PSCI470: Pharmacokinetics Module 2 Exam

What is the physiological relevance of bile?

It is released to aid in the absorption of fat. Bile contains lipids, cholesterol, bile salts, phospholipids, etc.

The most likely site of absorption of a controlled release form of an oral drug-

Large intestine

What are the factors effecting tubular reabsorption?

1. molecular weight or size of molecule (r): as mw increases, D decreases, reabsorption rate decreases, and renal excretion increases. Metabolites have higher molecular weight than parent, thus increasing renal excretion. 2. Urine concentration drug: as urine proceeds down tubule, water is reabsorbed and drug becomes more concentrated in urine. Increased urine concentration, increased driving force due to concentration gradient, and increased reabsorption. 3. Lipid solubility of the drug: In general, increased lipid solubility, increased reabsorption, decreased renal excretion. Liver often metabolizes drugs to more polar metabolites. Lipid solubility of metabolite is less than that of drug. Reabsorption decreases, and have greater renal clearance of metabolite. 4. Ionization: unionized form of the drug is more lipophilic and more likely to cross membrane. for reabsorption, need at least 1% unionized, and a nonpolar unionized form. Urine pH varies from 4.5-7.5 (average 6.3) and can have a profound effect on the excretion of weak acids and bases, through effects on reabsorption. The urine pH can be altered by drugs, diet and the clinical status of the patient.

Which of the following is NOT correct about the properties of carrier-mediated drug transport? A. Non-saturable B. Active transport C. Energy Requiring D. Similarity to the natural ligand

A. Non-saturable

Drugs that affect urinary pH and reasorption

Agents that increase urine pH: acetazolamide (diamox), a carbonic anhydrase inhibitor. sodium bicarbonate, high dose methotrexate therapy and aspirin overdose). low protein diet. Agents that decrease urine pH: Ascorbic acid (vitamin c). ammonium chloride. mandelic acid (in mendelamine-->urinary tract antiseptic). hippuric acid (in hiprex-->urinary tract antiseptic)

Which of the following are poorly perfused tissues?

Adipose tissue

Which of the following does albumin have the strongest affinity for?

Anionic Drug

What are the general rules for reabsorption of weak bases?

As pH increases, reabsorption increases, and renal excretion decreases. Very polar in the unionized formL so

Alternate elimination pathways

Bile, sweat, saliva, milk, other body fluids, expired air

Why is biliary clearance active?

Biliary clearance is usually active as bile concentration is much higher than blood concentration. Because of this, the body needs to move the drug against a concentration gradient, requiring an active process.

What is the fraction of unchanged drugs reaching systemic circulation?

Bio-availability

What is the consequence of biotransformation of an active drug to an active metabolite?

Can contribute to drug response.

What is the driving force for passive diffusion?

Concentration and electrochemical gradient

Phase II biotransformation

Conjugation reactions (glucuronidation, sulfation, methylation, acetylation) which attach small, polar and ionizable endogenous compounds to result in a large increase in hydrophilicity.

What is contained in the glomerular filtrate?

Ions, glucose, essential nutrients, waste products (urea), phosphate, sulfate, and other substances.

What is the major driving force in drug movement in aqueous diffusion model?

Drug concentration gradient

What are factors associated with drug absorption that can result in incomplete absorption?

Drug metabolized by GI flora, drug instability in gastric acid, drug hydrophilicity (opposite of lipophilicity), presence of food in the GI tract

What is a mechanism for drug interactions at the kidney level?

Drugs with similar structures may compete for the same carrier system. Probenecid (which is used for the treatment of gout) competes with beta-lactam (e.g. penicillin) and quinolone antibiotics for the same carrier system and decreases its renal clearance. Coadministration of probenecid decreases the renal clearance of these antibiotics, increases their AUC, and half-life.

Most of the oral absorption occurs in the

Duodenum

What are the tissues associated with biotransformation?

Enzymes involved in biotransformation are mainly located in the liver, but are also located in the kidney, lungs, small intestine, and skin.

What are the two major components of elimination processes?

Excretion and Metabolism or Biotransformation

Most important factor that affects a drugs volume of distribution is ______.

Extend of plasma protein binding

General characteristics of reabsorption for weak acids with pKa 2.0-7.5

Favorable equilibrium for reabsorption of unionized form. Renal clearance is pH sensitive. This is the basis for the use of urine alkalinization in aspirin overdose.

What are the factors that can affect renal clearance?

Filtration-Binding to plasma proteins and changes in cardiac output Reabsorption-Fick's Law (membrane diffusion) --> urinary pH and urinary flow Active secretion- carrier molecule saturation Factors that affect kidney function

Phase I biotransformation

Functionalization reactions (oxidation, reduction, hydrolysis) which introduce functional polar groups to increase solubility. This results in only a small increase in hydrophilicity.

The aqueous solubility of a weak base drug is poor. In an intubation (intestinal perfusion) study, the drug was not absorbed beyond the jejunum. What would be the correct strategy to improve drug absorption from the intestinal tract?

Give the drug as a hydrochloride salt.

The volume of distribution (Vd) for a drug highly bound in peripheral tissues would be?

High

What is a prodrug?

