Introduction

PHARMACOLOGY INTRODUCTION

Lecture Two

Factors Affecting Drug Absorption

Transport active vs. passive pH Physical factors Blood flow Total surface area Contact time Expression of P- glycoprotein


ATP
ADP + Pi
A- BH+

pH of GIT fluids

Variations exist due to: health - fasting < pH to 1.2 disease - ulcers, gastric cancer food - fats inhibit gastric acid other drugs - antacids, anticholinergics
Duodenum
Stomach
Ascending colon
Descending colon
Jejunum
Ileum
Small intestine
Transverse colon
Rectum
pH = 1 - 3.5
pH = 5 - 7
pH = 8
Blood = 7.4
Factors Affecting Drug Absorption

Effect of pH on drug absorption

Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a H + causing a charged anion (A-) to form:HA H+ + A–( Protonated ) ( nonprotonted )

Effect of pH on drug absorption

Weak bases (BH +) can also release a H+; however, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B). BH + B + H + ( Protonated ) ( nonprotonted )

Drug dissociation constant and lipid solubility

Henderson - Hassalbach theory of dissociation pH = pKa + [ nonprotonated species] [ protonated species]
Weak acidic drugs
where, [A-] = molar concentration of the salt of the acid [HA] = molar concentration of the weak acid
Weak basic drugs
where, [BH+] = molar concentration of the salt of the base [B] = molar concentration of the weak base
pH = pKa + [A–] [HA] pH = pKa + [ B ] [BH+]

Mechanism of Action

Inflammation: extracellular acidosis = decreased LA effect

Physical factors

Most absorption occurs in intestine due to: large area carrier density
blood flow: surface area: contact time: Expression of P-glycoprotein


Physical factors
Expression of P-glycoprotein

lamina propria

lining epithelium
basement membrane
capillary

An Important Concept:BIOAVAILABIITY

Defention:Fraction of a drug that reaches systemic circulation after a particular route of admin’nAffected by:1st pass metabolism (eg: Lidocaine, propranolol)SolubilityInstability (eg: Penicillin G, insulin)Nature of the formulation Serum Concentration
Time
Injected Dose
Oral Dose
Bioavilability = AUC oral * 100 AUC injected

Bioavailability

1st pass metabolism



What Happens After Drug Administration?
Drug at site of administration
Drug in plasma
Drug/metabolites in urine, feces, bile
Drug/metabolites in tissues
1. Absorption
2. Distribution
4. Elimination
3. Metabolism

2- Distribution

Drug distribution : is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.

What Factors Affect Distribution?

Blood flow brain vs. fat Capillary permeability differences in capillary structure. drug structure Binding to proteins role of albumin
Endothelial cells in liver capillary
Endothelial cells in brain capillary
Glial cell



Blood tissue barriers

Volume of Drug Distribution (Vd)

Drugs may distribute into any or all of the following compartments: Plasma Interstitial Fluid Intracellular Fluid
Plasma (4 litres) Interstitial Fluid (10 litres) Intracellular Fluid (28 litres)
Vd = D/C0

So What?

Most drugs distribute into several compartments; however …Some drugs distribute into only one or two compartmentsEg: Aminoglycoside antibioticsStreptomycinGentamycin Arggh! I can’t fit through thesedarn fenestrations!

More “So What?” It takes time for a drug to distribute in the body Drug distribution is affected by elimination
Time
Serum Concentration
0
0.5
1.0
1.5
0
Elimination Phase
Distribution Phase
Drug is eliminated
Drug is not eliminated

Albumin Affects Distribution

Drugs bind differentially to albumin 2 drug classifications: Class I: dose less than available binding sites (eg: most drugs) Class II: dose greater than binding sites (eg: sulfonamide) The problem: one drug may out-compete the other
Sulfonamide
Drug X
Albumin

3- Drug Metabolism(we’re still talking about Pharmacokinetics)

Drug Metabolism
First pass metabolism of drugs may occur as they cross the intestine or transit the liver eg: nitroglycerin Other drugs may be destroyed before absorption eg: penicillin Such reactions decrease delivery to the target tissues

First Pass Metabolism Occurs Primarily in the Liver and Gut

Drug Metabolism (cont’d) Two Phases: I and II Phase I: conversion of the lipophilic compounds Phase II: conjugation Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination
Drug
Phase I
Phase II
Oxidation Reduction Hydrolysis
Activation/Inactivation
Conjugation Products
Glucuronidation



