Drug excretion (Pharmacokinetics)

Excretion vs elimination

Excretion: remove polar drug out of body through urine by renal system.

Elimination:

• process of removing drug through hepatic metabolism & excretion.

• Metabolism + Excretion = Elimination

• (Hepatic metabolism = non polar drugs → polar drugs for excretion easily through urine)

4 Drug excretion routes ( + 1 key feature or examples)

1. Renal excretion

• Primary route for most drugs (incl glomerular filtration, active tubular secretion and passive reabsorption)

2. Biliary excretion

• Secretion from liver into bile, may undergo enterohepatic circulation

3. Pulmonary excretion

• Volatile substances like anaesthetic gases ,alcohol (ethanol)

4. Minor routes

• Small quantities but clinically relevant

• Eg: Sweat ,saliva, tears, breast milk (careful dose for lactating women)

Kidney functional and structural unit for filtering blood and forming urine.

Nephron structural and functional unit of kidney for filtering blood and forming urine

Components:

1. Glomerulus

2. Proximal convoluted tubules

3. Loop of Henle

4. Distal convoluted tubules

5. Collecting ducts

Renal excretion mechanism : Glomerular filtration

• Passive process where drugs & their metabolites filtered through glomerular capillaries

• only unbound (free) drugs can be filtered

• Lipid soloubility & pH DONT influence drug passage into glomerular filtrate

Renal excretion mechanism : Active tubular secretion ( def, types of acidic/basic drugs excreted, Transport of drugs)

• Active transport of drugs from blood to tubular lumen (by transporter)

• Acidic drugs (salicylates, sulfonamides, penicillin) (some antibiotics)

• Basic drugs (morphine, atropine, quinine)

• Transport of acidic drugs can be blocked by probenecid

Renal excretion mechanism : Passive tubular reabsorption ( Ionised vs unionised drug)

• Unionised, lipophilic drugs can be reabsorbed into blood circulation (low urinary excretion).

• Ionised drugs poorly reabsorbed (high urinary excretion)

Glomerular filtration rate + clinical note on glomerular filtrate)

Glomerular filtration rate 125mL/min is around 20% of renal plasma flow (600mL/min)

Clinical Note: Premature infants & neonates incomplete developed secretory mechanism → may retain certain drugs in glomerular filtrate

1. Water soluble free drugs (unbound to plasma protein) goes into Bowmans capsule

pH- dependent reabsorption: Urine acidification vs alkalisation (How, Effect, clinical application)

Acidification of Urine

How: Use Vit C to make urine more acidic

Effect: ↑ excretion of basic drugs

Clinical: Overdose cases to enhance elimination

Alkalisation of Urine

How: Use Sodium bicarbonate (NaHCO3) make urine more alkaline

Effect: ↑ excretion of acidic drugs

Clinical: Used in salicylate poisoning

Examples of Drug classes (and drugs) excreted by kidney , % unchanged in urine and caution

1. Aminoglycoside antibiotics (90 → 95% excreted unchanged in urine)

• Eg: Gentamicin, Tobramycin, Amikacin

2. Penicillins (60-90% excreted unchanged in urine)

• Eg: Amoxicillin,Ampicillin

3. Other : Digoxin, Lithium, Metformin (Primarily eliminated through renal excretion)

Caution : Prescribe drug carefully in elderly and renal disease patients as ↓ clearance & toxicity risk

Biliary excretion (process and enterohepatic circulation (def and steps))

Process:

• Drugs secreted from liver to bile by active transported into duodenum.