Inactive drug which must be metabolized in the body to produce a pharmacologically active metabolite. Example Hetacillin to Ampicillin. Prodrugs are designed for improved effectiveness and absorption.

Filtration from the plasma through the glomerulus is influenced by what 3 factors?

MW of the compound <60 kDa-->albumin MW~69kDa, only unbound drug is filtered; if bound to protein, it will not be filtered, glomerular integrity.

The pKa of a weak acid drug is 6.5. if the pH of the medium is 5.5, the drug will be_________.

Mainly neutral

General characteristics of reabsorption for weak acids with pKa > 8

Mostly unionized through normal urine pH range. If drug is non-polar, increased reabsorption and very low renal clearance. Example: Phenytoin, pKa 8.1-->filtered, but highly reabsorbed due to lipophilicity. perfect excreted unchanged in urine is 2%. polar metabolites excreted in urine.

What is the consequence of biotransformation of an active drug to an inactive metabolite?

No pharmacological response.

Active tubular secretion

Occurs primarily at proximal tubules. Active transport process from blood to urine (to be actively secreted, drug must have a certain chemical structure in order to interact with membrane carrier). Need energy to operate since drug is transported against concentration gradient (secretion goes from blood (low concentration of drug) to urine (high concentration of drug). Carrier system that is capacity limited and may be saturated.

What are the two active renal secretion systems that have been identified?

Organic anion transporter (OAT) for weak acids, and organic cation transporter (OCT) for weak bases.

Total body clearance

Overall elimination of drug from body by all routes.

Glomerular filtration

Passive diffusion of fluids and solutes across a porous membrane. Unidirectional (blood-->urine) and occurs for both ionized and unionized small molecules. Driving force is hydrostatic pressure at the glomerulus caused by high renal blood flow.

Renal excretion

Pathway by which most drugs are excreted-->by the kidney into the urine

What are the biotransformation pathways?

Phase I-functionalization reactions Phase II-conjugation reactions

Biotransformation (metabolism)

Process by which the drug is chemically converted in the body to a metabolite. It is usually an enzymatic process.

What does protein binding have to do with active tubular secretion?

Protein binding has very little effect on the elimination half-life of the drug excreted mostly by active secretion.

What drugs are least likely to diffuse across membranes?

Protein-bound drug

Clearance

Quantitative description of elimination. Can also be thought of as the volume of fluid completely and irreversibly cleared of drug per unit of time.

Which of the following is an advantage of sublingual administration?

Rapid absorption, convenient, avoids first pass effect

Renal clearance measurement

Rate of renal excretion = rate of filtration + rate of secretion - rate of reabsorption. Individual calculation of the three components is complex. Need to measure how drug is eliminated as a function of time (rate of elimination)-->collect urine. Need to measure driving force for elimination (take blood samples and determine plasma concentration)

General characteristics of reabsorption of example diazepam (Valium), weak bases

Renal clearance can vary with pH, but typically low especially if bound to proteins. Valium is filtered, but highly reabsorbed due to its lipophilicity. Total body clearance of diazepam is mainly due to its hepatic metabolism.

General characteristics of reabsorption of amphetamines (example phenylpropanolamine), weak bases

Renal clearance of these drugs is greatly influenced by pH. reabsorption can be negligible or complete, depending on urine pH

What are the processes associated with renal excretion?

Renal excretion of drugs is a complex phenomenon involving one or more of the following processes: Glomerular filtration (hydrostatic pressure), Tubular secretion (usually active), Tubular reabsorption (usually passive)

Nitroglycerine is administered by which route?

Sublingual

What is total systemic clearance?

Sum of renal and non-renal clearances.

Enteric-coated acetylsalicylic acid has been prescribed for a patient to treat chronic arthritis. The patient calls the clinic nurse because of gagging and difficulty swallowing the tablets. What response would the nurse give to the patient?

Swallow the tablets with large amounts of water or milk

Extraction Ratio

The efficiency of the organ to eliminate the drug from the blood.

Drug Elimination

The irreversible removal of drug from the body by all routes

Renal clearance

The major route of excretion for many drugs which have the following characteristics: Nonvolatile, water soluble, low molecular weight (<300), and slowly bio transformed by liver.

A patient requires a high dose of a new antihypertensive medication because the new medication has a significant first-pass effect. What does this mean?

The medication is extensively metabolized.

Active transport process

The process is saturable, requires structural specificity (separate mechanisms for anions and cations), and may be competitively inhibited by compounds of similar structure.

Rate of Elimination

The volume of plasma cleared per minute of time. Calculated by multiplying the clearance and plasma concentration.

True or False: Only free drugs can act on target sites and can be eliminated.

True

Tubular reabsorption

Tubular reabsorption occurs after the drug is filtered through the glomerulus and occurs in the distal tubule. It can be an active or passive process. If reabsorption increases, renal excretion decreases.

List two methods used by the pharmaceutical industry to measure the plasma protein binding of drugs.

Ultrafiltration and Equilibrium dialysis

General characteristics of reabsorption of aminoglycosides (Gentamicin, Tobramycin), weak bases

Very Polar in the unionized form: no reabsorption unless actively transported, urine pH has no effect

Excretion

loss of chemically unchanged drug