Presentation made by Dr. Resu Neha Reddy, M.D. Pharmacology, Osmania Medical College. The presentation is about excretion of the drugs by kidneys, liver and other routes and kinetics of elimination, which includes zero, first and mixed (Michaelis - Menton equation) order kinetics. It also includes information regarding clearance, half-life, loading dose, maintenance dose and fixed dose drug combinations.

1. DRUG EXCRETION AND
ELIMINATION KINETICS
By
Dr. Resu Neha Reddy
1st Year PG
MD PHARMACOLOGY OMC

2. Excretion
 After being absorbed and biotransformed the drugs or their
metabolites must be excreted out of the body
 ELIMINATION = BIOTRANSFORMATION + EXCRETION
 The process by which the body gets rid of the drug or its metabolites
is EXCRETION
Drug
excretion and
elimination
kinetics ……

3. REMEMBER !!
Drug
excretion and
elimination
kinetics ……
ELIMINATED /
DO NOT CROSS
THE MEMBRANE
RE-ABSORBED/
CROSSES THE
MEMBRANE
POLAR/
WATER SOLUBLE /
IONISED
NON-POLAR/
LIPID SOLUBLE/
UN-IONISED

4. Drug
excretion and
elimination
kinetics ……

5. ORGANS INVOLVED
MAJOR ROUTES :
Kidney
Biliary / hepatic
Pulmonary
faecal
MINOR ROUTES :
Saliva
Skin, Sweat
Tears
Breast milk
Vaginal fluids
Drug
excretion and
elimination
kinetics ……

6. Renal Excretion
Structure of Kidney :
 The structural unit of kidney is NEPHRON
 Consists of :
Glomerulus
Proximal convoluted tubules
Henle’s loop (Descending - Ascending)
Distal convoluted tubules
Collecting ducts
Drug
excretion and
elimination
kinetics ……

7. Normal Kidney Functions
 Regulation of electrolytes (Aldosterone)
 Regulation of water balance (Anti-diuretic harmone)
 Excretion of wastes & drug metabolites such as
Urea
Uric acid
Creatinine
Drug
excretion and
elimination
kinetics ……

8. RENAL EXCRETION
 Three processes are involved :
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
Drug
excretion and
elimination
kinetics ……

9. Glomerular filtration
Drug
excretion and
elimination
kinetics ……

10. Glomerular Filtration
 Blood is filtered across a semi-permeable membrane into Bowman’s Capsule
 Driving force – Hydrostatic pressure of blood flowing in capillaries
 Filtrate : Water, glucose, amino acids, sod.bicarbonates, organic solutes &
electrolytes (sodium, potassium, chloride)
 Not filtered : Blood cells, platelets, plasma proteins
 Depends upon renal blood flow
Drug
excretion and
elimination
kinetics ……

11. Drug
excretion and
elimination
kinetics ……
Glomerular Filtration Rate
 The amount of blood filtered by the glomeruli in a given time
 GFR is used as a marker or indicator for kidney function
 GFR determined by : Creatinine, Inulin (Inulin is easily filtered not reabsorbed)
 Slow decline in renal function, ~1% per year

12. Factore influencing Glomerular Filtration
 Molecular size : Small molecular size are filtered
>20,000 not filtered (e.g. Heparin, Dextran & Insulin)
 Plasma protein binding : Free drugs can be filtered
Protein binding decreases renal excretion
(e.g.Warfarin)
 Renal blood flow : Greater the glomerular perfusion, faster is the drug
removal
Drug
excretion and
elimination
kinetics ……

13. Drug
excretion and
elimination
kinetics ……

14. Active Tubular Secretion
 Glomerular filtration removes 20% of drug
 The rest 80% secreted Proximal tubule
 Tubular secretion Energy-requiring carrier-mediated active transport
 Protein binding – Do not interfere tubular secretion
 Decrease in plasma concentration of free drug dissociate protein-bound drug
Drug
excretion and
elimination
kinetics ……

15. Active Tubular Secretion
 Transports drugs against concentration gradients between blood & filtrate
 Secretion of ionized drugs into lumen (e.g. Penicillin)
 Requires carriers ( Transporters : Organic anionic & cationic )
 Saturable
 Not specific ( Competition may happen )
 Compound commonly used to measure – PAH, Diodrast
Drug
excretion and
elimination
kinetics ……

