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LONGITUDNAL SECTION OF KIDNEY

LONGITUDNAL SECTION OF KIDNEY. DEFINITION OF PHARMACOKINETICS AND PHARMACODYNAMICS. Renal Excretion. Glomerular filtration depends on : Renal blood flow & GFR; direct relationship Plasma protein binding; only free unbound drugs are filtered

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LONGITUDNAL SECTION OF KIDNEY

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  1. LONGITUDNAL SECTION OF KIDNEY KLECOP, Nipani

  2. DEFINITION OF PHARMACOKINETICS AND PHARMACODYNAMICS

  3. Renal Excretion • Glomerular filtration dependson: • Renal blood flow & GFR; direct relationship • Plasma protein binding; only free unbound drugs are filtered • Tubular Secretion in the proximal renal tubule mediates raising drug concentration in PCT lumen • Organic anionic & cationic transporters (OAT & OCT) mediate active secretion of anionic & cationic drugs • Passive diffusion of uncharged drugs • Facilitated diffusion of charged & uncharged drugs • Penicillin is an example of actively secreted drugs

  4. Renal Excretion • Tubular re-absorption in DCT: • Because of water re-absorption, urinary D concentration increases towards DCT favoring passive diffusion of un-ionized lipophillic drugs • It leads to lowering urinary drug concentration • Urinary pH trapping: • Chemical adjustment of urinary pH can inhibit or enhance tubular drug reabsorption • For example, aspirin overdose can be treated by urine alkalinization with Na Bicarbonate (ion trapping) and increasing urine flow rate (dilution of tubular drug concentration) • Ammonium chloride can be used as urine acidifier for basic drug overdose treatment

  5. Drug Elimination • Pulmonary excretion of drugs into expired air: • Gases & volatile substances are excreted by this route • No specialized transporters are involved • Simple diffusion across cell membrane predominates. It depends on: • Drug solubility in blood: more soluble gases are slowly excreted • Cardiac output rise enhance removal of gaseous drugs • Respiratory rate is of importance for gases of high blood solubility • Biliary excretion of few drugs into feces • Such drugs are secreted from the liver into the bile by active transporters, and then into duodenum • Examples: digoxin, steroid hormones, some anticancer agents • Some drugs undergo enterohepatic circulation back into systemic circulation

  6. CLEARANCE:- Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min. CL = kVD, k: elimination rate constant KLECOP, Nipani

  7. Clearance • It is ability of kidney, liver and other organs to eliminate drug from the bloodstream • Units are in L/hr or L/hr/kg • Used in determination of maintenance doses • Drug metabolism and excretion are often referred to collectively as clearance • The endpoint is reduction of drug plasma level • Hepatic, renal and cardiac failure can each reduce drug clearance and hence increase elimination T1/2 of the drug

  8. TOTAL BODY CLEARANCE:- Is defined as the sum of individual clearances by all eliminating organs is called total body clearance/ total systemic clearance. Total Body Clearance = CLliver + CLkidney + CLlungs +CLx KLECOP, Nipani

  9. Metabolism & Excretion Kinetics • Elimination (metabolism + excretion) of most drugs follow first-order kinetics at therapeutic dose level • Amount of drug cleared in a given unit of time is directly proportional to the concentration of the drug according to Michaelis-Menten (linear) kinetics: • Only few drugs (e.g., phenytoin, alcohol) show saturation clearance (Zero-order, non-linear) kinetics • Clearance mechanisms become saturated at therapeutic level, and clearance remain constant even with increased drug plasma level • SLOW ELIMINATION at therapeutic levels leads to toxic reactions E = Vmax x C km + C

  10. Therapeutic success of a rapidly & completely absorbed drug. Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important this is clear from the figure. Plasma Drug Conc. Minimum effective conc. Therapeutic failure of a slowly absorbed drug. Subtherapeutic level Time

  11. Loading Dose • Loading Dose = Target Plasma C x VD • What Is the is the loading dose required fro drug A if: • target concentration is 30 mg/L • VD is 0.75 L/kg, patients weight is 75 kg Answer • VD = 0.75 L/kg x 75 kg = 56.25 L • Target Conc. = 10 mg/L • Dose = 30 mg/L x 56.25 L = 1659 mg

  12. Half-life (t1/2) • Half-life: is a derived parameter, completely determined by volume of distribution and clearance. • (Units = time) • As Vd increases t1/2 increases

  13. Maintenance Dose • Maintenance Dose = CL x target steady state drug concentration • The units of CL are in L/hr or L/hr/kg • Maintenance dose will be in mg/hr

  14. Steady-State • Steady-state occurs after a drug has been given for approximately 4-5 t1/2 • At steady-state the rate of drug administration equals the rate of elimination • Plasma concentration after each dose is approximately the same

  15. Importance of Steady State (SS) • At SS Rate in = Rate Out • Steady state is reached usually within 4 – 5 half-lives at linear kinetics • It is important for drug concentrations interpretation in: • Therapeutic Drug Monitoring (TDM) • Evaluation of clinical response

  16. Dosing: Administration of medication over time, so that therapeutic levels can be achieved. • Steady-state: • drug accumulates and plateaus at a particular level • rate of accumulation determined by half life • reach steady state in about five times the elimination half-life Dosing and Steady State

  17. How Drugs Act: Pharmacodynamics

  18. Pharmacodynamics (how drugs work on the body) It is the study of biochemical and physiological effects of drugs and their mechanism of action at organ level as well as cellular level.

  19. Pharmacodynamics (how drugs work on the body) It is the study of biochemical and physiological effects of drugs and their mechanism of action at organ level as well as cellular level.

  20. Principles of drug action Do NOT impart new functions on any system, organ or cell Only alter the PACE of ongoing activity • STIMULATION • DEPRESSION • REPLACEMENT • CYTOTOXIC ACTION

  21. Targets of drug action Majority of drugs interact with target biomolecules: Usually a Protein • ENZYMES • ION CHANNELS • TRANSPORTERS • RECEPTORS

  22. I- Ion Channels Direct Physical blocking of channel local anesthetic & amiloride Modulator Bind to the channel protein itself Ca channel blockers

  23. II- Enzymes ChE inhibitors α-Methyl dopa

  24. II- Enzymes (cont.) • Drug acts as • Substrate leading to reversible OR irreversible inhibition of enzyme • reversible inhibition of cholinesterase by neostigmine • Irreversible inhibition of cyclo-oxygenase by aspirin • True/False substrate • L-DOPAconverted into dopamine • α-methyldopa converted into α-methylnorepinephrine (false transmitter)

  25. III- Carrier Molecules • What is carrier molecule? • Carrier protein molecules function to transport ions & small organic molecules (too polar to penetrate) across cell membranes.

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