introduction

INTRODUCTION

Lecture 2

II. Drug distribution

Is the process by which a drug reversibly leave the blood stream and enter the interstitium and or the cells of the tissues.

Volume of distribution

Distribution :refers to the movement of drugs throughout the body. Volume of distribution :Is a volume of fluid into which the drug is dispersed. ) Volume of distribution useful to compare the distribution of a drug with the volumes of the water compartment in the body.

Volume of Drug Distribution

Drugs may distribute into any or all of the following compartments: 1- Plasma eg drugs has very large molecular weight or bind extensively to plasma portions. Thus trapped within the plasma .eg heparin.
Plasma (4 litres) Interstitial Fluid (10 litres) (extracellular fluid ) Intracellular Fluid (28 litres)
Relative size of various distribution volumes within a 70-kg individual.


2- Interstitial Fluid (extracellular fluid ) If drug has a low molecular weight but its hydrophilic (water soluble) , it can move through the endothelial slit junctions of the capillaries into the Interstitial Fluid. Eg aminoglycoside antibiotic 3- Intracellular Fluid if a drug has a low molecular weight and hydrophobic (lipid soluble) , not only can move into interstitium through the slit junction , but it can also move through the cell membranes into the Intracellular Fluid eg ethanol 4- Other site In pregnancy the fetus may take up drugs and thus increase the volume of distribution


* What are the Factors that Affect on Distribution?
I- Blood flow in : brain, liver, kidney is grater than the skeletal muscle .

* II- Capillary permeability The basement membrane in liver allows drug to exchange
Endothelial cells in liver capillary
Endothelial cells in brain capillary
Glial cell


* While in the brain , the capillary structure is continuous and there are no slit junction . the tightly juxtaposed cells form tight junction that constitute the so called blood brain barrier
Endothelial cells in liver capillary
Endothelial cells in brain capillary
Glial cell


* Drugs enter to brain must pass through the endothelial cells of the capillaries of the CNS or by active transported. Lipid soluble drugs readily penetrate into the CNS while ionized or polar drugs generally fail to enter of the CNS

III- Drug structureThe chemical structure is influence for ability of drugs to cross cell membranes . Eg hydrophobic drugs (lipid soluble) , no net charge , readily move across most biologic membrane . These drug can dissolve in the lipid membranes ,therefore , permeate the entire cells surface . By contrast hydrophilic (water soluble) drugs + or – charge , do not readily penetrate cell membrane , therefore , must go through the slit junction .

IIII-Binding to proteins (role of albumin)

Drugs bind differentially to albumin Reversible binding to plasma proteins sequesters drugs in non diffusible form and slows their transfer out of the vascular compartment. Binding is relatively nonselective as to chemical structure.
warfarin
Drug X
Albumin


Plasma albumin is the major drug binding protein and may act as a drug reservoir, the concentration of the free drug decreases due to elimination by metabolism or excretion , the bound drug dissociates from protein this maintains the free drug concentration as a constant fraction of the total drug in plasma .
warfarin
Drug X
Albumin


* Drug molecules may bind to plasma protein (albumin). Bound drug are pharmacologically inactive only the free ,unbound drug can act on target site in the tissue , elicit biological response , and then elimination . Binding capacity of albumin the binding of drugs to albumin is reversible and may show low capacity (one drug molecule per albumin molecule ) or high capacity( number of drug molecule binding to a single albumin molecule)

* 
The drug with high affinity for albumin can be divided into 2 class Class I: dose less than available binding sites (e.g: most drugs) eg warfarin Class II: dose greater than binding sites (e.g: sulfonamide antibiotic ) The problem: one drug may out-compete the other for the available binding site (warfarin+ sulfonamide) leading to bleeding due to increase concentration of warfarin .

warfarin

Drug X
Albumin

* III. Drug metabolism

Drug biotransformation: mean chemical alteration of the drug in the body . Liver is the major site for drug metabolism but specific drugs may undergo biotransformation in other tissue such as the kidney , intestines, lungs and plasma

* Metabolism of drug may lead to: 1-inactivation of active drugs or drug metabolites e.g. lignocaine , paracetamol 2-active metabolite from an active drug e.g. diazepam ------ oxazepam codeine ------- morphine 3- activation of inactive drug : few drugs are inactive and need conversion in the body to one or more active metabolites ,such a drug is called a prodrug , it is more stable and having better bioavailability. Eg: Levodopa--------Dopamine

