Lecture 8

The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. Factors affecting drug delivery from the plasma: A- blood flow: kidney and liver higher than skeletal muscles and adipose tissues. B- capillary permeability: 1- capillary structure: blood brain barrier 2- drug structure C- binding of drugs to plasma proteins and tissue proteins

Vd = Amount of drug in the body Plasma drug concentration V D = Dose/Plasma Concentration  It is hypothetical volume of fluid in which the drug is disseminated.  Units: L and L/Kg  We consider the volume of fluid in the body = 60% of BW  60 X 70/100 = 42 L

 Drugs may distribute into  Plasma (Vascular) Compartment:  Too large mol wt  Extensive plasma protein binding  Heparin is an example  Extracellular Fluid Low mol wt drugs able to move via endothelial slits to interstitial water Hydrophilic drugs cannot cross cell membrane to the intracellular water  Total Body Water; Low mol wt hydrophobic drugs distribute from interstitial water to intracellular Plasma (4 litres) Interstitial Fluid (11 litres) Intracellular Fluid (28 litres) 4

Plasma Compartment Extracellular Compartment Intracellular Compartment Drug has large Mol. Wt. OR Bind extensively to pp Vd = 4L 6% of BW e.g. Heparin Drug has low Mol. Wt. Hydrophilic Distributed in plasma & Interstitial fluid Vd = 14L 21% of BW e.g. Aminoglycosides Drug has low Mol. Wt. Hydrophobic Distributed in three comp. Accumulated in fat Pass BBB Vd= 42L 60% of BW e.g. Ethanol

Plasma protein binding  Many drugs bind reversibly to plasma proteins especially albumin  D + Albumin↔ D-Albumin (Inactive) + Free D  Only free drug can distribute, binds to receptors, metabolized and excreted.

Clinical Significance of Albumin Biding  Class I: dose < available albumin binding sites (most drugs)  Class II: dose > albumin binding sites (e.g., sulfonamide)  Drugs of class II displace Class I drug molecules from binding sites→ more therapeutic/toxic effect  In some disease states → change of plasma protein binding  In uremic patients, plasma protein binding to acidic drugs is reduced  Plasma protein binding prolongs duration Sulfonamide 8 Displacement of Class-I Drug

1000 molecules % bound molecules free fold increase in free pharmacologically active concentration at site of action. Effective TOXIC

 Capillary permeability  Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement of drugs  Brain capillaries have no slits between endothelial cells, i.e tight junction or blood brain barrier  Only carrier-mediated transport or highly lipophilic drugs enter CNS  Ionised or hydrophilic drugs can’t get into the brain Liver capillary Endothelial cells Glial cell 10 Brain capillary Slit junctions Tight junctions

 Blood-Brain barrier: Inflammation during meningitis or encephalitis may increase permeability into the BBB of ionised & lipid-insol drugs  Placental Barrier: Drugs that cross this barrier reaches fetal circulation Placental barrier is similar to BBB where only lipophilic drugs can cross placental barrier 11

It is enzyme catalyzed conversion of drugs to their metabolites. Process by which the drug is altered and broken down into smaller substances (metabolites) that are usually inactive. Lipid-soluble drugs become more water soluble, so they may be more readily excreted.

 Most of drug biotransformation takes place in the liver, but drug metabolizing enzymes are found in many other tissues, including the gut, kidneys, brain, lungs and skin.  Metabolism aims to detoxify the substance but may activate some drugs (pro-drugs). 

