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Drug distribution and its clinical significance

  1. Drug distribution and its clinical significance Presented by- Deepak Pandey
  2. Introduction • After absorption of drug into systemic circulation drug is distributed to various tissues leading to decline in plasma concentration and subsequent increase in drug concentration in different tissues. The distribution of drug leads to • Therapeutic action of drug at the target site • Elimination of drug through liver, kidneys
  3. One-compartment open model • Pharmacokinetic models that simulate the kinetic process of drug absorption, distribution and elimination. • Assumed that the body acts as a single homogenous compartment into which drugs can enter and leave easily
  4. One-compartment open model • On a semi-log plot, the plasma drug concentration declines linearly with time • Ka and Ke are absorption constant and elimination constant respectively • Significance- Volume of distribution, clearance and elimination half life can be calculated based on kinetic order of elimination. • Aminoglycosides being polar aren’t extensively absorbed into tissues and remain mostly in plasma thereby following a one compartment open model
  5. Steady-state concentration • When the drug is administered at a constant rate or at regular intervals, the cumulative accumulation of drug and simultaneous elimination are balanced and a steady concentration is reached • For maintenance of steady state concentration, the vol of drug that is cleared of drug must be replenished continuously. • Significance- To calculate maintenance dose of drug as under- where, Cp is the plasma concentration of drug, CL is clearance and F is bioavailability of drug
  6. Volume of distribution (Vd) • It is an apparent volume available for administered amount of drug to disperse considering the whole human body as a homogenous solution • Volume of distribution = Quantity of drug administered/ Plasma concentration (C) • It shows the extent of distribution or accumulation of drug in tissues • Eg- Warfarin has low (Vd) owing to its high plasma protein binding while Chloroquine has high (Vd) because of its accumulation into peripheral fat.
  7. Volume of distribution
  8. Volume of distribution (Vd) • Factors affecting volume of distribution • Lipid solubility of the drug • Ionization of the drug at physiological pH • Plasma protein binding of the drug • Limitation- It is assumed that the concentration of drug in different tissues corresponds to the plasma concentration and that the response of drug varies in accordance with the plasma concentration which may not be true in each case.
  9. Volume of distribution (Vd) • It is used to determine the loading dose of a drug • Loading dose = Target concentration X Volume of distribution Suppose the target concentration of a drug is 15mg/ml and Volume of distribution of the same drug is 30 L. • Since, the Volume of distribution of a drug in a patient doesn’t depend on the amount of drug administered or the route of administration, it will remain same Then, the loading dose will be 15mg/ml X 30L = 1.5g/L X 30L i.e, 45 g
  10. Two compartment open model • Most drugs after entering systemic circulation are in different equilibrium with tissues and elimination through clearance depending on • Rate constant of drug absorption into tissues (K12 in diagram) • Rate constant of drug removal from tissue back into plasma (K21 in diagram) • Elimination rate constant of drug (K10 in diagram) • These rate constants are determined by properties of drug (mol weight, mol size, pKa of drug, lipid solubility of drug) and tissue ( tissue selectivity for drug, presence of transporters at tissue level, physiological pH)
  11. Two compartment open model • The plasma concentration of drug declines rapidly after IV bolus injection due to distribution into tissues (Distribution phase) • A prolonged elimination phase when tissues are in equilibrium with plasma drug concentration and the rate of decline of plasma concentration of drug depends on clearance of drug. • The peak tissue concentration of drug represent equilibrium between tissue and plasma.
  12. Two compartment open model • Concentration time graph represents the ongoing process of drug redistribution and drug elimination simultaneously • Lipid soluble drugs like benzodiazepines or drugs with high tissue affinity follow this pattern of distribution. • Significance- In drugs with narrow therapeutic index, if the minimum toxic concentration lies within the range of distributive phase, frequent dosing can overshoot the plasma concentration. • Thus, choice of dose and interval or the rate of infusion should be relative to the distribution half life of drug.
  13. Factors affecting distribution • Physiochemical properties of drug- Lipid solubility of drug (based on oil-water partition coefficient), size of drug molecule, pKa of drug • Amount of drug delivered to an organ depends on the regional blood flow to that organ- • Physical exercise increase blood flow- increased action of IM insulin after exercise.
