Drug Clearance by Biotranformation

Drug clearance :

Once a drug enters into the body, the process of elimination begins. The three major routes of eliminations are:

(i) Hepatic metabolism

(ii) Biliary elimination

(iii) Urinary excreation

Excreation is irreversible removal of the drug from the body. It involves BIOTRANSFORMATION & EXCREATION.

•> Metabolism results in products with increase polarity, which allows the drug to be eliminated.

•> Clearance(CL) estimates the vomume of blood from which the drug is cleared per unit of time.

CL = 0.693 x Vd / t 1/2

- Where T 1/2 is the elimination half life, Vd is apparent volume of distribution and 0.693 is natural log.

BIOTRANSFORMATION

• The general principle of biotransformation is the metabolic conversion of drug mollecule to more water soluble metabolites that are more readily excreated.

- In many cases, metabolism of drug results in its conversion to compounds that have little or no pharmacological activity.

- In other cases, biotransformation of an active compound may lead to the formation of metabolites that also have pharamacologic actions.

- A few compounds (prodrugs) have no activity until they undergo metabolic ativation.

- Some compounds also converted into toxic metabolities.

Drug =====> Active metabolite

Drug =====> Inactive mtabolite

Prodrug =====> Drug

Sites of Biotransformation :

(i) LIVER : microsomal & non-microsomal enzyme system.

(ii) GIT : gastric acids, digestive enzymes, enzymes in wall of intestine & intestinal microorganisms.

(iii) Lungs

(iv) Kidney

(v) adrenal glands

(vi) Skin

Significance of Biotransformation :

• Termination of drug action.

• Activation of prodrug (eg : Clorazepate==>nordiapizam)

• Conversion of parent mollecule into an even more potent form.

Factors affecting biotranformation:

• Genetics : it may alter enzyme level or cause polymorphism of enzymes involved in Acetylation, Hydroxylation, & Hydrolysis.

• Route of administration : oral route can result in extensive first pass effect.

• Chemical properties of drugs : Certain drugs may stimulates or inhibit the metabolism of other drugs by inhibiting or activating P450 system in Liver.

• Dosage : Toxic dose can deplete enzyme, which decrease the biotranformation.

• Diet : starvation depletes glycine and can alter glycine conjugation.

• Age : In liver of newborn or neonates cannot detoxify drugs due to undeveloped drug metabolizing enzymes system in liver, conjugation reactions are not effective as well.

• Sex : young males are more prone to sedation from batbiturates than females.

• Disease : Liver disease decrease drug metabolism which cause increase drug action.

Phases of Biotranformation

• The kidney cannot effeciently excreates lipophilic drugs that readily cross cell membranes and are reabsorbed in DCTs. Therefore lipids soluble agents are first metabolized into more polar( Hydrophilic) substances in liver via two sets of reactions, called phase 1 and phase 2.

PHASE 1 :

• Also known as Enzymatic tranformation.

• It convert lipophilic drugs into more polar mollecules by introducing or unmasking a polar functional group, such as -OH or -NH2.

• Phase 1 reactions usually involve reduction, oxidation, or hydrolysis.

• Phase 1 metabolism may increase, decrease or no effect on pharmcological activity.

(1) OXIDATION :

• It involves the addition of O2 or release of H2 from drugs by microsomal or non-microsomal systems.

(i) Microsomal Metabolism :

• It cause drug oxidation by oxidative drug metabolizing enzymes, located in lipophilic membranes of smooth ER of liver and other tissue cells.

(a) Cytochrome P450 isozymes : major enzyme involved in phase 1 reactions located in smooth ER(microsomal fraction) of cells (especially liver but also GI tract, lungs , kidney) .

- P450 have an absolute requirement for mollecular oxygen and NADPH.

- Oxidations include hydroxylations and dealkylations.

- Multiple Cytochrome P families differing by Aminoacids composition, by substrate specificity, and by sensitive to inhibitors and to inducing agents.

(ii) Non-microsomal metabolism :

(a) Cytochrome P450 independent oxidation : it involves the oxidation of soluble enzymes found in cytosol or mitochondria of cell.

Example : monoamine oxidase, Alcohal dehydrognase, Aldehyde dehydrogenase, Xanthine oxidase, Tyrosine hydroxylase.

(b) Reduction : it occurs in both microsomal and non-mocrosomal metabolising system.

Example : azo-reduction , nitro-reduction etc.

(c) Hydroysis : It involves non-microsomal hydrolases present in various body systems including plasma.

- It involves addition of water mollecule with subsequent bond breakage.

Example : esterase , amidases.

