DRUG ELIMINATION

Dr. Sourya Mohapatra

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Asst prof
PHARMACOLOGY
THE PHARMACOKINETIC PROCESS

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 DRUG ELIMINATION===

DRUG METABOLISM +
DRUG EXCRETION
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EXCRETION

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 EXCRETION

• Passage out of systemically absorbed drug irreversibly

from the body.
• Its excreted in
1. Urine( major)
2. Faeces
3. Exhaled Air
4. Saliva & sweat
5. Milk
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 EXCRETION : URINE

Most important channel for excretion of drugs.

It eliminates water soluble substances.
Amount of drug or its metabolites depends on
• Glomerular filtration (GFR)
• Tubular Resorption (TR)
• Tubular Secretion (TS)

Net Renal Excretion = (GFR+TS) - TR

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 GLOMERULAR FILTRATION

• GFR MARKER OF KIDNEY FUNCTION

• Non Selective And Uni Directional Process
• Only free drugs are filtered.
• Passive process---Glomerular capillaries –
larger pore than usual
• GFR = 120 ml/min normally
• It depends on renal blood flow, particle
size and PPB.
• Declines with age.
• ALL FACTORS AFFECTING GFR AND
KIDNEYS WILL AFFECT DRUG
GLOMERULAR FILTRATION
 TUBULAR RESORPTION

• Passive diffusion and depends on

• Lipid solubility
• 99 % of lipid soluble GF gets resorbed
• Non-lipid soluble are unable to do so
• Ionization of drug at existing pH – highly
ionized drugs not resorbed

Nature of Drugs pH of urine

Weakly basic Ionize more in Acidic urine------less
reabsorbed
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Weakly acidic Ionize more in basic/alkaline urine……less
reabsorbed
CLINICAL SIGNIFICANCE OF URINE pH and
DRUG ELIMINATION

 This principle is useful for drug in poisoning, i.e. urine is

alkalinized(SOD BICARB) in barbiturate and salicylate poisoning.

 BUT Elimination of weak bases (morphine, amphetamine) by

acidifying urine(AMMON CHLORIDE) is not practiced
much!!!!! Why???????

 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 process
• Drugs are pumped from blood to luminal fluid of PCT,
DCT, LOH through active transport systems.
• Increases drug content in filtrate ---may show abnormal
high gfr values than normal range.
• Capacity is limited.
• Mostly through p glycoproteins
 TUBULAR SECRETION

• PPB drugs gets dissociated to get eliminated via this route ------as
active transport reduces free form of drug in tubules leading to
the disscociation of protein bound form in tubular vessels.

• Organic Acid Transporter (OAT) : penicillin, probencid, uric acid,

salicylates, indomethacin, methotrexate, glucouronides

• Organic base transporter (OCT) : thiazides, amiloride,triamterene,

furosemide, quinine, choline, cimetidine

• Both transporter are bi-directional

• Its not well developed at birth – prolongs the action of
drugs (penicillin, cephalosporin)
• Gets matured in infancy
• Progressively declines after the age of 50 yrs and almost
lowers for most drugs after 75 yrs

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CLINICAL SIGNIFICANCE OF TUBULAR SECRETION

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CONT..

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 EXCRETION : FAECES

• Most of it derived from bile

• Large molecular drug is transported by this route
• Deconjugation by glucouronide drug
• Ex: Erythromycin, ampicillin, rifamipin,
tetracycline, oral contraceptives, phenolphthalein
• Drugs gets directly eliminated – anthracene
purgatives, heavy metals
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 CONT…

Exhaled air
• Gases and volatile drugs or paticulate matter –
irrespective of lipid solubility
• Alveolar transfer of gas – partial pressure in blood
• Ex: G.A., paraldehyde, alcohol
Saliva & Sweat
• Minor importance for drug excretion
• Ex: Lithium, pot. Iodide, rifampin and heavy metal
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 Excretion : Milk
• Important for infant sucking milk of mother on drug
• Most of drug enter – breast milk by passive diffusion
• Lipid soluble
• % of drug reaching infant is very less – majority of drugs can be given
to lactating mothers without ill effect

