Order Of Kinetics

Plasma concentration REF: Katzung’s pharmacology 10^th edition page 38 See APPENDIX-33 for ‘Chemical kinetics of drugs”

Drugs may follow zero order, first order or second order kinetics. It depends on following formula:

Rate of elimination a [plasma concentration]°r`l”

Thus for zero order kinetics, rate of elimination is independent of plasma concentration.

Phenytoin and Ethanol

According to first order kinetics of elimination the rate of elimination of a drug is directly propotional to the drug concentration.

Clearence of the drug remains constant and a constant fraction of drug is eliminated in unit time.

In first order/exponential kinetics:

• Rate of elimination is proportional to the plasma drug concentration
• Clearence and tl/2 remains constant
• Constant fraction of the drug is eliminated in unit time
• Most of the drugs follow first order kinetics

• Rate of elimination remains constant irrespective of the plasma drug concentration.
• CL decreases with increase in plasma drug concentration
• Constant amount of the drug is eliminated in unit time

In zero-order kinetics or saturation kinetics, elimination mechanisms become saturated and unable to process more drug when drug concentrations rise.

Consequently, for drugs that are eliminated by zero-order kinetics, a constant amount of drug is eliminated per unit time regardless of drug plasma concentration.

Ans. is ‘b’ i.e., A constant proportion of plasma concentration is eleminated

Ans. is ‘d’ i.e., Clearance is constant

Clearance is constant in first order kinetics

Ans. is `a>b’ i.e., Phenytoin>Propranolal

o The drugs whose kinetics changes from first order to zero order at therapeutic concentration are said to follow pseudo – zero order kinetics or mixed order kinetics or saturation kinetics.

o Drugs showing zero/pseudo-zero order kinetics :

          Tolbutamide                         Warfarin                            Salicylates (Aspirin)

          Propanolol (ref- Pharmocolgy recap)

About option b

o Some textbooks have mentioned that propranolol also shows zero order kinetics:

“Examples of drugs used in critically ill patients that have saturable elimination includes phenytoin. warfarin and propranolol’——————————- ‘Critical care medicine

“Some drugs where mechanics of elimination get saturated and elimination kinetics changes from _.first order to zero order at higher doses are phenytoin, theophylline, salicylates, propranolol and tolbutamide’——————– Essentials pharmacology

Ans. is ‘b’ i.e., 93%

Ans. is ‘c’ i.e., 87.5%

Ans. is ‘b’ i.e., Half-life

Steady stateplasma concentration

 After 5 t1/2, nearly complete drug is eliminated from the body

o If a constant dose of drug is repeated before 5 V/2, the concentration in blood will be higher, because some remnant of the previous dose will be present in the body.

o So, when a drug is infused at a constant rate the plasma concentration rises until a state is reached at which the rate of administration of drug to the body is exactly equal to the rate of elimination.

o This is called the steady state —> when it is attained the amount of drug in the body remains constant i.e. the plasma concentration is on a plateau —> plateau principal of drug accumulation.

o If a drug is administered by a constant rate the time to reach steady state depends onl^y on the t1/2.

o With passage of each V/2 period of time, the plasma concentration rises by half the difference between the current concentration and the ultimate steady state (100%) concentration.

o For all practical purposes, after 5 t1/2 the amount of drug in the body will be constant and the plasma concentration will be at a plateau.

o For example, if a drug with t1/2 4 hours and plasma concentration 100 mg/ml is given at a constant rate ie every 4 hrs.

1st dose             —> at 0 hrs

2nd    dose           —> at 4 hrs

3rd    dose                   at 8 hrs

4^th dose            —> at 12 hrs——————– so on.

o After 4 hrs (1 t1/2) the drug concentration —> 50 mg/ml.

o After 8 hrs (2 t1/2) 75 mg/ml (50 of 1 ^st dose + 25 of 2″ dose)

o After 12 hrs (3 t’/2) —> 87.5 mg/ml (50 of 3″ dose + 25 of 2″ dose + 12.5 of 1′ dose)

o After 16 hrs (4 t1/2) —> 93.75 (50 of 4^th dose + 25 of 3^rd dose + 12.5 of 2′ dose + 6.25 of 1″ dose)

o After 20 hrs (5 t1/2) —> 96.875 (50 of 5^th dose + 25 of 4^th dose + 12.5 of 3^rd dose + 6.25 of 2′ dose + 3.125 of V dose) o After 24 hrs (6 t1/2) –> 96.875 (50 of 6^th dose + 25 of 5^th dose + 12.5 of 4^th dose + 6.25 fo 3^rd dose + 3.125 of _2′ dose

+ nil from 1st dose, after 5 t1/2 nearly complete drug elimination occurs & first dose is eliminated after 5 VA).

o So, after 5 t1/2 plasma concentration will be constant.

Ans. C: Elimination of the drug is proportional to the serum concentration.

With first-order elimination, the rate of elimination is directly proportional to the serum drug concentration (SDC). There is a linear relationship between rate of elimination and SDC. Although the amount of drug eliminated in a first-order process changes with concentration, the fraction of a drug eliminated remains constant.

The elimination rate constant (Kel) represents the fraction of drug eliminated per unit of time.

Ans. is `d’ i.e., Fomipizole

• The drugs whose kinetics changes from first order to zero order at therapeutic concentration are said to follow pseudo – zero order kinetics or mixed order kinetics or saturation kinetics.

Drugs showing zero/pseudo-zero order kinetics :

• Phenytoin
• Theophylline
• Alcohol
• Tolbutamide
• Warfarin 
• Salicylates (Aspirin)
• Propanolol (ref- Pharmocolgy recap)

Ans. is ‘b’ i.e., 93%