Drug Excretion: Mechanisms and Importance

1. DRUG EXCRETION PHA 301 FEBRUARY 2017

2. INTRODUCTION • Drug excretion refers to the passage of systemically absorbed drug out of the body. • Drug is excreted in the following ways: • Urinary excretion via the kidney; • Most important as most drugs are excreted in urine. • Faecal excretion • Unabsorbed drug in the gastrointestinal tract is excreted this way e.g. purgatives • Biliary excretion of absorbed drug also occurs e.g. tetracycline, rifampin • Using various active transport proteins, the liver transports into bile, drugs and metabolites for biliary excretion.

3. Exhalation of gaseous and volatile liquid drug substances • The pair of lungs as excretory organs allows for the elimination of drugs such as general anaesthetics and alcohol • Drug excretion in milk • particularly of concern for breast fed infants • Some drugs are contraindicated in lactating mothers • Saliva and sweat • Minor drug excretion pathway • However, lithium, rifampin and heavy metals are present in these secretions in significant amounts.

4. RENAL EXCRETION • The kidney is critical for the excretion of a vast majority of systemically absorbed drugs. • Net renal excretion = (Glomerular filtration + tubular secretion) – tubular reabsorption. • Glomerular capillaries have relatively larger pores that allows non-protein bound drugs (lipid-soluble or insoluble) to be filtered out into the tubules.

5. Tubular secretion, the active transfer of organic acids and bases by non specific organic anion and cation transporters, OAT and OCT into the proximal tubules allows for excretion of some drugs. • Some drugs that do not get filtered by the glomerulus due to PPB still get excreted from the kidney via this process. • Tubular reabsorption occurs mostly by passive diffusion, depends on lipid solubility and ionization of the drug as well as urine pH. • Lipid soluble or unionized drugs filtered at the glomerulus back diffuse • Up to 99% of glomerular filtrate is normally reabsorbed.

6. Be mindful of the following…………….. • The transporters involved in renal excretion are important in drug interactions. • Such drug interactions occur due to drugs’ competition for tubular secretion, e.g. • Probenecid increases the duration of action of penicillin/ampicillin, • Salicylates on the other hand reduces the uricosuric effect of probenecid. Can you tell how? • Tubular transport mechanisms is usually under-developed in neonates, develops during infancy and progressively declines by over 50 years age.

7. DRUG CLEARANCE • Drug clearance refers to the theoretical volume of plasma from which the drug is completely removed per unit time. • It is determined as CL = Rate of elimination/Cp • where Cpis the plasma concentration. • Rate of Elimination is the amount of drug eliminated per unit time. • It is proportional to drug’s plasma concentration

8. Figure 1: The concept of drug clearance. A fraction of the drug present in plasma is removed on each passage through the organs of elimination. In the case shown, 50 mL of plasma is required to account for the amount of drug eliminated every minute ie clearance is 50 mL/min

9. ELIMINATION KINETICS • Understanding the elimination kinetics of a drug contributes significantly to arriving at rational dosage regimens for it. • Drug elimination refers to the total excretion via metabolic inactivation and excretion of drugs. • The processes involved in drug elimination follows certain orders, system or patterns of kinetics.

10. DRUG ELIMINATION ORDER OF KINETICS Zero order kinetics Bearing in mind the fact that Rate of Elimination ∝ (Plasma Concentration)order If drug follows zero order kinetics, Rate of Elimination ∝ (Plasma Concentration)0 The rate of elimination will be independent of plasma concentration

11. Constant amount of the drug is eliminated per unit time • This could allow for saturation of the elimination mechanisms such that an accumulation of plasma levels of the drug is observed at some point. • And CL could decrease with increase in concentration • e.g. ethanol.

12. First order (linear) kinetics • Most drugs’ elimination process follow first order kinetics when administered within the therapeutic range. • A constant fraction of the drug is eliminated • Their elimination process do not usually get saturated Rate of Elimination ∝ (Plasma Concentration)1 • The more the drug’s plasma concentration, the more itis excreted. • Thus, CL remains constant since a constant fraction of the drug is eliminated per unit time.