(d) Alcohal metabolism : Alcohals are metabolised to aldehydes and then to acids by dehydrogenases.

Phase 2

• It involves coupling or conjugation reaction of parent drug or their Phase-1-metabolite with an endogenous substance to yeild drug conjugates.

• It is catalyzed by various transferases located in microsomes or in cytosol.

• Drug conjugates are polar mollecules that are readily excreated & often inactive.

(a) Glucuronidation :

• inducible , may undergo enterohepatic cycling.

( drug glucuronide => intestinal bacterial glucuronidase => free drug).

- Morphine is activated to more potent morphine-6-glucuronide.

- It is the most common and the most important conjugation reaction.

(b) Acetylation :

• Drug induce SLE by slow acetylators with hudralazine >procainamide> isoniazed(INH).

- Acetylation of sulfonamides.

(c) Glutathione (GSH) conjugation :

• Depletion of GSH in liver is associated with acetaminophen hepatotoxicity.

- Ethenacrynic acid

(d) Glycine conjugation : Salicylic acid.

(e) Methylation : Dopamine, Epinephrine, histamine.

(f) Water conjugation : Carbamazepine

• Drugs already possesing an -OH, -NH2, or -COOH group may enter phase 2 directly and become conjugated without prior phase 1 metabolism.

• The highly polar-drug-conjugates are then excreated by the kidney or in bile.

Comments

Autonomic Nervous System Anatomy and Physiology

The Autonomic Nervous System • The Autonomic Nervous System(ANS) along with endocrine system coordinates the regulation amd integeration of body functions. •The ANS largerly independent (autonomous) in that its activities are not under direct conscious control. It is concenred primarily with visceral functions such as cardiac output, blood flow to various organs and digestions, which is necessary for life. • Drugs that produce their primary therpeutic effect by mimicking or altering the functions of ANS are called autonomic drugs. - The autonomic agents act either by stimulating portion of ANS or by blocking the action of autonomic nerves . Nervous System overview : • The N.S is divided into 2 anatomical divisions : The Central Nervous System which is composed of brain & spinal cord and the Peripheral Nervous System . • Peripheral nervous system includes neurons which located outside the brain and spinal cord. • The peripheral nervous syste

AGONIST & ANTAGONIST with types

AGONIST • Agonist is a chemical(drug) that binds to the receptor and activates the receptor to produce biological response. OR • Agonist is a drug that produce effects on endogenous compounds, when it interacts with it’s receptor. => Agonists are of following types: (1) Full agonists (2) Partial agonists (3) Inverse agonists (1) Full Agonists • If a drug binds to a receptor and produce maximal biological response that mimics the response to endogenous ligand is called full agonist. - All full agonists for a receptor population should produce the same E max. For Example : phenylephrine is a full agonist at alpha1-adrenoceptors, because it produce the same E max as the endogenous ligand, norepinephrine. Upon binding with aplha1-adrenoceptors on vascular smooth muscle, both phenylephrine and norepinephrine stablize the receptor in its active state, thereby increasing the Gq activation. Activation of Gq i

Mechanism of absorption of Drugs

Absorption of Drugs • Absorption concerns the process of entry of drug in to systemic circulation from site of administration. •The rate and extent of absorption depend on: -the environment where the drug is absorbed -chemical characteristics of drug -route of administration (which influence bioavailability) • The route of administration other than intravenous may result in partial absorption and lower bioavailability. (A) Mechanism of absorption of drug from GIT • Depending upon their chemical properties , drugs may be absorbed from GI tract by passive diffusion, facilitated diffusion, active transport or endocytosis. (1) Passive diffusion : • In this drug move from area of high concentration to area of lower concentration. - also known as non-ionic diffusion - The driving force for this process is concentration or electrochemical gradient. - P.D does not require carrier, is not saturable, and shows low structural specifity. - The

Elimination of the Drug

Drug Elimination • Drugs must be sufficiently polar to be eliminated from the body. • Removal of drugs from body occur via number of routes; the most important is elimination through kidney in to urine. Renal Elimination of Drug • A drug passes through several process in the kidney before elimination, Glomerular filtration, tubular seceration , and passive tubular reabsorption. (1) Glomerular filteration : • Drugs enter the kidney through renal artries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary bed into bowman’s space as a part of glomerular filterate. > Glomerular filteration rate is normally about 120mL/min. But may decrease sugnificantly in renal disease. > pH and lipid solubility do not influence the passage of drugs into glomerular filterate. > Variation in GFR and protein binding to drugs donot affect this process. > water and polar compounds easily enter in gl