16. Active Tubular Secretion
 Two independent carrier systems :
1) Acidic drugs - e.g. Penicillin, Salicylic acid, Thiazide diuretics,
Probenecid, Indomethacin, Sulfonamides
Endogenous – Uric acid
2) Basic drugs - e.g. Morphine, Quinine, Neostigmine, Procaine, Atropine
Endogenous – Dopamine, Choline, Histamine, Serotonin
Drug
excretion and
elimination
kinetics ……

17. Competitive Active Tubular Secretion
 Two structurally similar drugs having similar ionic charge and
employing the same carrier-mediated process for excretion enter into
competition
 A drug with greater rate of excretion will retard the excretion of
other drug with which it competes
 The half – life of both drugs is increased since the total sites for
active secretion are limited
Drug
excretion and
elimination
kinetics ……

18. Beneficial Competition :
 Probenecid on Penicillin & Amoxycillin :
Probenecid competitively inhibits tubular secretion of Penicillin and Amoxycillin
increasing plasma half – life and effectiveness of these drugs in infective conditions
Drug
excretion and
elimination
kinetics ……

19. Harmful Competition :
1) Weakly acidic drugs (e.g. Lactic acid, Salicylic acid) interfere
secretion of endogenous substance, Uric acid
GOUT
2) Probenecid inhibits renal secretion of Nitrofurantoin thus
decreases its efficacy in Urinary Tract Infections (UTIs)
Drug
excretion and
elimination
kinetics ……

20. Drug
excretion and
elimination
kinetics ……

21. REMEMBER !!
 Only nonionized and lipid soluble drug are Reabsorbed
 Ionized or polar drugs are Excreted
 Weak acids are excreted in basic medium
 Weak bases are excreted in acidic medium
 Urine is normally slightly acidic and favours excretion of basic drugs
Drug
excretion and
elimination
kinetics ……

22. Tubular Re-absorption of Drugs
 After glomerular filtration, drugs may be reabsorbed from tubular lumen
back into systemic blood circulation
 Renal tubule Typical lipid barrier Distal region
 Re-absorption increases half-life of a drug
 Re-absorption may be PASSIVE or ACTIVE
Drug
excretion and
elimination
kinetics ……

23. Passive Tubular Re-absorption
 Depends upon :
Lipid solubility
Ionisation constant ( pKa ) of the drug % of ionised &
pH of the urine unionised drug
Drug
excretion and
elimination
kinetics ……

24. Active Tubular Re-absorption of Drugs
 Occurs in endogenous substances or nutrients that the body needs to conserve
(e.g. glucose, electrolytes, aminoacids, uric acid, vitamins)
 Probenecid acts as a uricosuric agent in treatment of Gout
It increases excretion of uric acid in urine by
inhibiting active tubular re-absorption of endogenous metabolite uric acid
Drug
excretion and
elimination
kinetics ……

25. Urinary pH trapping ( Ion trapping )
 Changing pH of urine by chemicals can inhibit or enhance the tubular drug
re-absorption back into blood
 Ion trapping is used to enhance renal clearance of drugs during toxicity
 Urine is normally slightly acidic and favours excretion of basic drugs
Drug
excretion and
elimination
kinetics ……

26. Urinary pH trapping ( Ion trapping )
 Alkalization of urine using Sodium bicarbonate (NaHCO3) or
Sodium citrate increases excretion of acidic drugs as Aspirin,
Barbiturates, Sulfonamides
 Acidification of urine using Ammonium chloride (NH4Cl) increases
excretion of basic drugs as Morphine, Amphetamine
Drug
excretion and
elimination
kinetics ……

27. Factors affecting renal excretion of drugs
 Physiochemical properties of drugs
1) Molecular weight
2) Lipid solubility
3) Degree of ionization
4) Volume of distribution
5) Binding character
 Biological factor e.g. Age
 Disease states
 Urine pH
Drug
excretion and
elimination
kinetics ……