• Occurs for limited number of drugs that are excreted into feces

Enterohepatic circulation

Def: Some drugs recycle back into systemic circulation

1. Drugs excreted in bile in glucouronide form hydrolysed in intestine by bacterial flora

2. This liberates free drugs that can be reabsorbed in blood if drug is lipid soluble

3. Prolongs action duration of drugs like digoxin, morphine and thyroxine

Drug clearance concepts (Drug excretion, Drug clearance, Total body clearance)

Drug excretion:

• Drug movement from tissues & blood to external environment

Drug clearance (CL):

• Apparent vol (mL,L) blood cleared of drug per unit time (min,h)

Total body clearance:

• CL total = CLhepatic + CLrenal + CLpulmonary + CLother

• Hepatic and renal most imp (kidney often major organ of excretion mainly kidney but liver significant through metabolism or excretion into bile)

Factors affecting drug clearance (Hepatic CL, Renal CL, Patient)

Hepatic clearance factors

1. Hepatic blood flow (↓ in congestive heart failure)

2. Hepatic enzyme activity (affected by liver failure, drug inhibition, drug induction)

3. Plasma protein binding (only free drug metabolised)

Renal clearance factors

1. Kidney blood flow (↓ in congestive heart failure)

2. Secretion blockers (aspirin, probenecid)

3. Glomerular filtration rate (↓ in renal disease)

4. Urine pH (affects reabsorption)

Patient factor

1. Age ( elderly & newborns have ↓clearance)

2. Genetic variations in drug-metabolising enzymes

3. Disease states affecting liver or kidney function

4. Plasma protein binding (affects available drug)

Plasma ½ life (Def, Clinical significance, factors ↑ ½ life)

Def: Time needed for plasma conc of drug to be ½ initial conc

Clinical significance:

1. Measure action duration

2. determine drug dosing interval

• Short ½ life drugs (eg: penicillin) more frequent dosing

• Long ½ life drugs (eg: digoxin, thyroxine) less frequent dosing

Factors ↑ ½ life

1. ↓ metabolism ( liver disease, enzyme inhibitors…)

2. ↓ clearance ( renal disease, heart disease…)

3. ↑ protein/tissue binding

4. Enterohepatic cycling

Multiple dosing and steady state conc (when ssc attained)

Multiple Dosing concept:

Most drug administered regularly over time period (not single dose) so drug accumulates in body till steady state reached.

Steady state concentration

• State which therapeutic plasma conc is constant

• Steady state conc: Rate drug administered = Rate of elimination

• Steady state conc attained after (3 to) 5 half lives

• Eg: Morphine with ½ life of 3 hrs reach steady state in 9-15 hrs

Loading dose (Def, Purpose, Clinical application incl eg)

Def: Large initial dose to rapidly achieve therapeutic plasma levels

Purpose:

• Balance drug distribution to other tissue

• Particularly Important for drugs with long ½ lives

• Quick therapeutic levels if waiting for steady state would be too long

Clinical application

• Rapid relief is required and waiting for steady state would be too long

• Eg: Lidocaine (antiarrythmic drug) with t ½ of 1-2 hrs given a loading dose for life threatening arrhythmias after myocardial infarction

Maintenance doses (Def + features + 1 clinical example)

Def: Dose required to maintain therapeutic level of drug constant or maintain steady state of drug

Features

• Balance drug loss during metabolism & clearance

• Regular dosing intervals based on drug ½ life.

Clinical example

Amoxicillin 500mg every 8hrs to maintain therapeutic levels

Elimination Kinetics: First-Order elimination kinetics

• 1st order kinetics AKA non-saturable or linear kinetics

• Def: Elimination directly proportional to drug conc

(higher drug conc = higher elimination rate)

• Most drugs (95% therapeutic drugs) eliminated by 1st order kinetic

Zero order elimination kinetics

• 0 order elimination kinetics AKA saturable or dose independent

• Rate of elimination occur independently of drug conc in body

( incr drug conc NOT equal increase elimination)

• order 0 elimination rare mostly occurring when saturated elimination system (Large doses)

• Examples : Ethanol , Aspirin, Phenytoin, Warfarin, Theophylline

Equations for Assessment of drug clearance:

Kel (constant rate of elimination), Plasma CL (mL/kg/min)

Kel (constant rate of elimination) = 0.693÷ t½

Plasma clearance (mL/kg/min)  = Vd x Kel