Cholinergic neuron & Cholinergic Receptors

•Drugs affecting the autonomic nervous system(ANS) are divided into two groups according to the type of neuron involved in mechanism of action. •The cholinergic drugs, which act on receptors activated by acetylcholine(Ach), Where as adrenergic drugs act on receptors stimulated by epinephrine or norepinephrine. •The cholinergic drugs act by either stimulating or blocking the receptors of the ANS. The cholinergic neuron • The preganglionic fibres terminating in adrenal medulla. • The postganglionic fibres of parasympathetic division use ACh as a neurotransmitter. The postganglionic sumpayhetic division of sweat glands also uses ACh. • Ina ddition, cholinergicneurons innervate the muscles of somatic system and play an important role in CNS. NEUROTRANSMISSION @ CHOLINERGIC NEURON : • Neurotransmission at cholinergic neurons involves 6 sequential steps : (1) Synthesis of ACh (2) Storage of ACh (3) Release of ACh (4) Binding of ACh to the receptor (5) Degradati

Cholinergic Drugs (direct acting) Part-2

(3) CARBACHOL (Carbamylcholine ) • Carbachol is is an ester of carbamic acid and poor substrate for AChEsterase. It is biotransformed by other esters at very slow rate. • Carbachol has both Muscarinic and Nicotinic actions. Functions (i) Actions : • Carbachol has profound effects on both Cardiovascular system and GI system. • It has ganglion stimulating activity and it may first stimulate and then depress these systems. • It can cause release of epinephrine from adrenal medulla by its nicotinic functions. On Eye : • It cause miosis • It cause spasm of accomodatiom in which the ciliary muscle of the eye remains in a constant state of contraction. • Carbachol is also used to stimulate micturation by contraction of detrusor muscle. (ii) Therapeutic uses : • Carbachol has high potency, receptor non-selectivity and relatively long duration of action. • Carbachol is rarely used. • Carbachol administered ocularly to induce miosis to reduce the intr

PHARMACODYNAMICS & Drug Receptor Interaction

>Pharmacodynamics deals with the biochemical and physiological effect of drug as well as its mechanism of action. OR We can simply define it as, The action of drug on the body. •Most drug exert effects, both beneficial and harmful, by interacting with specialized target macromollecule called receptor. Receptor : it refers to the drug binding site in the cell or on the surface of cell which mediate the action of drug. • There are some drugs which do not require receptors Example = mannitol , anti-helmintic drugs, etc. NATURE OF DRUG RECEPTOR 1. Regulatory protein which mediates the action of endogenous chemical signals. For example : neurotransmitters , harmones and autocoids. 2. Enzymes. For example : dihydrofolic reductase 3. Transport protein. For example : sodium / potassium ATPase pump. 4. Structural protein. For example : tubulin. RECEPTOR REGULATION •Down Regulation : when receptors becom

Cholinergic Drugs (Direct acting) Part-1

Cholinergic Agonists (direct acting) • Cholinergic agonists mimic the effect of acetylcholine by binding directly to cholinoceptors (muscarinic & nicotinic). • These agents are classified into 2 groups; (1) Choline esters : it includes endogenous ACh and synthetic esters of choline. Such as Carbachol & Bethanechol . (2) Naturally occuring Alkaloids : Nicotine & Pilocarpine . • All direct-actings Cholinergic drugs have longer duration of action than Acetylcholine. (1) ACETYLCHOLINE • ACh is the quaternary ammonium compound that cannot penetrates membranes. • It is nuerotransmitter of parasympathetic, somatic nerves & autonomic ganglia. • It lacks the therapeutics importance b/c of multiple actions and its rapid inactivation by the cholinesterases. • ACh has both muscarinic and nicotinic activity. Functions : (a) Decrease in heart rate and cardiac output : • ACh mimics the effects of vagal stimulation on the heart. • If in

Drug clearance & Half Life & Dose

Drug Clearance It refers to the ratio of rate of drug elimination to the concentration of drug in biological fluid(C). CL = rate of elimination / C Rate of elimination • For most of the drugs, elimination is not saturable & rate of drug elimination is directly proportional to concentration. Rate of elimination = CL x C ==> The difference between drug clearance and drug elimination is that : • Clearance is Volume of blood cleared of drug per unit time and Elimination is amount of drug cleared from blood per unit time. Total Body Clearance • The total body systemic clearance , CLtotal is the sum of all clearances from drug metabolising and drug eliminating organs. OR • Dividing the rate of elimination at each organ by concentration of drug presented to it yeilds respective clearance at that organ and sum of these is total body clearance. CLx = rate of elimination x / C

Search This Blog