PHA6120: Drug Excretion

DRUG ELIMINATION

The irreversible removal of drug from the body by all routes of elimination.

DRUG EXCRETION

Final means of drug elimination, either as a metabolite or as unchanged parent drug.

DRUG EXCRETION

Drugs may be eliminated from systemic circulation by different pathways and then excreted through one or more of the excretory processes.

EXCRETION THROUGH LUNGS

Pulmonary elimination

EXCRETION THROUGH LUNGS

Removal of drug in a vapor state

EXCRETION THROUGH LUNGS

The concentration of a volatile compound excreted through the lungs may also be correlated with the concentration of volatile compound in plasma (eg.: alcohol in breath)

EXCRETION THROUGH LUNGS

Major pathway of volatile substances

EXCRETION THROUGH LUNGS

• Follows passive diffusion (blood à alveolus)

EXCRETION THROUGH LUNGS

Only the non-ionized form of the drug is excreted

EXCRETION THROUGH LUNGS

• Anesthetic gases

• Ammonium chloride

• Camphor

• Chloroform

• Ethanol

• Iodides

• Sodium carbonate

EXCRETION THROUGH PERSPIRATION

Low-molecular weight, water-soluble electrolytes (eg.: sodium chloride)

Ditophal

an anti-leprosy drug, is largely excreted through perspiration

Ditophal

concentration in sweat equals to or even exceeds the concentration in urine or feces

EXCRETION THROUGH PERSPIRATION

• p-aminohippuric acid (PAH)

• Sulfonamides

• Thiamine

• Urea

Bile

produced by the liver, stored in the gallbladder, and release into the small intestine

BILIARY EXCRETION

Requires that drugs have a molecular weight greater than about 300 and a strong polar group

BILIARY EXCRETION

Major pathways: passive diffusion, active transport, pinocytosis

BILIARY EXCRETION

• Drugs are excreted as glucuronide conjugates of the parent compound

  • Glucuronide compounds are highly polar

  • Formation of glucuronide increases MW of parent conjugates by nearly 200

BILIARY EXCRETION

• Cholesterol

• Chloramphenicol

• Diazepam

• Digitalis glycosides 

• Doxycycline

• Estradiol

• Quinine

• Indomethacin

• Penicillin

• Steroids

• Streptomycin

• Strychnine

• Tetracycline

INTESTINAL EXCRETION

Direct intestinal excretion via the feces

INTESTINAL EXCRETION

Substances that are poorly ionized in the plasma

INTESTINAL EXCRETION

Passive diffusion

INTESTINAL EXCRETION

Walls of capillaries → intestinal submucosa → intestinal lumen →  eliminated in feces

INTESTINAL EXCRETION

Slow process for drugs that have slow biotransformation or slow urinary or biliary excretion

SALIVARY EXCRETION

Ability to detect unpleasant taste of drug in mouth long after the dose had been administered

SALIVARY EXCRETION

Taste of the administered dose has been reported even, when the drug was administered by IV or rectal route

EXCRETION VIA MILK

Important since drugs can be passed with milk to nursing offspring

EXCRETION VIA MILK

• Major pathways: Passive diffusion and active transport

EXCRETION VIA MILK

• The pH of human milk is about 6.6 and pH of plasma is 7.4

Weak Bases

• will have a tendency to be more ionized in the acidic environment of milk than they would in more basic environment of plasma

  • conc of _ may be higher in mother’s milk than mother’s plasma

Drugs avoided by nursing mothers

• Weakly basic drugs

• Drugs with low therapeutic index

• Tertracyclines

• Sulfonamides

Tertracyclines

may cause deposition in the bones and teeth of newborn

Sulfonamides

may cause hyperbilirubinemia in the newborn

Newborns

• have less albumin and cannot metabolize bilirubin. Drugs with high affinity with proteins may displace bilirubin from binding sites

RENAL EXCRETION

Major route of elimination for many drugs

KIDNEY

Removal of metabolic waste products

KIDNEY

Maintaining salt and water balance

KIDNEY

• Excretes excess electrolytes, water, and waste products while conserving solutes necessary for proper body function

KIDNEY

• Secretion of renin, which regulates blood pressure

KIDNEY

Secretion of erythropoietin, which stimulates red blood cell production

CORTEX

Outer zone of the kidney

MEDULLA

Inner region

NEPHRONS

Basic functional units of the kidney

NEPHRONS

• Collectively responsible for the removal of metabolic waste and the maintenance of water and electrolyte balance

NEPHRONS

• Each kidney contains 1 to 1.5 million _

Cortical nephrons

have short loops of Henle that remain exclusively in the cortex

Juxtamedullary nephrons

have long loops of Henle that extend to the medulla

BLOOD SUPPLY

~0.5% of total body weight

BLOOD SUPPLY

Receive approximately 20% - 25% of the cardiac output

BLOOD SUPPLY

• Supplied by blood via the renal artery, which subdivides into the interlobar arteries penetrating within the kidney and branching further into the afferent arterioles.

Afferent arteriole

carries blood toward a single nephron → Bowman’s capsule → glomerulus (capillaries – where blood is filtered) → efferent arterioles → peritubule capillaries and vasa recti

Kidney Function

• Tests to measure _:

  • Excretion Ratio (ER)

  • Effective Renal Plasma Flow (ERPF)

Kidney Function

These tests can be used to determine the rate of excretion of drug and clearance by the kidneys and monitor the changes in kidney function.

