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: 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). 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 tissues throughout the body: 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 Lidocaine and tocainide which one of them is more water soluble ? Why? Why phenacetin removed from the market?