Contraindicated drugs : Amidarone, Anthraquinone,

Chloramphenicol, Ciprofloxacin, cyclosporine,
indomethacin, methotrexate, tetracycline

• Special precaution : \Ampicillin, aspirin, losarton,

metaclopromide, sulfonamide
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KINETICS OF ELIMINATION

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 KINETICS OF ELIMINATION

• Understand how dosage recommendations has

been derived.
• Use the drug optimally and understand its limitations
• Severely ill patient
• individualise the dose regimen depending on how rapidly a
therapeutic plasma concentration is required,
• whether the clearance of the drug is impaired because of renal
or liver disease.
 PHARMACOKINETICS PARAMETERS

• Bioavailability (F) : Fraction of administered drug that reaches

systemic circulation in unchanged form
F = amt. Of drug that enters systemic circulation (AUC)
Dose administered
• Volume of Distribution (V): Volume that accommodate all the
drugs in body, if the concentration throughout was same as in plasma

V = dose administered/plasma drug concentration

• Clearance (CL) :The clearance of a drug is the theoretical volume

of plasma from which the drug is completely removed in unit time .

CL = Rate of elimination/C
 RATE OF ELIMINATION

 Rate depends on the saturation of elimination pathways .

 1st order Kinetics : most of the drug

a constant fraction of the drug present in the body is eliminated in unit
time.
 Rate of Elimination of drug is directly proportional to drug
concentration
 CL remains constant

 Zero order kinetics : few drugs

• Rate of elimination remains constant irrespective of drug concentration

• CL decreases with increase of concentration
• Constant amount of drug is eliminated in unit time
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CONT…
 DRUGS FOLLOWING ZERO ORDER KINETICS

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 PLASMA HALF LIFE

• Def: Half-life = time required for serum plasma

concentrations of the drug to decrease by half
(50%) of its actual value.
• Mathematically
t ½ = 0.693/k
k = elimination rate constant i.e fraction of total amount
of drug removed per unit time
k = CL/V
• Complete drug elimination can occur in 4-5 half life
CONT..

Eg:
Aspirin 4 hr
Digoxin 40 hr
Penicillin-G 30 min
Digitoxin 7 days
 CONT..

1 half-life …………. 50%

2 half-lives………… 25%
3 half-lives …….…..12.5%
4 half-lives ………… 6.25%
50 + 25 + 12.5 + 6.25 = 93.75

93.75 + 3.125 + 1.56 = 98%

after 5 Hr

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 HALF LIFE AND KINETICS OF ELIMINATION

First order kinetics—t½ remains constant

because
V and CL do not change with dose.

Zero order kinetics—

t½ increases with dose because CL
progressively decreases as dose is increased
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 STEADY PLASMA CONCENTRATION

• Steady Plasma concentration (Cpss) – state at which drug

administration equals to drug elimination and on repeated
drug administration even the plasma conc curves become
superimposable or maintains a plateau phase.

• Input of drug balance = clearance

Cpss = dose rate/CL

DOSE RATE= target Cpss *CL and if oral admin

DOSE RATE = target Cpss * CL /F

VALID FOR DRUGS FOLLOWING 1ST ORDER KINETICS ONLY

 QUES

Calculate the dose rate if the desired plasma

conc of drug to be achieved is 2.5mg/l and
clearance of the drug is 40 l/hr.

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 PLATEAU PRINCIPLE OF DRUG ACCUMULATION

• When constant dose of a drug is repeated before the

expiry of 4 t ½ , it would achieve higher peak
concentration, because some remnant drug will be
present in the body.

• Subsequently plasma concentration becomes constant

and forms a plateau and fluctuates around desired
therapeutic level of drug.