Excretion Ratio

Excretion Ratio

Describes the fractional decrease in concentration of drug in the plasma due to removal of the drug by the kidney

ER = 0

no drug is excreted through the kidneys

ER = 1

100% of drug is excreted through the kidneys

EFFECTIVE RENAL PLASMA FLOW (ERPF)

Also known as clearance

EFFECTIVE RENAL PLASMA FLOW (ERPF)

A measure of the amount of drug excreted in urine as function of concentration of drug in the plasma

EFFECTIVE RENAL PLASMA FLOW (ERPF)

Major route of elimination for many drugs that are:

• Non-volatile

• Water-soluble

• Of low molecular weight

• Slowly biotransformed by the liver

GLOMERULAR FILTRATION

A passive process by which water and small-molecular-weight ions and molecules diffuse across the glomerular-capillary membrane into the Bowman’s capsule and then enter the proximal tubule

GLOMERULAR FILTRATION

Molecules with MW < 20,000 can pass through irrespective of the charge

shape

If MW > 20,000; the _ of the molecule becomes the determining factor for filtration

Glomerular hemoglobin

(MW = 64,500), readily filtered

Elongated serum albumin

(MW = 68,000), almost completely unfiltered

50,000

Upper limit of filterable MW = _

GLOMERULAR FILTRATION RATE (GFR)

The amount of fluid filtered from blood into glomerular capsule per unit time

131 ± 22 mL/min

Normal range: _ of GFR

FACTORS INFLUENCING GFR

• Total surface area available for filtration

• Permeability of the filtration membrane

• Net filtration pressure

Net filtration pressure

• greatly affects GFR

• ↑ arterial BP = ↑ glomerular filtration = ↑  GFR

• ↑ Dehydration: ↑ BCOP = ↓ filtrate

ACTIVE TUBULAR SECRETION

Drug is passed from blood into the glomerular filtrate via ATP

ACTIVE TUBULAR SECRETION

Active transport process

ACTIVE TUBULAR SECRETION

Requires energy input because drug is transported against a concentration gradient

ACTIVE TUBULAR SECRETION

This carrier-system is capacity-limited and may be saturated

ACTIVE TUBULAR SECRETION

Specificity for chemical structure

ACTIVE TUBULAR SECRETION

Competitive secretory transport mechanism

ACTIVE TUBULAR SECRETION

Accounts for the fact that certain plasma protein-bound drugs are rapidly eliminated from the body essentially by renal excretion

ACTIVE TUBULAR SECRETION

The kidney dissociates the drug-protein complex

ORGANIC ANION TRANSPORTER (OAT)

For weak acids

ORGANIC CATION TRANSPORTER (OCT)

For weak bases

Acidic Drugs that are Eliminated by Tubular Secretion

• Amino acids

• Acetazolamide

• p-aminohippuric acid (PAH)

• Benzyl penicillin

• Chlorothiazide

• Furosemide

• Indomethacin

• Penicillin

• Phenylbutazone

• Probenecid

• Salicylic acid

• Thiazide

Basic Drugs that are Eliminated by Tubular Secretion

• Cholines

• Dopamine

• Histamine

• N-methylnicotinamide

• Dihydromorphine

• Quinine

• Quaternary ammonium compounds 

• Tolazoline

competition

Principle of _ has been employed to provide a longer biological half-life for some drugs

TUBULAR REABSORPTION

Reclamation process

TUBULAR REABSORPTION

Occurs after the drug is filtered through the glomerulus

TUBULAR REABSORPTION

Can be an active or passive process involving transporting the drug back to the plasma

TUBULAR REABSORPTION

• This process can significantly reduce the amount of drug excreted

pH and pKa

The reabsorption of drugs that are weak acids or weak bases is influenced by:

pH and pKa

determine the percentage of dissociated (ionized) and undissociated (non-ionized) drug

Urinary pH

• may vary from 4.5 to 8.0, depending on: 

  • Diet

  • Pathophysiology 

  • Drug intake

SUBSTANCES THAT DECREASE URINARY pH:

• foods rich in protein

• ascorbic acid

• IV solution of ammonium chloride

• (and generally, initial morning urine is more acidic)

SUBSTANCES THAT INCREASE URINARY pH:

• Vegetables

• Fruits

• carbohydrate-rich foods

• antacids (ie, sodium carbonate)

• IV solution of bicarbonate

WEAKLY ACIDIC DRUGS

UNDER BASIC URINARY pH:

More ionized, dissociated, salt formation More polar

WEAKLY BASIC DRUGS

UNDER BASIC URINARY pH:

More unionized, undissociated, More non-polar

WEAKLY ACIDIC DRUGS

RENAL TUBULAR REABSORPTION UNDER BASIC:

DECREASED

WEAKLY BASIC DRUGS

RENAL TUBULAR REABSORPTION UNDER BASIC:

INCREASED

WEAKLY ACIDIC DRUGS

UNDER ACIDIC URINARY pH:

More unionized, undissociated More non-polar

WEAKLY BASIC DRUGS

UNDER ACIDIC URINARY pH:

More ionized, dissociated, salt formation, More polar

WEAKLY ACIDIC DRUGS

RENAL TUBULAR REABSORPTION UNDER ACIDIC:

INCREASED