EXCRETION

excretion

irreversible removal of drug from the body by all routes of administration

how are drugs removed from the body

• metabolism/ biotransformation (liver)

• renal excretion (kidney)

the decline from peak plasma conc after drug administration results from __

• drug elimination or removal by the body

• excretion and metabolism are not clearly defined individually

drug excretion

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

routes of drug excretion

• lungs

• perspiration

• bile

• ontestine

• saliva

• milk

• kidneys

excretion through lungs

• pulmonary excretion or expired air

• removal of drug in a vapor state

breath analyzers

• can quantify alcohol conc via expired air

increased alc conc in expired air

increased alc conc in plasma

excretion through lungs

major pathway of volatile substances

excretion through lungs

follows passive diffusion

excretion through lungs

only the __ of the drug is excreted

non ionized form

excretion through lungs

• anesthetic gases

• ammonium chloride

• camphor

• chloroform

• ethanol

• iodides

• sodium carbonate

• salbutamol

excretion through perspiration

• low mw; water soluble electrolytes

excretion through perspiration

• ditophal

• rifampicim

• p-aminohippiric acid

• thiamine

• sulfonamides

• urea

ditophal

• anti leprosy drug

• largerly excreted through perspiration

rifampicin

• anti tb

• hydrophilic; excreted via sweat

• red orange sweat

biliary excretion

fecal excretion

bile

• produced by liver

• stored in gall bladder

• released into the small intestine

biliary excretion

requires drugs thst have a molecular wt greater than 300 and a strong polar grp

biliary excretion

major pathways

• passive diffusion

• active transport

• pinocytosis

biliary excretion

drugs are excreted as __

glucuronide conjugates

glucuronide cmpds

• highly lipophilic

• increased mol wt by nearly 200

biliary excretion

• suvorexant

• cholesterol

• chloramphenicol

• diazepam

• digitalis glycosides

• doxycycline

• estradiol

• quinine

• indomethacin

• tetracycline

• penicillin

• steroids

• streptomycin

• strychnine

intestinal excretion

direct intestinal excretion via feces

intestinal excretion

• substances that are poorly ionized in the plasma

• 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 the 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 other routes aside from oral, such as ophthalmic route, iv or rectal route

salivary excretion

• iron

• dexamethasone (steroid eyedrop)

• some suppositories

excretion via milk

important simce drugs can be passed with milk to the nursing offspring

excretion via milk

major pathways

• active transport

• passive diffusion

pH of human milk

6.6

pH of plasma

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

drugs that should be avoided by nursing mothers

• weakly basic drugs

• drugs with low therapeutic index

• tetracyclines

• sulfonamides

• bzd (diazepam)

renal excretion

major route of elimination for many drugs

kidneys are main excretory organ for:

• removal of metabolic waste product

• maintaining salt and water balances

• bp

the kidney excretes excess __

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

endocrine functions

• secretion of renin

• secretion of erythropoietin

secretion of renin

regulates bp

secretion of erythropoietin

stimulates rbc production (erythropoiesis)

parts of the kidney

• cortex- outer

• medulla- inner

• nephrons

nephrons

basic functional unit of kidney

nephrons

collectively responsible for the:

• removal of metabolic waste

• maintenance of water and electrolyte balance

each kidney contains __ nephrons

1 to 1.5 million

cortical nephrons

have short loops of henle that remain exclusively in the cortex

juxtamedullary nephrons

have long loop of henle that extends to the medulla

blood supply is __ of total body wt

~0.5%

bloood supply receive approximately __ of cardiac output

20-25%

renal artery

brings blood supply to kidneys

renal artery

subdivides into the interlobar arteries penetrating within the kidneys and branching further into the afferent arterioles

each afferent arteriole carries blood towards:

• single nephron

• bowman’s capsule

• glomerulus (contains capillaries)

• efferent arterioles

• peritunular capillaries

• vasa recta

glomerulus

facilitates glomerular filtration

glomerular filtration

separation of nutrients to be reabsorbed and metabolic waste to be excreted

tests to measure the kidney function

• extraction ratio

• effective renal plasma flow

• extraction ratio

• effective renal plasma flow

can be used to:

• determine the rate of extraction of drug clearance by the kidneys

• monitor the changes in kidney function

extraction ratio

describes the fractional decrease in conc of drug in the plasma due to removal of drug by the kidney

effective renal plasma flow

drug clearance

effective renal plasma flow

measure of the amt of drug excreted in the urine as a function of conc of the drug in the plasma

mechanism of renal function

major route of elimination for many drugs that are

• non volatile

• water soluble

• low mw

• slowly biotransformed by liver

the process by which a drug is excreted via the kidneys may include any combination of the ff:

