Pharmacokinetics- ABSORPTION, DISTRIBUTION.pptx

Pharmacokinetics.......................

1. Pharmacokinetics Dr. Ajeet Katroliya

2. Pharmacokinetics WHAT BODY DOES TO THE DRUG? Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. processes of pharmacokinetics – ADME -Absorption - Distribution - Metabolism and -Elimination of drugs Pharmacokinetic property of a particular drug is important to determine the route(s) of administration, dose, latency of onset, time of peak action, duration of action and frequency of administration of a drug.

3. Single compartment

4. MECHANISM OF DRUG TRANSPORT Drug molecules can cross cell membrane (which is a bilayer (about 100 A thick) of phospholipid and cholesterol molecules) by:- PASSIVE/SIMPLE DIFFUSION CARRIER MEDIATED TRANSPORT ACTIVE TRANSPORT FACILIATED TRANSPORT/ DIFFUSION PINOCYTOSIS/PHAGOCYTOSIS FILTRATION

5. Solute carrier SGLT transporter

6. Passive transport (down hill movement) most important mechanism as majority of drugs diffuses across the membrane in the direction of concentration gradient no active role of the membrane . Diffusion depends on lipid solubility of the drug Affecting factors:- Size of molecule Lipid solubility Polarity Degree of ionization pH of the environment

7. Lipid solubility Diffusion depends on lipid solubility of the drug as biological membrane is made of lipid. Lipid solubility of a drug depend on degree of ionization Most drugs exists in two forms ionized and non-ionized at equilibrium Only non ionized form is absorbable Nonionised/ionised fraction is determined by pH and pKa of the solution which is derived from Henderson-Hasselback equation- pKa = pH + log[ionised fraction /non ionised fraction]

8. pH EFFECT Weak acids (HA) donate a proton (H + ) to form anions (A - ), whereas weak bases (B) accept a proton to form cations (HB + ). Only the nonionized form of a drug can readily penetrate cell membranes.

9. Henderson-Hasselbalch equation pKa - ionization/dissociation constant If the concentration of ionized drug [A - ] is equal to concentration of unionized drug [HA], then pH = pKa Thus, pKa is the pH of the medium at which the drug is 50% ionized. The ratio of unionized to ionized fraction is changed by 10 fold with change in pH of environment by every unit.

10. Influence of pH and p Ka on PK of drugs Acidic drugs, e.g. aspirin ( pKa 3.5) are largely unionized at acid gastric pH and are absorbed from stomach, while bases, e.g. atropine ( pKb 1 0) are largely ionized in stomach and are absorbed only when they reach the intestines. The unionized form of acidic drugs which crosses the surface membrane of gastric epithelial cell, reverts to the ionized form within the cell(pH 7.0) and becomes less diffusible and remains localized. This is called ion trapping . Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4 of plasma) Acidic drugs are ionized more in alkaline urine- do not back diffuse in the kidney tubules and are excreted faster. Accordingly, basic drugs are excreted faster if urine is acidified.

11. ABSORPTION Movement of the drug from its site of administration into the circulation. Not only the amount of absorption, but also the rate of absorption is important. For solid dosage forms absorption first requires dissolution of the tablets or capsule thus liberating the drugs.

12. Factors affecting absorption Aqueous solubility :- dru gs given in solid form must dissolve in the aqueous biophase before being absorbed. Concentration:- Passive transport depends on the concentration gradient. A drug given as concentrated solution is absorbed faster than dilute solution. Area of absorbing surface :- area is larger the absorption is faster. Vascularity of the absorbing surface :- Blood circulation removes the drug from the site of absorption and maintains concentration gradient across the membrane. Increased blood flow hastens drug absorption. Route of administration

13. Factors affecting drug absorption by oral route Oral route:- lipid solubility/ ionization/ PH: Gastric Emptying & gut motility- Particle size and formulation- Food and presence of other substance/drug Gastric juice Gastrointestinal disease Efflux proteins Splanchnic blood flow First pass metabolism

14. Subcutaneous and intramuscular route Rate depends on absorption by capillary membrane and solubility of substance Large aqueous channel in endothelial membrane facilitates absorption even when lipid insoluble Topical route Depends on lipid solubility – only lipid soluble drugs penetrate intact skin – only few drugs are used therapeutically. Examples – GTN, Hyoscine, Fentanyl, Nicotine, testosterone and estradiol

15. Bioavailability Extent or fraction of drug or percentage of the drug that reaches the systemic circulation in the unchanged form after administration by any route. Bioavailability of drug injected i. v. is 100%, BUT, it is lower after oral /S.C,/I.M because of- First pass metabolism :- It is a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation. The first pass effect is often associated with the liver, can also occur in the lungs, vasculature, gastrointestinal tract, and other metabolically active tissues in the body. Incomplete absorption Local binding of the drug.

16. Factors affecting bioavailability Pharmaceutical factors:- particle size salt form crystal form water of hydration nature of excipients and adjuvants degree of ionization Pharmacological factors : gastric emptying and gastrointestinal motility gastrointestinal diseases food and other substances Drug-Drug Interaction Example :-antacids reduces bioavailability of tetracycline because it forms chelated complex

17. Measurement of bioavailability Bioavailability of a drug can be determined by giving it by i.v route and measuring the plasma concentration at different time intervals and similar process if repeated after giving the drug oral/subcutaneous/intramuscular. Bioavailability can also be calculated as-

18. To compare the bioavailability, the absorption pattern of two brand products of the same drug is studied after oral administration. The plasma concentration of the drug ,from both the formulations is plotted against time. From the plasma concentration-time curve, three characteristics are noted and compared- (a) peak plasma concentration( Cmax ) (b) Time to attain the peak plasma concentration( Tmax ) (c) area under the curve(AUC) Cmax and Tmax are the parameters of rate of absorption, while AUC reflects the extent of absorption. Cmax , Tmax , and AUC are not significantly different for the product to be considered bioequivalent . However, the measurement of AUC is a better index of bioavailability for drugs to be given for a longer period because here total drug absorbed become more crucial than Cmax or Tmax .

