Excretion of drugs and kinetics of elimination

Dr. Sanooz Raheem

Objectives: • Enumerate various routes of drug excretion• List the types of renal excretion and their consequences • Define the term drug clearance • List and discuss types of kinetics of elimination• Explain the principles underlying repeated drug administration • Explain 1. plateau principle 2. Target level strategy • Define 1. loading dose 2. Maintenance dose • Enumerate the different methods of prolongation of drug action

Excretion • Excretion is the passage of systemically absorbed drug• Excreted via - Urine- Faeces - Exhaled air- Saliva and sweat- Milk

Urine:Through kidneyMajority of drugs excreted

Faeces:Unabsorbed + derived from bile Larger molecules eliminated in bileFree drug & deconjugated molecules enter the enterohepatic cycle and excreted via urine Enteroheaptic cycle contributes to the longer stay of drug in the body

Exhaled air: Gases and volatile liquids eliminated by lungs Irrespective of their lipid solubility Alveolar transfer depends on the partial pressure in the blood

Saliva and sweat:Minor importance Li, iodide, rifampin and heavy metals present in these secretions

Milk:Important to the babyMost drugs enter breast milk by passive diffusionAdvised to administer any drug to lactating mother only when essential

Renal Excretion • Responsible for excreting all water soluble substances

Net renal excretion = (Glomerular filtration + tubular secretion) – tubular reabsorption

Schematic depiction of glomerular filtration, tubularreabsorption and tubular secretion of drugsFD—free drug; BD—bound drug; UD—unionized drug; ID—ionized drug, Dx—actively secreted organic acid (or base)drug

• Glomerular filtration:Glomerular capillaries have pores larger than usual All nonprotein bound drug filtered Depends on the plasma protein binding and renal blood flow

• Tubular reabsorption:Occurs by passive diffusionDepends on lipid solubility and ionization of drug at the existing urinary pHLipid soluble drugs are filtered at glomerulus and back diffuse againNonlipid soluble and highly ionized drugs are not reabsorbed – these drugs parallels

g.f.r Urinary pH-Weak acids ionize more in alkaline urine and less reabsorption Weak alkaline ionize more in acidic urine and less reabsorption

This principle is utilized for facilitating elimination of the drug in poisoning, i.e.

urine is alkalinized in barbiturate and salicylate poisoning.

Elimination of weak bases (morphine, amphetamine) can be enhanced by

acidifying urine, this is not practiced clinically, because acidosis can induce

rhabdomyolysis, cardiotoxicity and actually worsen outcome.

The effect of changes in urinary pH on drug excretion is greatest for those having

pKa values between 5 to 8, because only in their case pH dependent passive

reabsorption is significant.

Tubular secretion • Active transfer of organic acids and bases by two separate nonspecific

transporters in the proximal tubules • Also efflux transporters are located in luminal membrane of proximal tubular

cells • If renal clearance of a drug is greater than g.f.r additional tubular secretion has

happened • Organic acid and base transport occurs through transporters- they can

transport bi-directionally • Drug reactions may occur due to competition for tubular secretion Ex: probenecid decreases urinary concentration of nitrofurantoin, increase the

duration of action of penicillin• Tubular transport mechanisms not well developed at birth- duration of action

prolonged

Kinetics of elimination • Helps to devise rational dosage regimens and to modify them accordingly to

individual needs• Drug elimination: sumtotal of metabolic inactivation and excretion

Clearance (CL):- Theoretical volume of plasma from which the drug is completely in unit time

(analogy creatinine clearance)

CL= rate of elimination/CCL= rate of elimination/CC- plasma concentration

Illustration of the concept of drug clearance. Afraction of the drug molecules present in plasma are removedon each passage through the organs of elimination. In thecase shown, it requires 50 mL of plasma to account for theamount of drug being eliminated every minute: clearance is50 mL/min

Kinetics of elimination Majority of drugs the processes involved in elimination are not saturated over the clinically obtained concentrations. They follow:1.First order kinetics2.Zero order kinetics

First order kinetics• Rate of elimination is directly proportional to the drug concentration • CL is constant / a constant fraction of the drug present in the body

eliminated in unit time. • Applies to majority of drugs which do not saturate the elimination

processes over the therapeutic concentration range • If the doses are high enough the elimination pathways of all drugs will

get saturated

Semilog plasma concentration-time plot of a drugeliminated by first order kinetics after intravenous injection

Zero order kinetics• The rate of elimination remains constant irrespective of drug

concentration • CL decrease with increase in concentration • Also called capacity limited elimination/ Michaelis-Menten elimination• Elimination of some drugs approaches saturation over the therapeutic

range, kinetics change from 1st order to zero order at higher doses • As a result plasma concentration increases disproportionately with

increase in dose

Ex: Phenytoin , tolbutamide, theophylline, warfarin

Plasma half-time (t 1/2)• Time taken for its plasma concentration to be reduced to half of its original

value Rapid one compartment distribution1st order eliminationGiven I.V

Two slopesAlpha- initial rapidly declining due to distributionBeta- later less declined due to elimination