28. RENAL EXCRETION
DRUG EXCRETED = ( FILTERED + SECRETED ) – RE ABSORBED
Drug
excretion and
elimination
kinetics ……

29. Drug
excretion and
elimination
kinetics ……
Biliary Excretion
 Transporters are present in the canalicular membrane of hepatocytes
 P-gp & BCRP or ABCG2 transport amphipathic lipid soluble drugs
 MRP2 Secretion of conjugated metabolites (e.g. Glutathione conjugates,
Glucoronides and Sulfates)
 Secretory transpoters also expressed on apical membrane of enterocytes
 Elimination through bile :
E.g. Quinine, Colchicine, D-tubocurarine, Corticosteroids & Erythromycin

30. Drug
excretion and
elimination
kinetics ……
Biliary Excretion
 Enterohepatic circulation :
E.g. Digitoxin, Vitamin D3, Indomethacin
 Drugs excreted in bile in form of glucoronides will be hydrolized in intestine
by bacterial flora liberating free drugs that can be reabsorbed back into blood
if lipid soluble
 E.g. Digoxin, Morphine, thyroxine, Chloramphenicol, Tetracycline
 Thus prolongs duration of action

31. Drug
excretion and
elimination
kinetics ……
Biliary Excretion
EXAMPLES :
 Mercury poisoning – Resin administered orally binds with Dimethyl mercury excreted in
the bile preventing re-absorption & toxicity
 Ezetimibe – Drug that specifically reduces intestinal absorption of cholesterol.
Interfere with sterol transporter system
Prevent both free cholesterol and plant sterols absorption
Drug – rapidly absorbed and glucoronidated to active metabolite in intestine
Drug taken up by liver from portal blood and excreted in bile
Half-life - >20 hours
BENEFIT – Reduction in LDL cholesterol

32. Drug
excretion and
elimination
kinetics ……
Pulmonary Excretion
 Gaseous and volatile substances such as general anesthetics are absorbed through lungs
by simple diffusion
 Factors affecting :
Pulmonary blood flow
Rate of respiration
Solubility of substances
 Alcohol which has high solubilty in blood and tissues are excreted slowly by lungs
 Eucalyptus oil & garlic oil are eliminated through expectoration

33. Drug
excretion and
elimination
kinetics ……
Faecal Excretion
 Orally ingested drugs which are not absorbed
E.g. Magnesium sulfate, Streptomycin, Neomycin, Bacitracin, Purgatives
 Drugs excreted through bile and not re-absorbed from gut
E.g. Erythromycin & Corticosteroids

34. Drug
excretion and
elimination
kinetics ……
Excretion through Breast Milk
 Basic drugs : Chloramphenicol,
Tetracyclines, Ergotamine,
Morphine, Metronidazole,
Immunosuppressives,
Bromocriptine, OCPs, Purgatives
 Acidic drugs : Sulfonamides,
Penicillin, Ampicillin,
Phenobarbitone, Phenytoin
 Ethanol & Urea enter breastmilk
readily ,independent of pH

35. Drug
excretion and
elimination
kinetics ……
Salivary Excretion
 pH of saliva varies from 5.8 to 8.4
 Unionized lipid soluble drugs are excreted passively
 The bitter after taste in the mouth of a patient is an indication
 E.g. Caffeine, Phenytoin, Theophylline, Iodine, Potassium iodide, Lithium

36. Drug
excretion and
elimination
kinetics ……
Excretion through Skin, Hair, Sweat
DRUG EXCRETORY ORGAN
Griseofulvin Skin (keratin precursor cells)
Arsenic, Mercury salts, Iodide Hair follicles
Amines & Urea Sweat

37. Clearance
 Volume of biological fluid which is completely cleared of the
drug per unit time
 The units of Clearance – (volume/time)
mL/min or L/hr
Drug
excretion and
elimination
kinetics ……
CLEARANCE = Us x V
Ps

38. Drug
excretion and
elimination
kinetics ……

39. Drug
excretion and
elimination
kinetics ……

40. Clearance
Clearance = Rate of Elimination
Plasma concentration
Drug
excretion and
elimination
kinetics ……
Clearance = Rate of Elimination
Plasma concentration
CL RENAL = RATE OF FILTRATION + RATE OF SECRETION – RATE OF RE-ABSORPTION
PLASMA CONCENTRATION

41. Drug
excretion and
elimination
kinetics ……
CL R = dX / dt
C
CL R = Renal Clearance
dX / dt = Elimination Rate Constant
C = Concentration of drug in plasma
CL R = Ke X
C
Ke = First order elimination rate constant
X = Amount of drug in the body remaining to be
eliminated at time T
CL R = Ke Vd
Where X / C = Vd then above equation becomes