Drug Metabolism (cont’d) Phase I reaction – (oxidation, reduction, hydrolysis)Generally, the parent drug is oxidized or reduced to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH)The more polar the drug, the more likely excretion will occurThis reaction takes place in the smooth (no ribosomes) endoplasmic reticulum in liver cells (hepatocytes)

Drug Metabolism (cont’d) Phase I reactionThe smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolismImportant class of enzymes – mixed function oxidases (MFOs)The activity of these enzymes requires a reducing agent, NADPH and molecular oxygen (O2)

Drug Metabolism (cont’d)

An Example of Phase I and IIBiotransformation:
-OC2H5
CH3CON- H
-OH
CH3CON- H
-O-
CH3CON- H
-OH
OH
COOH
HO
O
PHASE I
PHASE II
Phenacetin
Paracetamol
Glucuronic Acid Conjugate

An Example of Drug Metabolism

Cytochrome P450
Is a family of isoenzymes Drugs bind to this enzyme and are oxidized or reduced Can be found in the GI epithelium, lung and kidney Cyp3A4 alone is responsible for more than 60% of the clinically prescribed drugs metabolized by the liver

Cytochrome P450 enzyme induction

Stimulation of hepatic drug metabolism by some drugs Enzyme inducers stimulate their own metabolism and also accelerate metabolism of other drugs Ex of inducers: phenobarbital, rifampin, phenytoin, carbamazepine, griseofulvin, cigarette smoking

Cytochrome P450 enzyme inhibition

Some drugs may decrease the activity of hepatic drug-metabolizing enzymes Could lead to increase levels of active drug in the body Ex of inhibitors: alcohol, allopurinol, grapefruit juice, cimetidine, amiodarone, ciprofloxacin, clarithromycin, erythromycin, fluoxetine, isoniazid, metronidazole, verapamil, omeprazole, oral contraceptives

Cytochrome P450 enzyme inhibition

Two different mechanisms examples: Cimetidine binds tightly to Cyp450 and through competitive inhibition reduces metabolism of other drugs Erythromycin is metabolized at Cyp3A, its metabolite forms complex with enzyme and renders it catalytically inactive

3. Metabolism (biotransformation)Phase II reaction

This involves coupling the drug or it’s polar metabolite with an endogenous substrate (glucuronic acid, sulfate, glycine, or amino acids)The endogenous substrates originate in the diet, so nutrition plays a critical role in the regulation of drug conjugation

Enterohepatic recirculation

some drugs, or their metabolites, which are concentrated in the bile then excreted into the intestines, can be reabsorbed into the bloodstream from the lower GI tract

Biotransformation in the fetus or neonate

These individuals are very vulnerable to the toxic effects of drugs Their liver and metabolizing enzymes are under-developed They also have poorly developed blood brain barrier Can get hyperbilirubinemia which leads to encephalopathy Have poorly developed kidneys which can alter excretion and cause jaundice

Biotransformation in the elderly

Hepatic enzymes and other organs deteriorate over timeVariations in drug metabolism:Generally, men metabolize faster than women (ex: alcohol)Diseases can affect drug metabolism (ex: hepatitis, cardiac (↓ blood flow to the liver), pulmonary disease)Genetic differencesEx: Slow acetylators (autosomal recessive trait mostly found in Europeans living in the high northern latitudes and in 50% of blacks and whites in the US)

4- Drug Elimination(Excretion)

Elimination of unchanged drug or metabolite from the body – terminating its activityMost important route is the kidneyMay also involve bile, intestine, lung, breast milk exhaled air, sweat, saliva, and tears. What clinical scenarios may affect drug elimination?

Elimination of a drug is usually linked to renal filtration, secretion and reabsorption.

Mechanisms of Renal elimination of a drug
Three mechanisms for renal excretion:Glomerular filtration – passive diffusionSmall nonionic drugs pass more readily. Drugs bound to plasma proteins do notTubular secretion - drugs which specifically bind to carriers are transported (ex: penicillin)Tubular reabsorption – Small nonionic drugs pass more readily (ex:diuretics)

Pharmacokinetics 4- Excretion

Clearance The measure of the ability of the body to eliminate the drug The rate of elimination is directly proportionate to drug concentration CL = rate of elimination/concentration of drug in biologic fluid CLsystemic = CLrenal + CLliver + CLother Other = lungs or other sites of metabolism Half-life (t1/2) The time required for the plasma concentration of a drug to be reduced by 50% 4 half-lives must elapse after starting a drug dosing regimen before full effects will be seen > 90% steady state concentration


Food for Thought
What conditions might affect renal function (and therefore drug elimination)? What other organ systems are involved in drug clearance?

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