Cytochrome P450 enzyme inductions (Enzyme induction )

some drugs Stimulation the hepatic drug metabolism and increase the metabolism of other drugs . Enzyme inducers stimulate their own metabolism and also accelerate metabolism of other drugs Ex of drug inducers: phenobarbital, rifampin, phenytoin, carbamazepine , Cigarette smoking

Cytochrome P450 enzyme inhibition

Some drugs may decrease the activity of hepatic drug-metabolizing enzymes lead to increase levels of active drug in the body that lead to serious adverse effect . Ex of inhibitors: alcohol,, erythromycin,, oral contraceptives, cimetidine

Reaction of drug metabolism

the kidney cannot efficiently eliminate lipophilic drugs and reabsorbed in the distal tubules, therefore , lipid soluble drug must be first metabolize in the liver using two general sets of reaction called: Phase I and Phase II

Drug Metabolism (cont’d) Drug

Phase I
Phase II
(Oxidation Reduction Hydrolysis)
Activation/Inactivation
Conjugation Products
Glucuronidation

Phase I reaction

Phase I reaction – (oxidation, reduction, hydrolysis)Generally, the parent drug is oxidized or reduced to a more polar metabolite by introducing a functional group (-OH, -NH2, -SH).The more polar the drug, the more likely excretion will occur.This reaction takes place in the smooth endoplasmic reticulum in liver cells (hepatocytes)


Phase II reaction
This involves coupling the drug metabolite with an endogenous substrate (glucuronic acid, sulfate, glycine, or amino acids) results in polar , usually more water soluble compounds that are most often therapeutically inactive . Some parent drugs may already possess a functional group that may form a conjugate directly without prior Phase I reaction

First-pass effect metabolism

some drugs go straight from the GI tract to the portal system where they undergo extensive metabolism in the liver (ex: morphine, nitroglycerin) before entering the systemic circulation. Other drugs may be destroyed before absorption . eg: penicillin G Such reactions decrease delivery drug to the target tissues.

Example of First Pass Effect

Enterohepatic Cycle 
After an orally ingested drug has been absorbed from the gut, it is transported via the portal blood to the liver, where it can be conjugated to glucuronic or sulfuric acid or to other organic acids. At the pH of body fluids, these acids are ionized; and, hence, low membrane penetrability. The conjugated products may pass from hepatocyte into biliary fluid and from there back into the intestine. (conjugated products) can be cleaved by bacterial.

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The enterohepatic cycle acts to trap drugs in the body. Drugs that are subject to enterohepatic cycling are, therefore, excreted slowly. Eg contraceptive pills
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Elimination of unchanged drug or metabolite from the body and terminating its activity.Drugs may be eliminated by several different routes: 1- urine2- Feces3- exhaled air4- sweat5- saliva6- Tears 7- MilkUrine is the principle route of excretion
IV. Excretion

MAJOR organ of drug excretion

1- KIDNEY: 2- LIVER: 3- GIT and lung Minor organ of drug excretion 1-Milk gland 2- Salivary gland 3- sweat

* V- drug clearance by the kidney (Renal excretion)

Kidney is responsible for excreting all water soluble substances

Net renal excretion = (glomerular filtration + tubular secretion) - tubular reabsorption

renal excretion:
Three mechanisms for renal execration1. Glomerular filtration – passive diffusionSmall molecules water soluble, free drugs pass more readily. Note: Drugs bound to plasma proteins do not pass through the glomerular filtration 2.Tubular secretion - drugs which specifically bind to carriers are transported (ex: penicillin)Tubular reabsorption – Small nonionic ( lipid soluble) drugs may diffuse out of the nephric lumen back into the systemic circulation (ex: diuretics).

* Glomerular filtration

All non protein bound (free ) drugs presented in the glomerulus is filtered , thus glomerular filtration of drug depends on it is plasma protein binding and renal blood flow Glomerular filtration rate ~125 ml/min

Tubular secretion : is the active transfer of drug across tubules . 

Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier requiring) systems: one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur .
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* Tubular reabsorption
This depend on lipid solubility and ionization of drug at the existing urinary PH Lipid soluble drugs filtered at the glomerulus back diffuse passively in the tubule


* Non lipid soluble and highly ionized drugs are not tubular reabsorption of drug , so change in urinary PH affect on the tubular reabsorption of drugs that are partially ionized so : Weak bases ionize more and less reabsorbed in acidic urine (acidification can done by NH4CL) Weak acids ionize more and are less reabsorbed in alkaline urine (alkalization can be done by bicarbonate) e.g. barbiturate Toxicity , salicylate Toxicity