42. Estimation of Creatinine Clearance
Drug
excretion and
elimination
kinetics ……
 The Cockcroft – Gault Equation is used
MALE Cr CL = (140 – age) x Body Weight
Serum Creatinine x 72
FEMALE Cr CL = (140 – age) x Body Weight x 0.85
Serum Creatinine x 72

43. Estimation of Creatinine Clearance
Drug
excretion and
elimination
kinetics ……
In ICU 80-yr-old man
Serum Creatinine Levels = 1 mg/100mL
Creatinine Clearance = 60 mL/min
In ICU 40-yr-old man
Serum Creatinine Levels = 1 mg/100mL
Same weight
Creatinine Clearance = 100 mL/min
Thus, normal serum creatinine values in patients in ICU may
sometimes be associated with significant impairment of renal function

44. Drug
excretion and
elimination
kinetics ……
Total Body Clearance ( CLTOTAL ) = CLRENAL + CLHEPATIC + CLOTHER
Rate of Elimination = Q CA - Q CV
= Q ( CA - CV )
Q = Blood flow
CA = Arterial drug concentration
CV = Venous drug concentration
CL ORGAN = Q [ CA - CV ]
CA
Extration Ratio ( E ) = [ CA - CV ]
CA
CL ORGAN = Q E

45. Drug
excretion and
elimination
kinetics ……
CORRECTED DOSE
Corrected Dose = Normal Dose x Patient’s creatinine clearance
Normal creatinine clearance (100ml/min)
Q : Normal TD = 100 mg IV BD
entirely glomerular filtration
Creatinine clearance = 33 ml/min
Corrected Dose = ??
Q : 70% kidney 30% liver
TD = 100 mg/day
Creatinine clearance = 50 ml/min
Corrected Dose = ??
33 mg IV BD 65 mg / day

46. HALF - LIFE
Drug
excretion and
elimination
kinetics ……
 The time duration in which the plasma concentration of the drug falls by 50%
 The BIOLOGICAL EFFECT HALF-LIFE is the time duration in which the priniciple
pharmacological effect of the drug declines by half
 Does not reflect absorption kinetics
 Reflects on elimination ( clearance ) kinetics
100 50
T ½ = 0.693
k
T ½ = 0.693 x Vd
CL

47. Drug excretion
and
elimination
kinetics ……
KINETICS OF DRUG ELIMINATION
PART - II

48. Drug
excretion and
elimination
kinetics ……
 HALF-LIFE
 STEADY STATE CONCENTRATION
 ORDER OF KINETICS
 FIRST ORDER KINETICS
 ZERO ORDER KINETICS
 MIXED ORDER KINETICS
 LOADING DOSE
 MAINTENANCE DOSE
 FIXED-DOSE DRUG COMBINATIONS
CONTENTS :

49. HALF - LIFE
Drug
excretion and
elimination
kinetics ……
 The time duration in which the plasma concentration of the drug falls by 50%
 The BIOLOGICAL EFFECT HALF-LIFE is the time duration in which the priniciple
pharmacological effect of the drug declines by half
 This is not regarded as fundamental parameter – as it is determined by
 Clearance
 Volume of Distribution
 Reflects on elimination ( clearance ) kinetics
100 50
T ½ = 0.693
k
T ½ = 0.693 x Vd
CL

50. HALF - LIFE
Drug
excretion and
elimination
kinetics ……
DRUG CLEARANCE
(L / hr )
VOLUME OF DISTRIBUTION
( L )
HALF-LIFE
( hrs )
Ethosuximide 0.7 49 48
Flucytosine 8 49 4.2
Digoxin 7 420 40
Choloroquine 45 12,950 200
T ½ α Vd
CL

51. Drug
excretion and
elimination
kinetics ……
1) Determines the duration of action
After a single dose, how longer the drug plasma concentration will stay
in effective range
Clinical significance of half-life
2) Determines the time required to reach steady state concentration
It takes 5 half-lives to reach 97% of steady state concentration