• glomerular filtration

• active tubular secretion

• tubular reabsorption

Afferent Arteriole

where blood enters, carrying nutrients and waste materials = pass through glomerular capillaries

Glomerular capillaries

• retains nutrients

• filters out waste

Bowman’s capsule

• where waste goes from Glomerular capillaries

• expels waste via urine

• some nutrients can still be reabsorbed

Peritubular capillaries

• reabsorbs some nutrients

• [what’s reabsorbed] could go to the renal vein

MECHANISMS OF RENAL FUNCTION

process

• Filtration → Reabsorption → Secretion → Urinary Excretion

MECHANISMS OF RENAL FUNCTION

equation

• Excretion = Filtration - Reabsorption + Secretion

GLOMERULAR FILTRATION

 passive process 

GLOMERULAR FILTRATION

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.

MW < 20,000 g/n

• can pass through irrespective of the charge

• This is passive diffusion

MW > 20,000g/n

shape of the molecule becomes the determining factor for filtration

GLOMERULAR HEMOGLOBIN (MW = 64,500)

readily filtered because of the rounded shape

ELONGATED SERUM ALBUMIN (MW = 68,000)

• almost completely unfiltered

MW = 50,000

Upper limit of filterable

Protein with MW = 70,000

can’t be filtered, only reabsorbed, and thus, cannot be excreted

Proteinuria

• presence of protein in the urine

• may indicate rhabdomyolysis (muscle breakdown) or an autoimmune disease

Drugs that are associated with plasma proteins are not filtered because

they are not free drugs (plasma protein-bound).

↑ free portion of drug in plasma,

↑ glomerular filtration

A drug that is excreted exclusively by glomerular filtration and is highly plasma protein-bound, has

↑ (longer) half-life, unless it undergoes relatively extensive biotransformation.

GLOMERULAR FILTRATION RATE (GFR)

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

GLOMERULAR FILTRATION RATE (GFR)

normal range

131 ± 22 mL/min

FACTORS INFLUENCING GFR

1. Total surface area available for filtration

2. Permeability of the filtration membrane

3. Net filtration pressure greatly affects GFR

↑ arterial BP =

↑  glomerular filtration BP = ↑ GFR

Dehydration:

↓ BCOP  = ↓  filtrate

ACTIVE TUBULAR SECRETION

• Drug is passed from blood into the glomerular filtrate

• Active transport process

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

ACTIVE TUBULAR SECRETION

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

• Specificity for chemical structure

• Competitive secretory transport mechanism

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

• The kidney dissociates the drug-protein complexOrganic Anion Transporter (OAT)

Organic Anion Transporter (OAT)

• For weak acids

Organic Anion Transporter (OAT)

• Amino acids

• Acetazolamide

• P-aminohippuric acid (PAH)

• Benzyl penicillin

• Chlorothiazide

• Furosemide

• Indomethacin

• Penicillin

• Phenylbutazone

• Probenecid

• Salicylic acid

• Thiazide

Organic Cation Transporter (OCT)

• For weak bases

Organic Cation Transporter (OCT)

• Cholines

• Dopamine

• Histamine

• N-methylnicotinamide

• Dihydromorphine

• Quinine

• quaternary ammonium compounds

• Tolazoline

TUBULAR REABSORPTION

• Reclamation process

• Occurs after the drug is filtered through the glomerulus 

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

• This process can significantly reduce the amount of drug excreted

Factors Influencing Reabsorption of WA/WB

1. pH of the fluid in the renal tubule (ie, urine pH)

2. pKa of the drug

1. pH of the fluid in the renal tubule (ie, urine pH)

2. pKa of the drug

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

NON-IONIZED SPECIES

• more lipid-soluble and has:

  • ↑ membrane permeability: since it is non-ionized

  • ↑ passive diffusion

  • ↑ reabsorption

  • ↓ amount of drug excreted

pKa of the drug is

constant

Urinary pH may vary from 4.5 to 8.0, depending on:

1. Diet

2. Pathophysiology

3. Drug Intake

↓ urinary pH (acidic)

• foods rich in protein

• ascorbic acid

• IV solution of ammonium chloride

• Coffee, Tea, Fruit juice, Soda

• Meat

• initial morning urine

↑ urinary pH (basic)

• Vegetables & fruits = less prone to UTI

• carbohydrate-rich foods

• antacids (ie, sodium carbonate)

• IV solution of bicarbonate

• Pescetarian = mainly eat fish

• Water

pH - PARTITION THEORY

WEAKLY  ACIDIC DRUGS: Under Basic Urinary Ph

• More ionized, dissociated, salt formation, More polar

• Decreased Reabsorption

• Excreted