4d.Drug Excretionand kinetics of elimination_22 Mar 2024.ppt

Drug excretion and kinetics of elimination

1. DRUG EXCRETION

2. Drug excretion
Passage out of systemically absorbed drug
Removal of the drug and its metabolite
from the body (Drugs are eliminated from the body either
unchanged or as metabolites. )
1.Urine most drugs
2.Faeces bile excreted drugs
3.Lungs Gases & volatile liquids
4.Saliva& Sweat KI, Li, rifampin
5.Milk Antibiotics,
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6.Skin Metals –Mercury, Arsenic

3. Renal excretion
•Glomerular filtration-small molecular size
•Tubular secretion (PCT)-active process
•Tubular reabsorption (DCT) -passive.
•Glomerular filtration and active tubular
secretion facilitate drug excretion
•Tubular reabsorption decreases drug
excretion.
•Rate of renal excretion = (Rate of filtration +
Rate of secretion) –Rate of reabsorption

6. GlomerularFiltration
•Depends on
Plasma protein binding
Renal blood flow
•GlomerularCapillaries have large pores
All non-protein bound drugsboth lipid
soluble & non-lipid soluble, pass through
the pores.Hencedrugs with small
mol.sizesare easily filtered

7. Active Tubular Secretion at
PCT
•Carrier mediated transport requires energy
•Unaffected by change in pH
•Active transfer of organic acids & bases by two
separate mechanisms which are bidirectional
( efflux transporters)
•Organic acid transport : Acidic drugs
penicillin,probenacid,uric acid,
salicylates, drug-glucuronides
•Organic base transport : Basic drugs
Thiazides,amiloride,quinine

8. General Rule
Drugs using same transport compete with
each other & thus their excretion can be
modified
USE:
•To prolong the duration of a desired drug.
Probenecid prolongs the DOA of penicillin
•To ↑excretion of unwanted substance
Probenecid ↑excretion of uric acid in gout

9. Tubular Reabsorption
Factors depends on :
•Lipid solubility
90% of lipid soluble drugs reabsorbed
•Ionization at urinary pH
Highly ionized drugs are excreted more
Eg. AGs, QA compounds

10. •Partially ionized drugs as salts of
weakly acidic drugs (Salicilates, Barbiturate)
in acidic urine:
reabsorbtionexcretion
weak basic (Morphine, amphetamine) drugs in
alkaline urine :
reabsorbtionexcretion
Use:In drug poisoning
acidify (Vit C) urineto eliminate basic drugs
alkalinize (NaH2Co3) urineto eliminate acidic drugs

11. Faeces
•Apart from the unabsorbed fraction, most of the
drug present in faecesis derived from bile.
•Drugs with MW > 300
•Liver actively transports into bile Organic acids
(OATP & MRP2), organic bases (OCT) & steroids
eg.erythromycin, ampicillin, rifampin, TCAs.,
OCPs.,
Drugs undergoing enterohepatic recycling:
excreted in urine

13. Excretion in milk
•Important to suckling infant
•Entry by passive diffusion of :
-more lipid soluble
-less protein bound drugs
•Access for basic drugs> acidic drugs
Important drugs:
1.chloramphenicol 2. bromocriptine
3.
131
I-radioactive iodine4. gold salts

14. Kinetics of elimination
•Needed for rational dosage regimens
•Fundamental kinetic parameters:
1.Bioavailability (F)
2.Volume of distribution (V)
3.Clearance (CL)
4. Plasma Half Life (T ½)

15. •Bioavailability -( F )
is a measure fraction of administered dose
of a drug that reaches systemic circulation
in unchanged form
•Volume of distribution -( Vd)
the volume that would accommodate all
the drug in the body if the conc.
Throughout is the same as in plasma

16. Clearance
•Volume of plasma from which the drug is removed in
unit time.
Rate of elimination per Min
CL = -----------------------------------------
Plasma conc. ( C ) per mL
•For elimination
Most drugs follow First order kinetics
Few drugs follow Zero order kinetics

18. Plasma half life ( t ½ )
•T ½ of a drug is the time taken for its plasma
conc. to become ½ its original value
•A drug given by iv route with rapid one
compartment distribution and 1
st
order
elimination will have:
1. Distribution (Alpha) phase –initial,rapidly
declining
2. Elimination (Beta) phase –later,less declined
Note: The Beta phase half life is actually called as real
half life

20. •t½ is a simple & useful guidefor planning
dosing scheduleof a drug. Elimination at
the end of :
1 t½is -50%
2 t½is -75%(50 +25)
3 t½is -87.5%(50 +25 +12.5)
4 t½is -93.75%(50 +25 +12.5 +6.25)
5 t½is -97%(50 +25 +12.5 +6.25 + 3.125)
For complete elimination 4 -5 t ½s needed

21. •Clinical Importance of Plasma Half-Life.
•It helps to
•determine the duration of drug action.
•determine the frequency of drug
administration.
•estimate the time required to reach the
steady state

22. First order kinetics/ Linear
kinetics
•Definition: A constant fraction
/proportion (%) of the drug is
eliminated in unit time
•The rate of elimination is:directly
proportional to the plasma conc..
Clearanceremains constant
•i.eHalf life is constant –Time to
Metabolize 50% of drug.