52. THERAPEUTIC WINDOW
Drug
excretion and
elimination
kinetics ……

53. Drug
excretion and
elimination
kinetics ……
 To attain the steady-state condition, rate of infusion = rate of elimination
 True steady-state concentration ( Cpss ) will be attained theoritically only at
time INFINITY
 After 5 half-lives steady state level is reached
Time & Steady State
50% = 1 x Half-life
90% = 3.3 x Half-life
95% = 4 to 5 x Half-life ( CLINICAL )
STEADY STATE CONCENTRATION
E.g. Half-life = 5 hrs
Steady state = ??
Ans. 4 x 5 = 20 or 5 x 5 = 25
= 20 to 25 hrs ( CLINICAL )

54. Drug
excretion and
elimination
kinetics ……

55. ORDER OF KINETICS
Drug
excretion and
elimination
kinetics ……
 FIRST - ORDER KINETICS
 ZERO - ORDER KINETICS
 MIXED – ORDER KINETICS
n = 1
n = 0
n = variable

56. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
 Majority of drugs obey First – Order Kinetics
1) A constant fraction of drug is eliminated at constant interval of time
2) Rate of drug elimination is directly proportional to the plasma concentration
100 50 25
50% 50% 50%
2 hr 2 hr 2 hr
And so on
100 50 25 And so on200
50%
2 hr
50%
2 hr
50%
2 hr
50%
2 hr

57. HALF – LIFE IN FIRST-ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
 T1/2 for one compartment model = 0.693 K = Elimination Rate Constant
K 0.693 = log 2
 T1/2 for multi-compartment model = 0.693 x Vss (Vss=Volume of drug at steady state)
CL

58. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
3) Half-life remains constant irrespectibe
of the dose
Slope = - K
2.303
4) Plasma Fall-Out Curve - Curvilinear &
logarithms – Linear

59. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
5) After a single dose, 97% of drug gets eliminated in 5 half-lives
6) For multiple dose,it takes 5 half-lives to reach steady state level
100 50 25
50%
2 hr
12.5 6.25 3.125
50%
2 hr
50%
2 hr
50%
2 hr
50%
2 hr

60. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
• 7) DOUBLING the dose leads to increase in “one” more half-life
100 50 25
50%
2 hr
50%
2 hr
Effect vanishes
Duration of effect = 4 hr
100 50 25
50%
2 hr
50%
2 hr
200
50%
2 hr
Effect vanishes
Duration of effect = 6 hr

61. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
8) The log plasma conc. Fall-out curve – 2 slopes

62. FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……

63. SUMMARY FIRST - ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
 CHARACTERISTICS OF FIRST – ORDER KINETICS :
1) A constant fraction of drug is eliminated at constant interval of time
2) Rate of drug elimination is directly proportional to the plasma concentration
3) Half-life remains constant irrespectibe of the dose
4) Plasma Fall-Out Curve - Curvilinear & logarithms – Linear
5) After a single dose, 97% of drug gets eliminated in 5 half-lives
6) After 5 half-lives steady state level is reached
7) DOUBLING the dose leads to increase in “one” more half-life
8) The log plasma conc. Fall-out curve – 2 slopes

64. ZERO – ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
1) A constant or fixed quantity / amount of the drug is eliminated per unit time
2) Rate of drug elimination is independent of the plasma concentration
50 25 NIL
25
1 hr
25
1 hr
100 75 50
25
1 hr
25
1 hr
25
25
1 hr

65. Drug
excretion and
elimination
kinetics ……
 Drugs following constant amount of drug elimination per unit time
ZERO WATT Power
W = Warfarin
A = Alcohol, Aspirin
T = Theophylline
T = Tolbutamide
P = Phenytoin, Phenylbutazone
ZERO – ORDER KINETICS

66. ZERO – ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
3) Half-life is never constant
4) Plasma Fall-Out Curve – steeply Linear
& logarithms – Curvilinear
T1/2 = [ A ]
2 K

67. SUMMARY ZERO – ORDER KINETICS
Drug
excretion and
elimination
kinetics ……
 CHARACTERISTICS OF ZERO – ORDER KINETICS :
1) A constant or fixed quantity of the drug is eliminated per unit time
2) Rate of drug elimination is independent of the plasma concentration
3) Half-life is never constant
4) Plasma Fall-Out Curve – steeply Linear & logarithms – Curvilinear

