A Powerpoint presentation on drugs excretion and elimination suitable for UG medical students. This ppt is already presented to my students in one of the theory classes.

1. Excretion of Drugs and Kinetics
of elimination
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Goal
• Different organs of drug excretion and
mechanism
• Renal excretion of drugs
• Concepts of drug clearance and plasma half
life
• Concept of the platue principle

3. Organs of Excretion
• Excretion is a transport procedure which the
prototype drug (or parent drug) or other metabolic
products are excreted through excretion organ or
secretion organ
• Hydrophilic compounds can be easily excreted.
• Routes of drug excretion
– Kidney
– Biliary excretion (Faeces)
– Exhaled air
– Sweat and saliva
– Milk

4. Faeces (Hepatic Excretion)
• Unabsorbed and derived from bile
• Drugs can be excreted in bile, especially when
they are conjugated with – glucuronic acid
 Organic acids - OATP and MRP2
 Organic Bases – OCT
 Lipophilic drugs – P-gp
 Larger molecules are eliminated (MW>300)
• Drug is absorbed  glucuronidated or sulfatated in the liver and secreted
through the bile  glucuronic acid/sulfate is cleaved off by bacteria in GI
tract  drug is reabsorbed (steroid hormones, rifampicin, amoxycillin,
contraceptives) - ENTEROHEPATIC CIRCULATION
• Anthraquinone, heavy metals – directly excreted in colon

5. Renal Excretion
 All water soluble substances
 Amount of Drug in urine is
Net Renal Excretion = (GF + Tubular secretion) –
Tubular reabsorption
• Glomerular Filtration
• Tubular Reabsorption
• Tubular Secretion

6. Glomerular Filtration
• Net Renal excretion: (GF + tubular secretion) – tubular
reabsorption
• Glomerular capillaries have pores larger than usual
• All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered
• Glomerular filtration of drugs depends on their plasma
protein binding and renal blood flow - Protein bound drugs
are not filtered !
• Normal GFR – 120 ml/min
• Renal failure and aged persons – declines progressively

7. Tubular Re-absorption
• Physiologically 99% of Glomerular Filtrates are reabsorbed
• Back diffusion of Drugs (99%) – lipid soluble drugs
• Depends on pH of urine, ionization etc.
• Lipid insoluble ionized drugs excreted as it is – aminoglycoside
(amikacin, gentamicin, tobramycin)
• Changes in urinary pH can change the excretion pattern of drugs
– Weak bases ionize more and are less reabsorbed in acidic urine.
– Weak acids ionized more and are less reabsorbed in alkaline urine
• Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine
• Acidified urine – atropine and morphine etc.
• Effects of changes in urine pH is best observed with Drugs having
pKa of 5 – 8

8. Tubular Secretion
• Active transfer of organic acids and bases: Proximal tubule
– OAT – organic acid transport: penicillin, probenecid, uric acid salicylates,
methotrexate
– OCT – organic base transport: quinine, thiazides, furosemide, amiloride
– Also P-gp and MRP2
• Renal clearance >120 ml/min – tubular secretion
• Advantage: Reduces the free concentration of drugs – further, more drug
dissociation from plasma binding – again more secretion (protein binding
is facilitator for excretion for some drugs)
• Bidirectional transport – Blood Vs tubular fluid
• Exogenous (drugs) Vs Endogenous (uric acid)
• Utilized clinically – penicillin Vs probenecid and probenecid Vs uric acid
• Salicylate Vs uricosuric action of probenecid in gout (gets block)
• Quinidine decreases renal and biliary clearance of digoxin by inhibiting
efflux carrier P-gp

9. Renal Excretion – must remember!
• Acidic urine
• alkaline drugs eliminated
• acid drugs reabsorbed
• Alkaline urine
- acid drugs eliminated
- alkaline drugs absorbed

10. Kinetics of
Elimination
• Provide basis for devising dosage regime and modify them
• Pharmacokinetics - F, V and CL
•
AUC p.o.
F = ------------ x 100%
AUC i.v.
10 mcg/ml
Drug in
>10 mcg/ml
Plasma
500mcg/min (RoE)
10 mcg/ml (C)
= 50 ml/min
CL =
500 mcg/min
Organ of Drug
Elimination
(Kidney, liver etc.)

11. Clearance
• Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug
is completely removed in unit time
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml and RoE is 100
mcg/min
CL = 100/20 = 5 ml /min

12. Kinetics of Elimination
• First Order Kinetics (exponential): Rate of elimination is
directly proportional to drug concentration, CL
remaining constant
– Constant fraction of drug is eliminated per unit time
• Zero Order kinetics (linear): The rate of elimination
remains constant irrespective of drug concentration
– CL decreases with increase in concentration
– Alcohol, theophyline, tolbutmide etc.

13. Plasma half-life
• Defined as time taken for its plasma concentration to be
reduced to half of its original value – 2 phases rapid declining
and slow declining
t1/2 = In2/k
In2 = natural logarithm of 2 (0.693)
k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
CL = RoE/C
V = dose IV/C

14. Kinetics of Elimination
Zero Order 1st Order
conc.
Time

15. Plasma half-life
1 half-life …………. 50%
2 half-lives………… 25%
3 half-lives …….…..12.5%
4 half-lives ………… 6.25%
5 half-lives ………… 3.125%
• 1st order kinetics – t1/2 does not change (V and CL
remains unchanged
• 0 order kinetics – t1/2 increases (CL decreases as
dose is increased)
50 + 25 + 12.5 +
6.25 = 93.75
93.75 + 3.125 +
1.56 = 98%
after 5 HL

16. Repeated Dosing
• At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL
F
Dose Rate
AveCpss

17. Excretion - The Platue Principle
Repeated dosing:
• When constant dose of a
drug is repeated before the
expiry of 4 half-life – peak
concentration is achieved
after certain interval
• Balances between dose
administered and dose
interval

18. Target Level Strategy
• Drugs whose feect are not quantifiable, low safety margin drugs
(anticonvulsants, antidepressants, Lithium, Theophylline etc. –
aimed at achieving certain concentration within therapeutic range
• Drugs with short half-life (2-3 Hrs) – drugs are administered at
conventional intervals (6-12 Hrs) – fluctuations – target levels only
intermittently – however therapeutically acceptable for many drugs
• Long acting drugs: Prolonged half-life – accumulate and toxicity
– Have to wait for 4 half-life for steadty state
– Single dose or repeated dose in quick succession – to attain target
conc. Quickly
• Loading dose = target Cp X V/F
– Maintenance dose: dose to be repeated at specific intervals
– Dose Rate = target Cpss x CL
F

19. Summary – Must Know
• Drug Clearance
• Orders of kinetics
• Plasma half-life
• The Platue principle