Conversion of Lipophyllic molecules Into more polar molecules by oxidation, reduction and hydrolysis reactions Phase I Phase II Conjugation with certain substrate ↑↓or unchanged Pharmacological Activity Inactive compounds

 Oxidative reactions: Catalyzed mainly by family of enzymes; microsomal cytochrome P450 (CYP) monoxygenase system. Drug + O 2 + NADPH + H + → Drug modified + H 2 O + NADP +  Many CYP isoenzymes have been identified, each one responsible for metabolism of specific drugs. At least there are 3 CYP families and each one has subfamilies e.g. CYP3A.  Many drugs alter drug metabolism by inhibiting (e.g. cimetidine) or inducing CYP enzymes (e.g. phenobarbital & rifampin).  Pharmacogenomics

 Oxidative reactions: A few drugs are oxidised by cytoplasmic enzymes. ◦ Ethanol is oxidized by alcohol dehydrogenase ◦ Caffeine and theophylline are metabolized by xanthine oxidase ◦ Monoamine oxidase  Hydrolytic reactions: Esters and amides are hydrolyzed by: ◦ Cholineesterase  Reductive reactions: It is less common. ◦ Hepatic nitro reductase (chloramphenicol) ◦ Glutathione-organic nitrate reductase (NTG)

 Drug molecules undergo conjugation reactions with an endogenous substrate such as acetate, glucuronate, sulfate or glycine to form water-soluble metabolites.  Except for microsomal glucuronosyltransferase, these enzyems are located in cytoplasm.  Most conjugated drug metabolites are pharmacologically inactive. ◦ Glucuronide formation: The most common using a glucuronate molecule. ◦ Acetylation by N-acetyltransferase that utilizes acetyl-Co-A as acetate donar. ◦ Sulfation by sulfotransferase. Sulfation of minoxidil and triamterene are active drugs.

 Excretion is the removal of drug from body fluids and occurs primarily in the urine.  Other routes of excretion from the body include in bile, sweat, saliva, tears, feces, breast, milk and exhaled air.

LONGITUDNAL SECTION OF KIDNEY 21

 Glomerular filtration depends on:  Renal blood flow & GFR; direct relationship  Plasma protein binding; only free unbound drugs are filtered  Tubular Secretion in the proximal renal tubule mediates raising drug concentration in PCT lumen Organic anionic & cationic transporters (OAT & OCT) mediate active secretion of anionic & cationic drugs Passive diffusion of uncharged drugs Facilitated diffusion of charged & uncharged drugs Penicillin is an example of actively secreted drugs 23

 Tubular re-absorption in DCT:  Because of water re-absorption, urinary D concentration increases towards DCT favoring passive diffusion of un- ionized lipophillic drugs  It leads to lowering urinary drug concentration o Urinary pH trapping:  Chemical adjustment of urinary pH can inhibit or enhance tubular drug reabsorption  For example, aspirin overdose can be treated by urine alkalinization with Na Bicarbonate (ion trapping) and increasing urine flow rate (dilution of tubular drug concentration)  Ammonium chloride can be used as urine acidifier for basic drug overdose treatment 24

 Pulmonary excretion of drugs into expired air:  Gases & volatile substances are excreted by this route  No specialized transporters are involved  Simple diffusion across cell membrane predominates. It depends on: Drug solubility in blood: more soluble gases are slowly excreted Cardiac output rise enhance removal of gaseous drugs Respiratory rate is of importance for gases of high blood solubility  Biliary excretion of few drugs into feces o Such drugs are secreted from the liver into the bile by active transporters, and then into duodenum o Examples: digoxin, steroid hormones, some anticancer agents o Some drugs undergo enterohepatic circulation back into systemic circulation

CLEARANCE:- Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min. CL = kV D, k: elimination rate constant CLEARANCE:- Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min. CL = kV D, k: elimination rate constant KLECOP, Nipani

 It is ability of kidney, liver and other organs to eliminate drug from the bloodstream  Units are in L/hr or L/hr/kg  Used in determination of maintenance doses  Drug metabolism and excretion are often referred to collectively as clearance  The endpoint is reduction of drug plasma level  Hepatic, renal and cardiac failure can each reduce drug clearance and hence increase elimination T 1/2 of the drug 27

 Half-life: is a derived parameter, completely determined by volume of distribution and clearance.  (Units = time)  As Vd increases t1/2 increases