68. Drug
excretion and
elimination
kinetics ……
Michaelis-Menton Kinetics (Mixed/Saturation)
( 1879 - 1960 ) ( 1875 - 1949 )
Maud Menton & Leonar Michaelis
MICHAELIS – MENTON EQUATION :
VO = Vmax [ C ]
Km + [ C ]

69. Drug
excretion and
elimination
kinetics ……
Michaelis-Menton Kinetics (Mixed/Saturation)
MICHAELIS – MENTON EQUATION :
VO = Vmax [ C ]
Km + [ C ]
VO = Rate
Vmax = Max. rate of drug elimination
[ C ] = Initial plasma drug concentration
Km = Michaelis-Menton Constant
SCENARIO 1 SCENARIO 2
[ C ] <<< Km
Vo α [ C ]
Similar to 1st order kinetics
[ C ] >>> Km
Vo = Vmax
Similar to zero-order kinetics

70. Michaelis-Menton Kinetics (Mixed/Saturation)
Drug
excretion and
elimination
kinetics ……
 Dose – dependent kinetics
 Smaller dose First – Order Kinetics
 Larger dose Zero – Order Kinetics
 E.g. Phenytoin, Digoxin, Warfarin, Tolbutamide & Aspirin (higher doses)
 Plasma Fall – Out Curve – ZERO ORDER – LINEAR
FIRST ORDER - CURVILINEAR
 On log scale – ZERO ORDER – CURVILINEAR
FIRST ORDER - LINEAR

71. Design and Optimization of Dosage Regimen
Drug
excretion and
elimination
kinetics ……
 Very short half-life Constant IV infusion
E.g. Nor-epinephrine(1-2min), Dopamine(5min), Oxytocin(3-5min)
 Between 30min to 2 hrs Dose is increased so as to administer every 6-8 hourly
E.g. Cephalaxin <1hr, Benzylpenicillin <1hr, Paracetamol 2hrs
 Between 4 to 12hrs Every half-life interval
 Between 12 to 24hrs 12 hourly interval
 Longer half-life Depending upon : Vd, CL RENAL & Accumulation

72. Design and Optimization of Dosage Regimen
Drug
excretion and
elimination
kinetics ……
Therapeutic dose = 50 mg
Half-life = 24hrs
Dosing schedule = 12hourly
Dose = ??
50 x 12 = 25 mg to be given
24 12 hourly interval
Digoxin
Half-life = ~40 hrs
Rate of Clearance = 640 L
Desipramine
Half-life = 20-60 hrs
Rate of Clearance = 30-60 L
LOADING
DOSE

73. LOADING DOSE
Drug
excretion and
elimination
kinetics ……
 It is the large initial dose that is given to achieve rapid therapeutic plasma level
 After administration of the drug, the plasma concentration decreases due to
distribution of drug to other tissues
 This dose balances the drug distribution
 This is important for drugs with long half-life
Loading Dose = C P x Vd
F

74. Drug
excretion and
elimination
kinetics ……

75. Drug
excretion and
elimination
kinetics ……
MAINTENANCE DOSE
 It is the dose required to maintain the therapeutic level of the drug constant
or in the steady state level
 These doses balance the amount of drug lost during metabolism & clearance
 The patient needs to take regular doses of a drug
E.g. Amoxicillin (500 mg) 8 hourly to maintain the therapeutic level
Maintenance Dose = C P x CL
F

76. Drug
excretion and
elimination
kinetics ……
DOSING RATE ( INFUSION RATE )
The rate at which the drug should be administered to achieve a steady state level
Dosing Rate ss = Cp x CL
F
Dosing Rate oral = Dosing Rate ss
F oral
If intermittent doses are given :
Maintenance Dose = Dosing Rate x Dosing Interval
F

77. Drug
excretion and
elimination
kinetics ……
LOADING DOSE PROBLEM 1
TD of Theophylline = 10 mg/L to relieve acute bronchial asthma
Vd = 35L/70kg ; as drug is given IV - so Bioavailability F = 1
Loading Dose = ??
Loading Dose = Vd x Cp
F
= 35 x 10
1
= 350 mg