• Desired therapeutic level reaches after 4-5 half lives

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SPSS
SPSS AND DOSING

So its better to administer the drug in small dose over small regular interval
rather than large dose in large interval of time
 TARGET LEVEL STRATEGY DOSING
Target Level Strategy Example

Narrow safety margin with Range of therapeutic Anticonvulsant,

unquantified concentration antidepressant, lithium,
pharmacokinetic data antirythmics, theophyline
and some antimicrobials

Short half life Conventional interval (6-12 Penicilllin, amipicillin,

hrs) – fluctuating plasma chloramphenical,
concentration erythromycin, propranolol

Long half life Daily/weekly/Single dose MAO inhibitors, reserpine,

omeprazole

Steady drug concentration Loading Dose and Steroids

maintenance dose
 LOADING DOSE

• Single or few quickly repeated dose to attain target

concentration rapidly .
• Used in case of emergency or when rapid plasma
levels are needed for effect.

Loading dose = (target Cp x V )

F

So loading dose is governed by V not CL or half life of drug.

E.G DIGOXIN, iv LlDOCIANE IN CARD ARRY, CEFTRIAXONE

 MAINTENANCE DOSE

• The amount of drug given to maintain the steady state plasma

concentration (Cpss) of drug at regular interval so as to balance the
elimination.

• Maintainance dose rate = (target Cpss X CL)

F

Or MD= DOSING RATE * DOSING INTERVAL

F

So its dependent on CL or half life of drug

 QUES

What will be the loading dose of drug X in a

75kg person to achieve a target
concentration of 10mg /l if its Vd is
0.75L/kg.

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 Ques

CALCULATE THE MAINTENANCE DOSE FOR

A 70 KG PERSON IF , F IS 0.96 , DI IS 12HRS
AND DOSING RATE IS 28MG/HR

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 QUES

•CALCULATE THE MAINTAINANCE DOSE FOR A

DRUG FOR A 65 KG PERSON IF THE DESIRED
PLASMA CONC TO BE ACHIEVED IS 20MG/L AND
THE CLEARANCE RATE OF THE DRUG IS 5.5 L/HR.

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 THERAPEUTIC DRUG MONITORING (TDM)

• Measurement of plasma concentration of drug after

initial drug administration (based on average patient)
can give all this parameter of a individual.

• Cpss of a drug depends on its F, V and CL – each

of this parameters varies from patient to patient

• This helps for the subsequent quantification of

drug dose regimen
TDM AND SAFETY MARGIN

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TI= LD 50/ED 50
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 USE OF TDM

1. Low safety margin – Digoxin, anticonvulsants,

antiarrhythmics, theophylline, aminoglycosides,
lithium.
2. If individual variation are large – antidepressant, lithium
3. Potentially toxic drug used in renal failure –
aminoglycoside antibiotics, vancomycin
4. In case of poisoning
5. Failure of response without any reason
6. Check patient compliance
PIC

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 PROLONGATION OF DRUG ACTION

• Frequency of drug administration

• Improved patient compliance

• Large fluctuation of plasma concentration should be

avoided

• Drug effect could be maintained overnight without

disturbing sleep

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 METHOD TO ACHIEVE THIS OBJECTIVE

• Prolonging the absorption from site of administration

• Enteral : Sustained release tablets, spansules
• Parenteral: Insoluble form (oily), pellet implantation,
sialistic and biodegradable implant, inclusion of
vasoconstriction
• Transdermal patches
• Increasing plasma protein binding
• Retarding metabolism
• Retarding elimination
TAKE HOME MESSAGE AT END OF
PHARMACOKINETICS :::::::MUST KNOW

Definition of Pharmacokinetics
Transport of Drugs across Biological Membrane –
different processes with example
Factors affecting absorption of drugs
Concept of Bioavailability
Distribution of Drugs – Vd and its concept
Biotransformation Mechanisms with examples
Enzyme induction and inhibition concept and
important examples
Routes of excretion of drugs
Orders of Kinetics
Definition and concept of drug clearance
Definition of half-life and platue principle