1. SIVANAGESWARARAO MEKALA ASSISTANT PROFESSOR DEPT OF CLINICAL PHARMACOLOGY

2. The four most important parameters governing drug disposition are :  clearance  volume of distribution  half-life  bioavailability

3. Clearance (CL): The clearance of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time. Clearance (CL) = __Rate of elimination___ Plasma conc. of the drug

5.  For most drugs, clearance is constant over the concentration range encountered in clinical settings, and the rate of drug elimination is directly proportional to concentration  This is referred to as first-order elimination.  Here a constant fraction of drug present in the body is eliminated in unit time  The t1/2 of the drugs will always remain constant

6. For first order kinetics, Clearance is calculated from the dose divided by the AUC  CL = Dose AUC Half life of a drug following first order kinetics would remain constant irrespective of dose

7.  The rate of elimination remains constant irrespective of drug concentration OR  a constant amount of drug is eliminated in unit time

8.  Rate of elimination is constant and is unrelated to the amount of drug in the body.  1hr 10mg  2hr 20mg  3hr 30mg  10hr 100mg  e.g.-ethyl alcohol  Zero order kinetics – t ½  with dose since CL progressively  as dose is increased.

9. Half life of the drug is never constant

10.  Phenytoin  Tolbutamide  Theophylline  Warfarin  Aspirin

11. Phenytoin, Aspirin ↓ At low doses, follow first order kinetics As the plasma conc. increases Elimination processes get saturated ↓ Kinetics changes over to zero order (saturation kinetics)

12. It is the time required for the plasma concentration of the drug to decrease by 50% of its original value. Initial rapidly declining ( α) phase – due to distribution Later less declined (β) phase – due to elimination At least two half-lives (distribution t1/2 and elimination t1/2) can be calculated from the two slopes. The elimination half-life derived from the β slope is simply called the half life of the drug.

13. Mathematically,elimination t 1/2 is = ln2/k * ln2 is the natural logarithm of 2 (or 0.693) * k is the elimination rate constant of the drug. i.e. the fraction of the total amount of the drug in the body which is removed per unit time. Eg: 2g of drug present in the body & 0.1g is eliminated every hour then k =0.1/2=0.05 or 5% per hour. k=CL/v, therefore t 1/2 = 0.693xV/CL

14.  1 t1/2 = 50% drug is eliminated ;  2 t1/2 = 75% ; (50% + 25%)  3 t1/2 = 87.5% ; ( 75% +12.5%)  4 t1/2 = 93.75% (87.5% + 6.25%)  Nearly complete elimination occurs in 4 -5 half life  Half life of Aspirin is 4hrs, Digoxin =40 hrs, Digitoxin is 7 days.  First order kinetics – t 1/2 remains constant because V and CL do not change with dose  Zero order kinetics – t 1/2 increases with dose because CL progressively decreases as dose is increased (elimination process get saturated)

15.  Half life is useful in estimating : time to reach steady state concentration duration of drug action time for plasma concentration to fall after the drug has stopped determine the frequency of drug administration

16.  Single or few quickly repeated doses given in the beginning to attain target concentration rapidly  loading dose= Target Plasma conc X Vd bioavailability

17. Time Plasma Concentration Repeated doses – Maintenance dose Therapeutic level Single dose – Loading dose

18.  Drugs are administered in such a way so as to maintain a steady state of drug in the body

19.  Monitoring drug therapy by measuring plasma concentration of a drug for the benefit to patient by achieving maximum therapeutic benefit with minimum side effects.

20.  With narrow therapeutic index/low safety margin Eg: Digoxin, Phenytoin, carbamazepine,Gentamicin Antidepressants, Lithium.  Altered physiological states affecting drug concentration  Check patient compliance  Poisonings  Failure of drug response without any reason  Drug response  Used for adjustment of doses  To check bioavailability

21.  It is the combination of two or more drugs in a single pharmaceutical combination Advantages:  Increases patient compliance  Synergistic combination. Eg: Sulfamethoxazole + Trimethoprim: Cotrimoxazole Levodopa + Carbidopa: Parkinsonism Estrogen + Progesterone : Oral contraceptive  Reduced side effects - the side effect of one component may be counteracted by the another Eg: thiazide +potassium sparing diuretic

22.  Reduced cost  Prevents emergence of antimicrobial resistance  Increased efficacy (produce Max effect of the drug) Disadvantages:  The patient may not actually need all the drugs present in a combination: he is subjected to additional side effects and expense.  Inflexible fixed dose ratio  Incompatible pharmacokinetics  Difficult to identify one particular drug causing harmful effect  Increased toxicity due to inappropriate combinations  Physician and pharmacists ignorance of the contents.

23.  Levodopa + Carbidopa: Parkinsonism  Isoniazid + Rifampicin + Pyrazinamide: Tuberculosis.  Ferrous sulfate + Folic acid: Anemia of pregnancy.  Sulfamethoxazole + Trimethoprim: Cotrimoxazole.  Amoxicillin + Clavulanic acid: Augmentin.  Estrogen + Progesterone : Oral contraceptive  Aspirin + Codeine: As an analgesic.

24.  To decrease frequency of drug administration and improve compliance  Avoiding large fluctuations in plasma concentration  Maintaining the drug effect overnight without disturbance

25. METHODS A. For orally administered drug:  Enteric coated e.g., erythromycin  Sustained release preparation e.g: Diclofenac B. For parenterally administered drug: 1) By decreasing the vascularity of the absorbing surface : This is achieved by adding a vasoconstrictor to the drug. Eg: Adrenaline with local anesthetics  Adrenaline prolongs the duration of action and reduce the systemic toxicity of local anesthetics. And also minimizes bleeding in the operative field.  Adding Adrenaline is contraindicated in cardiovascular disease patients.

26. 2) By decreasing the solubility : Decreasing the solubility of the drug by combining it with a water insoluble compound. Eg: Injection penicillin G has a duration of action of 4-6 hours Injection penicillin G +Procaine : procaine penicillin G has a duration of action of 12-24 hours and also less painful. 3) Injecting the drug in oily solution : Depot progestins (depot medroxy progesterone acetate ) 4) Pellet implantation : Norplant for contraception 5)Pilocarpine ocusert and progestasert 6)Transdermal patch

27. 7) By increasing the plasma protein binding of the drug : Eg: Sulphadiazine is less bound to plasma proteins and has duration of action of 6 hours. Sulphadoxine is highly protein bound and has a duration of action of one week 8) By inhibiting the drug metabolism : Anticholinesterases (Physostigmine,neostigmine )prolongs the duration of action of Ach by inhibiting the cholinesterases 9) By delaying renal excretion of the drug : Probenecid prolongs duration of action of pencillin/Cephalosporins