The elimination half time derived from the beta slope is simply called the half-time of the drug. Most drugs have multicompartment distribution and multiexponential decay of plasma concentration-time plot. Half-lives calculated from the terminal slopes are exceptionally long

Mathematically:

T1/2= In2 k

In2 – natural logarithm of 2 ( 0.693)k– elimination rate constant of the drug

K= CL V

t1/2= 0.693 *V CL

1st t1/2= 50% drug eliminated

2nd t1/2= 75% (50+25) eliminated

3rd t1/2= 87.5 (50+25+12.5) eliminated

4th t1/2= 93.75 (50+25+12.5+6.25) eliminated

Nearly complete elimination occurs in 4-5 half

lives

1st order kinetics- t1/2 remains constant

Zero order kinetics-t1/2 increase with dose

Half life of some representative drugs:•Aspirin 4 hr •Digoxin 40 hr•Penicillin-G 30 min• Digitoxin 7 days•Doxycycline 20 hr •Phenobarbitone 90 hr

Repeated drug administration • When a drug is repeated at relatively short intervals, it accumulates in the body

until elimination balances input and a steady state plasma concentration(Cpss)

Cpss= dose rate Cpss= dose rate CLCLIf the therapeutic plasma concentration has been worked out, the dose needed to achieve the target Cpss can be determined:

Dose rate= target Cpss* CLDose rate= target Cpss* CLAfter oral administration only a fraction (F) of the dose reaches systemic circulation. In such caseDose rate= target Cpss*CLDose rate= target Cpss*CL FF

• The dose rate- Cpss relationship is linear only in case of drugs eliminated by 1st order kinetics

• For drugs with zero order kinetics:Increase in their dose beyond saturation level causes an increase in

Cpss which is out of proportion to the changes in dose rate.

Relationship between dose rate and averagesteady-state plasma concentration of drugs eliminated byfirst order and Michaelis-Menten (zero order) kinetics

Plateau principle

Target level strategy • For drugs whose effects are not easily quantifiable and safety margin is not

big, it is best to aim at achieving a certain plasma concentration which has been defined to be in the therapeutic range

Ex: anticonvulsants, antidepressants, lithium, theophylline• Drugs with short t1/2 administered at conventional intervals achieve the

target levels only intermittently and fluctuations in plasma level are marked• Drugs with longer t1/2- after single dose target level will be achieved, if

repeated accumulate as plateau principle and will cause toxicity • If the target level is at the steady state, the therapeutic effect will be delayed

by 4 half lives. These drugs are administered with loading dose and a maintenance dose.

Loading dose • Single or few quickly repeated doses given in the beginning to attain

target concentration rapidly.

loading dose= target Cp* VF

Loading dose is only governed by V and not by CL or t1/2

Maintenance dose • This dose is repeated at specified intervals after the attainment of

target Cpss so as to maintain the same by balancing elimination • Governed by CL or t1/2• Dose rate= target Cpss* CL

F•If drug level monitoring facility available the attainment of target level can be verified and dose rate is adjusted

Loading + Maintenance dose provide rapid therapeutic effect with long term safetyEx: digoxin, chloroquine, long acting sulfonamides, doxycycline, amiodaroneIf there are no urgency maintenance dose only enough from start

•Loading and maintenance dose concept applicable to short t1/2 drugs and IV administration in critically ill

Monitoring of plasma concentration of drugs 1. Drugs with low safety margin2. If individual variations are large3. Potentially toxic drugs used during renal failure4. In case of poisoning5. Failure of response without apparent reason6. To check patients compliance

Prolongation of drug action Benefits of prolonging the actions are:a.Frequency of administration is reducedb.Improved patient compliance c.Large fluctuations in plasma concentration is avoidedd.Drug effect can be maintained overnight without disturbing the sleep

All drugs not needed to be made long acting eg: drugs used for brief therapeutic effect/ drugs with long duration of action

Methods for prolonging the drug action1. By prolonging absorption from the site of administrationa. Oral: sustained release tablets, spansule capsule- coated with resins

controlled release tablet/capsule- semipermeable membrane to control the release

b. Parenteral: S.C or I.M in insoluble form /oily solution/pellet implantation/ sialistic and biodegradable

implants /addition of vasoconstrictor c. Transdermal drug delivery systems: drug impregnated in adhesive

patches, strips/ as ointment

2. By increasing plasma protein binding: drug congeners with drugs which bind to plasma protein and

slowly released in the active form 3. By retarding the rate of metabolism: small chemical modification without affecting the biological action/inhibition of specific enzyme4. By retarding renal excretion: tubular secretion of a drug suppressed

by a competing substance

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