  14. Factors affecting distribution • Capillary permeability of tissue- • Hepatic and renal capillaries permeable in comparison to brain capillaries- Allow large molecules to pass easily • Can be affected in disease conditions- Meningitis- Increased drug uptake in brain • Plasma protein binding of drug • Presence of barriers- Blood brain barrier, Placental barrier • Tissue selectivity of drug (Incorporation of bisphosphonates into bone)- Accumulation of drug into tissues • Presence of specific transporters in tissues • Pathophysiological conditions
  15. Drug uptake into tissues • Entry of drug from systemic circulation into different tissues can occur through- • Passive diffusion- • Spontaneous • Depends on membrane thickness, capillary permeability and concentration gradient of drug • Hydrostatic/Filtration pressure- • Arterial end- Hydrostatic pressure higher than mean tissue pressure by around 8mm Hg- Drug absorption, • Venous end- Hydrostatic pressure is less- Absorptive pressure- Remaining drug is absorbed back into systemic circulation
  16. Drug uptake by organs • First order kinetics at tissue systemic circulation partition
  17. Drug uptake by organs • R– Ratio of drug concentration in tissue vs systemic circulation. • Also estimated from partition coefficient of a drug. R value- 20 in flutamide in prostate, digoxin 60 in myocardial tissues • High R value- Long distribution phase and accumulation of drug in tissues • Drug accumulation- • DDT in adipose tissue- high lipid solubility • Digoxin- specific proteins in myocardial tissue • Phenothiazines- to melanin of skin and eye • Tetracycline- insoluble chelate with calcium • Specific transporters- amphetamine into adrenergic tissues
  18. Drug uptake by organs • Perfusion/Flow limited uptake of drug- Drug diffuses rapidly across membrane (hepatic and renal vessels)- a person with CHF- reduced filtration and reduced clearance • Diffusion/Permeability limited- Across Blood brain barrier- Increased absorption in inflammatory states that promote increased capillary permeability
  19. Plasma protein binding
  20. Plasma protein binding • Protein bound drug- Reversibly bound but unable to diffuse and therapeutically inactive • Albumin- Binds acidic drugs like salicylates, phenylbutazone and penicilins • Alpha-1 acid glycoprotein-Binds basic drugs like- Imipramine, & lidocaine
  21. Plasma protein binding • Factors affecting plasma protein binding • Drug- • Physiochemical properties of drug • Total concentration of drug in body • Protein- • Physicochemical nature of protein to which drug is bound • Quantity of protein available to be bound to drug • Affinity between drug and protein i.e, magnitude of association constants • Drug interactions- • Competition by other substances at the protein binding site- Phenylbutazone and warfarin • Alteration of protein that modifies affinity of protein for drug. Eg- Aspirin acetylates lysine residues of albumin • Pathophysiologic condition of patient- Plasma protein binding reduced in uremia or hepatic diseases
  22. Plasma protein binding • Drugs highly bound to plasma protein like ceftriaxone, cefoperazone, warfarin, - Low Volume of distribution, Low clearance • Disease states decreasing plasma protein binding- Increased free fraction available for interaction with receptors- increased chances of toxicity of highly plasma protein bound drugs • Disease states increasing plasma protein binding (acute phase response leads to increase in alpha-1 acid glycoprotein)- Reduced therapeutic effect of drug
  23. Blood brain barrier • Brain vasculature has specialized endothelium (tight intercellular junctions, paucity of intracellular vesicles, abundant mitochondria) surrounded by pericytes and astroglial process. • Drugs with high lipophilicity or those with specific transporters can enter through blood brain barrier- Gabapentin and L-Dopa via LAT1 Neutral amino acid carrier • Blood brain barrier permeability may be altered in disease states and aging.
  24. Placental barrier • Physiological barrier between maternal circulation and fetal circulation at placenta • Passage of drug through placenta depends on- • Drug factors- Molecular weight, lipophilicity, Unionized fraction, protein binding of drug • Maternal factors- Drug concentration in maternal circulation, Uterine blood flow, functional integrity and thickness of placental barrie
  25. Therapeutic drug monitoring • Purpose- To adjust plasma concentration and maintain it within a specified range. • Measurement of both values of minimum and maximum concentrations are to be recorded. • The necessary dose adjustment is done considering the clearance of drug to remain constant. • Applied when- • The drug has a low therapeutic index • There is a good plasma concentration- biological response relationship • There are no other easily measurable physiological parameters • Or, to monitor adherence or adverse drug reactions
  26. Therapeutic drug monitoring • Sampling of blood is to be done only after steady state of plasma concentration is reached, ie, after five half lives except in case of toxicity • After the steady state is reached, sampling to be done after proper time for distribution of drug to finish. • A therapeutic range of plasma concentration is used to guide the desired concentration of drug • The subsequent dosing and intervals are titrated accordingly