13. However, at excessive concentration of the drug, the metabolic or elimination pathway gets saturated, the drugs may then follow a zero order kinetics i.e. a constant amount of the drug now gets eliminated per time. • E.g. phenytoin, tolbutamide and warfarin. • This usually occurs above the therapeutic range of the drug,

14. Contrasting first and zero order elimination kinetics

15. HALF LIFE (T½) • The Plasma half-life (t½) of a drug is the time taken for its plasma concentration to be reduced to half of its original value. • Half-life is a derived parameter from two variables Vdand CL both of which may change independently with time, as such t1/2 is not an exact elimination index but a useful simple guide to the body’s disposition of drugs

16. For instance, after • 1 t½ – 50% drug is eliminated. • 2 t½ – 75% (50 + 25) drug is eliminated. • 3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated. • 4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is eliminated. • Thus, nearly complete drug elimination occurs in 4–5 half lives.

17. Note • Only the t½ calculated over the therapeutic plasma concentration range is clinically relevant. • It is this t½ which is commonly referred to. • t½ determines the dosing interval and time required to reach the steady state of a drug. • Drugs with short half lives are administered more frequently than those with longer half life.

18. STEADY STATE • If a given dose of a drug is administered at regular intervals such that a new dose is given before it is completely eliminated, its plasma concentration starts accumulating. • As plasma concentration continues to rise, the rate of elimination also starts increasing. • With time, the rate of administration equals the rate of elimination, plasma concentration stabilizes (sort of) and the drug is said to be in a steady state in plasma.

19. Within this steady state plasma concentration of the drug, the plasma level will actually continue to rise (peak) and fall (trough) as dosing is continued at a regular interval. • The plasma concentration at steady (Css) state depends on the amount administered per dosing interval (dosing rate) and the clearance (Cl). Thus, Css= dose rate/clearance • Time taken to reach steady state depends on the rate of elimination of drug.

20. Figure 2: E.g. of plasma conc vs time curve for an intravenously administered drug that reached steady state

21. Figure 3: E.g. of plasma conc vs time curve for an orally administered drug that reached steady state, observe that the preceeding dose is administered before it its half life

22. The amplitude of fluctuations in plasma concentration at steady-state depends on the dose interval, i.e the difference between the maximum and minimum levels is less if smaller doses are repeated more frequently (dose rate remaining constant as shown in Figure 4). • Dose intervals are generally a compromise between what amplitude of fluctuations is clinically tolerated (loss of efficacy at troughs and side effects at peaks) and what frequency of dosing is convenient. • Changing dose rate changes the average Cpssover the next 4–5 half lives.

23. Figure 4: Accumulation: dose, dose interval, and fluctuation of plasma level for same drug with different dosing rates

24. Figure 5: Time course of drug concentration with irregular intake after plasma steady state has been initially achieved

25. TWO DOSE STRATEGY • Drugs with high volume of distribution (and long half lives) usually require a two dose strategy. • The strategy involves an initial administration of a large dose i.e. loading dose, which is administered to attain the steady state quickly and later on, to maintain the plasma concentration, a smaller dose maintenance dose is given. • The loading dose is actually meant to load (saturate) the tissue stores such that subsequent maintenance dosing helps maintain plasma concentration required for drug activity.

26. THERAPEUTIC DRUG MONITORING (TDM) TDM is a process by which the dose of a drug is adjusted according to its plasma concentration. It is usually done for • drugs with low safety margin, e.g. digoxin, anticonvulsants, antiarrhythmics, aminoglycosides, tricyclic antidepressants • drugs such as antidepressants, having wide variation in pharmacokinetics both intra- as well as inter- individual. • Potentially toxic drugs used in conditions of renal failure, e.g. aminoglycoside antibiotics, vancomycin • Psychopharmacological agents to check for patient compliance