78. Drug
excretion and
elimination
kinetics ……
TD of Theophylline = 10 mg/L to relieve acute bronchial asthma
CL = 2.8 L/hr/70kg ; as drug is given IV - so Bioavailability F = 1
Maintenance Dose = ??
MAINTENANCE DOSE PROBLEM 1
Dosing rate = CL x Cp
= 2.8 x 10
= 28 mg/hr/70kg
F oral = 0.96
Dosing Interval 12 hourly = ??
Maintenance Dose = Dosing rate x Dosing Interval
F
= 28 x 12hourly
0.96
= 350 mg 12 hourly

79. Drug
excretion and
elimination
kinetics ……
DIGOXIN
Target Therapeutic Level = 1-2 μg/L
aVd = 640 L
LOADING DOSE = Vd x Cp
= 640 x 1 = 640 μg/L
or = 640 x 2 = 1280 μg/L
0.64 to 1.28 mg
IN PRACTICE = 0.9 mg is administered
MAINTENANCE DOSE = Usually half the LD
0.45 mg every 40 hours
But inconvenient , hence scaled down to 24hours
0.45 x 24 = 0.27 mg
40
IN PRACTICE = 0.25 mg is administered every 24 hours
Because of accumulation – 5 days / week

80. Drug
excretion and
elimination
kinetics ……
FIXED – DOSE DRUG COMBINATIONS
 The combination of two different drugs in a single pharmaceutical formulations
 Rules :
1) Should have approx. equal half-life
E.g. Cotrimoxazole – Sulfamethoxozole ( 11 hrs ) + Trimethoprim ( 10 hrs )
Clavulanic acid ( 1-1.5 hr ) + Amoxy/Ampicillin ( 1-1.5 hr )
Carbidopa ( 2 hrs ) + Levodopa ( 1.7 hrs )

81. Drug
excretion and
elimination
kinetics ……
FIXED – DOSE DRUG COMBINATIONS
2) The ratio of doses in each component in a formulation depends on:
a) Volume of distribution
b) Peak plasma concentration ( at steady state )
E.g.
DRUG HALF-LIFE VOLUME OF DISTRINUTION
AMOXYCILLIN 1-2 hrs 0.21 L/kg
CLAVULANIC ACID 1-1.5 hrs 0.20 L/kg
AMOXYCILLIN 500 mg + CLAVULANIC ACID 125 mg 8 hourly

82. Drug
excretion and
elimination
kinetics ……
FIXED – DOSE DRUG COMBINATIONS
Minimum Inhibitory Concentration : ??
For synergism optimal ratio of MIC = 1:20
Vd of Sulfamethoxazole = 0.2 L/kg
Vd of Trimethoprim = 1-2 L/kg (5-6 times more)
Hence given in ratio = 5:20

83. Drug
excretion and
elimination
kinetics ……
FIXED – DOSE DRUG COMBINATIONS
 Dosing schedule
1) Convenience and Compliance
 Cotrimoxazole - Bactericidal
2) Enhanced effect
 Carbidopa & Levodopa
3) Minimization of side effects
ADVANTAGES :

84. Drug
excretion and
elimination
kinetics ……
FIXED – DOSE DRUG COMBINATIONS
 Cannot be adjusted independently
1) Dose adjustment
 Fluctuations in plasma concentration
2) Pharmacokinetics - Do not match
 Anemia – Iron + Vit B12 + Folic acid = ???
3) Harmful / Benficial effects identity
DISADVANTAGES :

85. Drug
excretion and
elimination
kinetics ……
“Only the
dose makes a
thing not a
poison.” - Paracelsus

86. REFERENCES
 Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th ed. P.17-40
 Bertram G Katzung Basic & Clinical Pharmacology 13th ed. P.37-68
 Rang & Dale’s Pharmacology 8th ed. P.98-130
 Sunil S Jambhekar & Philip J Breen Basic Pharmacokinetics 1st ed.
 Donald J Birkett Pharmacokinetics Made Easy 2nd ed.
 Lippincott’s Illustrated Reviews Pharmacology 5th ed.
 KD Tripati Essentials of Medical Pharmacology 7th ed. P.10-36
 R S Satoskar Pharmacology and Pharmacotherapeutics 24th ed
 Sharma & Sharma’s Principles of Pharmacology 3rd ed. P.48-58
 Images - web
Drug
excretion and
elimination
kinetics ……

87. Drug
excretion and
elimination
kinetics ……