Pharmacokinitic

pharmacokinitics

1. Pharmacokinetics Yousaf khan Renal dialysis lecturer IPMS KMU

2. Passage of drug across cell membrane Ability of drug to cross cell membrane Molecular size and shape Solubility at the site of absorption, degree of ionization and lipid solubility. Passive diffusion : Concentration gradient Depend upon lipid solubility and ionization Unionized drugs are more lipid soluble. Filtration: Water soluble drugs Through porous membrane Hydrostatic pressure or osmotic pressure

3. 2. Facilitated diffusion S pecialized transmembrane carrier proteins These carrier proteins undergo conformational changes A llowing the passage of drugs or endogenous. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. 3. Active transport : involves specific carrier proteins Energy-dependent active transport is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient. The process is saturable , selective and may be compete inhibited by other cotransported substances.

4. 4. Endocytosis and exocytosis This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drugfilled vesicle. Exocytosis is the reverse of endocytosis..

5. Absorption Absorption is the transfer of a drug from its site of administration to the blood stream. Factors affecting drug absorption 1.Solubility: Higher lipid soluble – greater absorption rate Aqueous solution rapidly absorbed than those given in oily solution, suspension or solid form. 2.Degree of ionization: Greater ionization – less absorption Lipid soluble are in unionized form – readily absorbed Water soluble drugs are in ionized form – can be absorbed – very small molecular size

6. 3.Effect of PH on drug absorption Most of drug are either weak acid or weak bases Acidic drug (HA) release proton causing a charged anion to form Weak bases (BH + ) can also release H+ ion. Protonated form of basic drug is usually charged. 4. Pharmaceutical preparation: Solution are better absorbed than suspension Smaller the particle size of powders the more efficient their absorption. 5. Route of administration: Parenteral routs is rapid than oral route Intramuscular route is rapid than from subcutaneous route

7. 6 . Surface area: Greater surface, larger will be the amount of drug absorbed 7 . Concentration of drug: Greater concentration of the drug, greater will be the concentration gradient 8 . Local blood flow: Rate of absorption is directly proportional to the local blood circulation

8. Factors modifying absorption from Gut 1.Motility of the Gut: Helps in dissolution of tablets, increase the motility also increase rate of absorption 2.Ph of the Gut: Weak acid are mostly unionized in acid medium- better absorbed Weak bases are unionized in alkaline medium- better absorbed 3.Disease condition: Effect rate of absorption 4.Presence of other substance :

9. Plasma half-life: Time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50 %. The half-life of a drug depends on its  clearance  and  volume of distribution E.g For example, after  intravenous administration , if maximum concentration is 16 mg and the half life is 2 hours, after 2 hours 8 mg will be left, and so on . Factors affecting half-life Clearance decrease Volume of distribution

10. Steady state: Steady state concentration of drug occurs when the rate of drug elimination is equal to the rate of drug administration. Steady state plasma concentration is directly proportional to rate of infusion and inversely proportional to the total body clearance of the drug. Biological half life: The biological half-life or terminal half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity,

11. Bioavailability The fraction of unchanged drug reaching the systemic circulation following administration by any route” or The percentage of administered drug that reaches the systemic circulation in a chemically unchanged form” Thus by definition a drug that is administered by intravenous route has 100% bioavailability

12. Factors affecting bioavailability 1-Rout of administration: 2-First-pass hepatic metabolism: when a drug is absorbed across GIT, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver ,the amount of unchanged drug that gains access to the systemic circulation is decreased 3-Absorption 4 -Solubility of the drug: hydrophobic drug will absorb more so bioavailability will be more 5 -Chemical instability: some drugs are unstable in pH of the gastric contents. Others are destroyed in GIT by degradative enzymes 6 -Particle size: smaller the particle size more absorption will be there.