19. Absolute and relative bioavailability Absolute bioavailability- If a drug excreted unchanged in urine then total urinary concentration can be measured instead of plasma concentration. Relative bioavailability- if a drug cannot be given by i.v. route then its bioavailability can be determined by comparing the AUC of test drug with AUC of the same drug by administering both drugs orally.

20. Equivalence Chemical equivalence- if two or more dosage forms of drug contain the same amount of drug, said to be chemically equivalent.- Bioequivalence - based on plasma concentration if two or more dosage forms of a drug achieved same bioavailability they are called bioequivalent. Therapeutic Equivalence- if two different drugs produce the same therapeutic or clinical response they are called therapeutically equivalent. e.g. imipramine(TCA)and fluoxetine (SSRI) produce the same effect in depression. Clinical equivalence- response produced by two or more brand of a generic drug is same they are called clinically equivalent e.g. if response produced by calpol ( pcm )500 mg and crocin ( pcm ) 500mg are same they are clinically equivalent.

21. DISTRIBUTION Once the drug has gained access to the blood, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues Movement of drug proceeds until an equilibrium is established between unbound drug in the plasma and the tissue fluids. Most of the drug is in areas remote from the site of action (of interest), such as:- Plasma binding sites, Muscle tissue, Adipose tissue (fat), Liver, Kidneys The extent of distribution of drug depends on its lipid solubility, ionization at physiological pH (dependent on pKa ), extent of binding to plasma and tissue proteins and differences in regional blood flow, Affinity for different tissues.

22. Apparent volume of distribution (V) The volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma".

23. Low volume of distribution- Drugs extensively bound to plasma proteins are largely restricted to the vascular compartment and have low values of V, e.g. diclofenac and warfarin(99% bound) High volume of distribution- large value of distribution indicates that larger quantity of drug is present in extravascular tissue. In case of poisoning, drugs with large volumes of distribution are not easily removed by haemodialysis.

24. Redistribution Highly lipid soluble drugs gets distributed to- Initially-High perfusion low capacity organs i.e. Heart, Brain & Kidney later-Low perfusion High capacity i.e. muscle and Fat. When plasma concentration of drug falls, drug is withdrawn from highly perfused site prolonging the action of drug. Greater the lipid solubility faster is its redistribution Ex- action of Thiopentone sodium terminated in few min. due to redistribution

25. Blood-brain barrier (BBB)- Capillary endothelial cells in brain have tight inter endothelial junctions and lack large paracellular spaces. They have densely laid glial cells making it difficult for entry of ionised water soluble drugs Blood CSF barrier- lies in choroid plexus as choroidal epithelium that secrets CSF has tight junctions and lined by including zonulae Both these barriers are lipoidal and limit the entry of non lipid soluble drugs, e.g. streptomycin, neostigmine, etc. Only lipid-soluble drugs are able to penetrate and have action on the central nervous system. e.g Dopamine does not enter brain but its precursor levodopa does; so used in parkinsonism.

26. There are certain regions of brain which are relatively permeable to drugs because of absence of occluding zonulae Area postrema it includes chemoreceptor trigger zone(CTZ) near vomiting center so all the drugs reach CTZ even on peripheral administration and may cause vomiting due to stimulation of CTZ. Choroid plexus capillaries The areas concerned with hormone regulation and endocrine glands in CNS are also devoid of barrier and these includes median eminence between pituitary gland and pineal gland

27. Placental barrier Placental membranes are lipoidal and allow free passage of lipophilic drugs, while restricting hydrophilic drugs. ALSO, Placental efflux P- gp and other transporters like BCRP, MRP3 also serve to limit foetal exposure to maternally administered drugs. BUT , it act as INCOMPLETE BARRIER and almost any drug taken by the mother can affect the foetus or the newborn.

28. Drug secreted during lactation B asic drugs (chloramphenicol, tetracycline, morphine etc )are secreted more through the breast milk compared to acidic drugs.

29. Plasma protein binding Most drugs possess physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs bind to plasma albumin and basic drugs to α -1 acid glycoprotein.

30. Clinical significance of PPB Highly plasma protein bound drugs are largely restricted to the vascular (except through large paracellular spaces, in capillaries). They have smaller volumes of distribution. Temporary storage of the drug- bound fraction is not available for action. High degree of protein binding makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or kidney. Degree of protein binding should be taken into account while relating these to concentrations of the drug that are active in vitro,

31. One drug can bind to many sites on the albumin molecule. Conversely, more than one drug can bind to the same site. The drug bound with higher affinity will displace that bound with lower affinity and tend to increase the concentration of its free form. Ex. warfarin displaced by sulphonamides In hypoalbuminemia, binding reduced and high concentrations of free drug may be attained, e.g. phenytoin and furosemide α1 acid glycoprotein is a acute phase reactant increase in acute MI, RA, crohn’s ds, thus increase binding of basic drug, so free drug is reduced.

32. Tissue Storage Drugs may also accumulate in specific organs by active transport or get bound to specific tissue constituents Drugs sequestrated in various tissues are unequally distributed, tend to have larger volume of distribution and longer duration of action. Some may exert local toxicity due to high concentration, e.g. tetracyclines on bone and teeth, chloroquine on retina, Streptomycin on vestibular apparatus, emetine on heart and skeletal muscle.

33. Thank you