25. Zero order kinetics /Exponential
Capacity limited/ Michaelis
Menten
•The processes involved in elimination are
saturated
•Definition: A constant AMOUNT (mg,gm)of
the drug is eliminated in unit time
•The rate of elimination :remains constant
irrespective ofplasma conc.
Clearancewith in concentration.
e.g. –ethyl alcohol

28. •For some drugs elimination reaches saturation over
therapeutic range.
•Kinetics then changes from1
st
order to zero orderat
high dosesdisproportionate in Plasma conc.
•Non-linear elimination kineticsis the term which
describes drug clearance by Michaelis-Mentenprocesses,
wherea drug at low concentration iscleared byfirst-order
kineticsand at high concentrations by zero order kinetics
(eg.phenytoinor ethanol).
E.g. : phenytoin,tolbutamide, theophylline,
warfarin

29. Kinetics of drug metabolism
•High dose :
Zero order
•Low dose :
1
st
order

30. t½ of a drug is
not dependant on
dose
•t½ of some drugs
•Aspirin 4 hr
•Digoxin 40 hr
•Digitoxin 7 days
•Doxycycline 20 hr
•Penicillin G30 min

31. STEADY STATE PLASMA CONCENTRATION
(Constant dose of a drug is given at constant interval)
Repeated drug administration
oral Vs IV infusion
•Repeating the same dose at each t½ :
results in a steady state plasma conc. Cpss
at the end of four t½& thereafter the input
will = output thereafter
•In infusion rate will Cpssbut not the
time taken to attain steady state

34. In Oral dosing since F = < 100 %
Target CpssX CL
Dose rate= -------------------------
F
Plateau principle:
When same dose of a drug is repeated before
the expiry of 4 t½a higher peak results with
each admn. until plasma conc. pleateausand
fluctuates about an average steady state.

36. •The amplitude of fluctuation depends
on dose interval
•The diff. between peak & trough is less
if dose intervals are short.
•Significance?
Trough –loss of efficacy
Peak –side effects

37. TARGET
LEVEL
STRATEGY
How to fix
the infusion
rate?
Target = CpssX CL

38. Loading dose:
Single / few quickly repeated doses to rapidly
reach Cpss
Target Cp X V
LD = -------------------------
F
Maintenance dose:
Dose to be repeated at fixed intervalsafter
achieving target Cpss
Target CpssX CL
Dose rate= -------------------------
F

39. Uses of two phase dosing?
•Rapid therapeutic effect with long term safety
Applicable to drugs
•with long t½ : eg. Digoxin, doxycycline, etc.
•with short t½
•iv admn. incritically ill patients
Lignocainein arrhythmiaiv bolus followed by
fractional doses / solowiv infusion

40. Therapeutic drug monitoring
Monitoring drug therapy by measuring plasma concentration of
a drug is known as
therapeutic drug monitoring (TDM).
Indications of TDM
1. Drugs with narrow therapeutic index, e.g. lithium, digoxin,
phenytoin, aminoglycosides,etc.
2. Drugs showing wide interindividual variations, e.g. tricyclic
antidepressants.
3. To ascertain patient compliance.
4. For drugs whose toxicity is increased in the presence of
renal failure, e.g.
aminoglycosides.
5. In patients who do not respond to therapy without any
known reason.
In drug poisoning, estimation of plasma drug concentration is done.

41. TDM is not required in the following
situations:
1. When clinical and biochemical
parameters are available to assess
response:
a. Blood pressure measurement for
antihypertensives.
b. Blood sugar estimation for antidiabetic
agents.
c. Prothrombin time, aPTT and International
Normalized Ratio (INR) for anticoagulants.
2. Drugs producing tolerance, e.g. opioids.
3. Drugs whose effect persists longer than

42. Methods of Prolongation of drug
action
•More convenient
(in no. of doses / day )
•Improved patient compliance
•Avoidance of large plasma fluctuations
•Maintenance of drug effect at night

43. Methods of prolonging drug action
1.Retarding absorption
a. After Oral absorption:
-Giving after food
-using coated formulations like
Enteric coated (erythromycin estolate)
Sustained release (GTN SR)
Controlled release( CR )
Time release( Timsules, Spansules )

44. b.After Parenteral administration
-in vascularity of site using VC (LA + Ad)
-solubility of drug (procaine penicillin)
-complexing with bee’s wax / oil
-complexing with protein ( PZI )
-Esterification( steroids )
-Pegylation with polyethylene glycol
-Depot preparation( DOCA )
-Special delivery system:
Transdermal disc / ointment(GTN )

45. 3.Retarding drug metabolism
-carbedopa + levodopain parkinsonism
4.Retarding renal excretion
-probenacid + penicillin
5.Increasing plasma Protein binding
-sulfamethoxypyridazine(Long acting )
6.Sequestering in tissues
-quinestrolby fat
( cyclopropyl ester of estradiol)

46. Fixed Dose Combination
•It is the combination of two or more drugs in a
fixed-dose ratio in a single formulation.
Some of the examples of WHO approved FDCs
are
•Levodopa + carbidopa for parkinsonism
•Isoniazid + rifampicin + pyrazinamide +
ethambutol for tuberculosis (HRZE +S).
•Ferrous sulphate + folic acid for anaemiaof
pregnancy
•Sulphamethoxazole+ trimethoprim in
cotrimoxazole (antimicrobial agent)
•Amoxicillin + clavulanic acid (antimicrobial
agent)

48. END