13. Distribution of drugs Process by which drug reversibly leave blood stream and enter interstitial and tissue. Such as plasma, extra cellular and intracellular fluid depending upon its physicochemical properties. Substance of high molecular weight almost remain in water plasma. Drug that can pass capillary wall but can not pass across the cell membrane are localized mainly in extra cellular fluid. E.g mannitol iv administration Cross cell membrane and do not have specific affinity for specific tissue are distributed equally. E.g alcohol , urea Some drugs are concentrated especially in one or more tissue of the body. E.g. iodide in thyroid gland

14. Factors that determine drug distribution Binding of drug to plasma protein and tissues Binding to plasma protein Bound to plasma protein to varying extent Binding of drug to albumin is reversible and may show low or high capacity Albumin has the strongest affinity for anionic drugs and hydrophobic drugs. Binding to tissue protein Drug accumulate in tissue leading to higher conc. In tissue. As result of binding to lipid, protein or nucleic acid. Drug may also be actively transported into tissue. Tissue reservoirs may serve as major source of the drug and prolong its action

15. Blood flow How rapidly drug molecules are delivered to a given tissue How effectively the conc. Gradient b/w blood and tissue is maintained Drug equilibrate rapidly b/w the blood and organs with high blood flow Capillary permeability Capillary structure and chemical nature of drug.

16. lipophilicity Lipophilic drug readily move across most biologic membranes Dissolved and penetrate entire cell surface Hydrophilic drug do not readily penetrate cell membrane and must pas through slit junction.

17. Drug metabolism/biotransformation The series of chemical alterations of drug that occurs within the body How activity of drug terminated or altered. Some drug – excrete through kidney – no need of metabolism. Lipophilic– promote- biological membrane- site of action- reduce elimination Lipophilic drug convert into hydrophilic metabolites- terminate biological activity and eliminate from the body. Site of drug metabolism: liver, kidney, GIT, skin and lungs

18. enzyme Cytochrome P-450 system Drug- elevate level of cytochrome p-450- increase rate of metabolism– reduce action and duration of the drug. Drug– inhibit p-450 system and may potentate the action of other drug that are metabolized by this system

19. Phases of metabolism First phase I and than Phase II Some drug pass through phase II and the phase I Some drug directly undergo through phase II. Phase I: Generally result in loss of pharmacological activity of drug Increase pharmacologically inactive become active after metabolism Conversion of drug to a toxic compound Reaction include in type I reaction are Oxidative reaction Reduction reaction hydrolysis .

20. Phase ii reaction Conjugation of the parent compound with certain acid radical or amino acids Metabolite from phase I metabolism is sufficient polar – excreted by kidneys Many metabolite are too lipophilic to be excreted and they must undergo conjugation reaction with endogenous substrate Phase II reaction result in inactivation of the parent drug but not always Phase II reaction Glucuronidation Acetylation Glutathion conjugation Sulfate conjugation Methylation Water conjugation

21. Factor affecting biotransformation Difference in drug distribution, metabolism and elimination due to following factor Individual difference: Different people have different level of metabolism Genetic factors: Influence enzyme levels resulting in difference in drug metabolism Diet and environmental factors: Certain vegetables and fruits induce or inhibit enzymes affecting the drug metabolism Age and Sex; Drug have more effect and more toxicity – young and old patient due decrease drug metabolism In newborn the enzyme in the liver are not developed. Male have more rapid drug metabolism than female.

22. Drug – Drug interaction Interaction b/w drugs and endogenous compounds Diseases affecting drug metabolism Pharmacokinetic factors

23. Clearance of drug Clearance estimates the amount of drug cleared from the body per unit of time. First order kinetics: if a constant fraction of drug is eliminated per unit time, it is called first order kinetic e.g. 5% or 10% Zero order kinetics: if a constant amount of drug is eliminated per unit time it is called first order kinetics, e.g. 5mg or 10 mg

24. Drug clearance through metabolism Major route of elimination hepatic metabolism, biliary elimination and urinary elimination, Elimination processes decrease plasma concentration. Constant fraction of drug present is eliminated in given unit of time A . Kinetics of metabolism: First order kinetics: if a constant fraction of drug is eliminated per unit time, it is called first order kinetic e.g. 5% or 10% Zero order kinetics: if a constant amount of drug is eliminated per unit time it is called first order kinetics, e.g. 5mg or 10 mg

25. B: Reaction of drug metabolism: Kidney can not eliminate lipophilic drug First metabolized lipid soluble into more polar in the liver through phase I and phase II.

26. Drug clearance by the kidney Polar to be eliminated Eliminate through kidney Glomerular filtration Proximal tubular secretion Distal tubular reabsorption

27. Clearance by other route Intestine, bile lungs and breast milk Orally not absorbed directly eliminate through intestine or into bile eliminate in the faces. Lung – anesthetic gases Excretion of most drugs into sweat, saliva, tears, hair and skin.