Excretion

DRUG ELIMINATION

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

Metabolism (Biotransformation) and Excretion (Renal)

How are drugs removed from the body?

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.

metabolite; unchanged parent drug

Final means of drug elimination, either as a ___________ or as _______________.

systemic circulation; excretory processes

Drugs may be eliminated from _____________ by different pathways and then excreted through one or more of the _________________.

Lungs

Perspiration

Bile

Intestine

Saliva

Milk

Kidneys

ROUTES OF DRUG EXCRETION

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

passive diffusion; blood; alveolus

Excretion through Lungs follows ____________ (_______ to _______)

Excretion through Lungs

Only the non-ionized form of the drug is excreted

Excretion through Lungs

Examples: Anesthetic gases, ammonium chloride, camphor, chloroform, ethanol, iodides, and sodium carbonate

Excretion through Perspiration

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

• Ditophal, an anti-leprosy drug, is largely excreted through perspiration

equals; exceeds

Ditophal concentration in sweat ____ to or even ______ the concentration in urine or feces

Excretion through Perspiration

Examples: 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

passive diffusion, active transport, pinocytosis

Major pathways of Biliary Excretion

Biliary Excretion

Drugs are excreted as glucuronide conjugates of the parent compound

highly polar; increases; nearly 200

• Glucuronide compounds are ____________

• Formation of glucuronide ______ MW of parent conjugates by ___________

Biliary Excretion

Examples: cholesterol, chloramphenicol, diazepam, digitalis glycosides, doxycycline, estradiol, quinine, indomethacin, penicillin, steroids, streptomycin, strychnine, and tetracycline

Intestinal Excretion

• Direct intestinal excretion via the feces

• Substances that are poorly ionized in the plasma

Passive diffusion

What pathway is used in intestinal excretion?

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

What is the pathway for substances in passive diffusion of intestinal excretion?

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

T

T/F: In salivary excretion, the 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

Passive diffusion and active transport

Major pathways of Excretion via Milk

6.6

pH of human milk

7.4

pH of plasma

F - ionized

T/F: Weak bases will have a tendency to be more nonionized in the acidic environment of milk than they would in more basic environment of plasma

• Weakly basic drugs

• Drugs with low therapeutic index

• Tertracyclines

• Sulfonamides

Drugs that should be avoided by nursing mothers:

Tertracyclines

It may cause deposition in the bones and teeth of newborn

Sulfonamides

It may cause hyperbilirubinemia in the newborn

F - less albumin and cannot metabolize bilirubin

T/F: Newborns have more albumin and can metabolize bilirubin.

T

T/F: Drugs with high affinity with proteins may displace bilirubin from binding sites.

• The Kidneys

• Kidney Function

• Mechanisms of Renal Excretion

Major route of elimination for many drugs

• Removal of metabolic waste products

• Maintaining salt and water balance

Kidneys are the main excretory organ for:

Kidneys

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

• Secretion of renin, which regulates blood pressure

• Secretion of erythropoietin, which stimulates red blood cell production

Endocrine functions of kidneys:

Renin

it regulates blood pressure

erythropoietin

it stimulates red blood cell production

Cortex

outer zone of the kidney

Medulla

inner region of the kidney

Nephrons

basic functional units of the kidney

1 to 1.5 million

Each kidney contains ____________ nephrons

Nephrons

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

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

20% - 25%

Kidneys receive approximately ______________ of the cardiac output

renal artery

The kidney’s blood supply is supplied by blood via the ________, which subdivides into the interlobar arteries penetrating within the kidney and branching further into the afferent arterioles.

single nephron to Bowman’s capsule to glomerulus to efferent arterioles to peritubule capillaries and vasa recti

Each afferent arteriole in the kidneys carries blood toward a:

glomerulus

capillaries – where blood is filtered

• Excretion Ratio (ER)

• Effective Renal Plasma Flow (ERPF)

Tests to measure kidney function:

• Excretion Ratio (ER)

• Effective Renal Plasma Flow (ERPF)

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 (ER)

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

Excretion Ratio (ER)

no drug is excreted through the kidneys

If ER = 0

no drug is excreted through the kidneys

If CV = CA

100% of drug is excreted through the kidneys

If ER = 1

100% of drug is excreted through the kidneys

If CV = 0

Effective Renal Plasma Flow (EPRF)

Also known as clearance

Effective Renal Plasma Flow (EPRF)

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

Effective Renal Plasma Flow (EPRF)

Effective Renal Plasma Flow (EPRF)

amount of drug in urine per unit time

(concentration of drug in urine) - (volume of urine per unit time)

Renal Excretion

Major route of elimination for many drugs that are: ̶

• Non-volatile

• Water-soluble

• Of low molecular weight

• Slowly biotransformed by the liver

• GLOMERULAR FILTRATION

• ACTIVE TUBULAR SECRETION

• TUBULAR REABSORPTION

The processes by which a drug is excreted via kidneys may include any combination of the following:

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

water; small-molecular-weight ions and molecules; glomerular-capillary; Bowman’s capsule; proximal tubule

Glomerular Filtration is a passive process by which ____ and ________________________ diffuse across the __________ membrane into the ______________ and then enter the _____________

Glomerular Filtration

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

shape

In glomerular filtration, if MW > 20,000; the _______ of the molecule becomes the determining factor for filtration

readily filtered

Glomerular filtration:

• Glomerular hemoglobin (MW = 64,500),

almost completely unfiltered

Glomerular filtration:

• Elongated serum albumin (MW = 68,000)

50,000

In glomerular filtration, upper limit of filterable MW = ______

T

T/F: In glomerular filtration, drugs that are associated with plasma proteins are not filtered

increase; increase; longer

• ______ free portion of drug in plasma, ______ glomerular filtration

• A drug that is excreted exclusively by glomerular filtration and is highly plasma protein-bound, has _________ half-life, unless it undergoes relatively extensive biotransformation.

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

• Total surface area available for filtration

• Permeability of the filtration membrane

• Net filtration pressure

FACTORS INFLUENCING GFR:

Net filtration pressure (NFP)

it greatly affects the GFR

NFP

GBHP - (CHP + BCOP)

increase; increase; increase; increase; decrease

___ arterial BP = ___ glomerular filtration = ___ GFR

Dehydration: ___BCOP = ___ filtrate

Active Tubular Secretion

• Drug is passed from blood into the glomerular filtrate

• Active transport process

• Requires energy input because drug is transported against a concentration gradient

capacity-limited; saturated

The carrier-system in active tubular secretion is __________ and may be _______________

Active Tubular Secretion

• Specificity for chemical structure

• 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

• For weak acids: ORGANIC ANION TRANSPORTER (OAT)

• For weak bases: ORGANIC CATION TRANSPORTER (OCT)

Active renal secretion systems:

ORGANIC ANION TRANSPORTER (OAT)

Active renal secretion systems for weak acids

ORGANIC CATION TRANSPORTER (OCT)

Active renal secretion systems for weak bases

Active Tubular Secretion

Principle of competition has been employed to provide a longer biological half-life for some drugs (Example: Penicillin)

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 of the fluid in the renal tubule (i.e. urine pH)

• pKa of the drug

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