antagonists.
 Their selectivity is very complex because it depends on the organ
in which receptor is located .
 Tamoxifen is used for estrogen –sensitive breast cancer and
reducing bone loss from osteoporosis , prolonged treatment
increases the risk of endometrial cancer because of the response
from the uterine estrogen receptors.
 Tamoxifen is an estrogen antagonist in the mammary gland and
an agonist in the uterus and bone .
 In contrast, raloxifene does not appear to have much agonist in
the uterus but, like tamoxifen , is an antagonist in the breast
and agonist in the bone.
Phosphodiesterase type 5 inhibitors
The PDE5 inhibitors are the recommended first-line
treatment for erectile dysfunction
 The phosphodiesterase type 5 (PDE5) inhibitors cause vasodilation in the
penis by blocking the breakdown of cyclic guanosine monophosphate (cGMP)
which results in prolongation of the action of mediators of vasodilation
including nitric oxide (NO) and enhance erectile function .
Summary
Drug metabolism
Drug excretion
Receptor
Home work
1. Lidocaine and tocainide which one of them is more water
soluble ? Why?
2. Why phenacetin removed from the market?