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Pharmacokinetics
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- 2. Pharmacokinetics Absorption, distribution,metabolism and elimination of a drug Involves passage across numerous cell membranes Plasma membrane is the basic barrier Characteristics of drugs that predict the availability and movement are 1. Molecular size 2. Degree of ionisation 3. Relative lipid solubility 4. Its binding to serum and tissue proteins
- 3. Modes of permeation and transport 1.PASSIVE DIFFUSION 2. CARRIER MEDIATED TRANSPORT 3. PINOCYTOSIS AND PHAGOCYTOSIS 4. FILTRATION
- 4. Passive diffusion Diffusionalong a concentration gradient by virtue of its solubility in the lipid bilayer Non electrolyte – steady state concentration same on both sides of the membrane Ionic compounds – steady state concentration depends on the electrochemical gradient and difference in pH across the membrane Ratio of non ionised to ionised at any pH is calculated by Henderson - Hasselbalch equation
- 5. Henderson–Hasselbalch equation 𝑝𝑘𝑎 =𝑝ℎ + 𝑙𝑜𝑔 𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚 𝑢𝑛𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚 pka – dissociation constant Acidic drug accumulates more on the basic side of the membrane and vice versa This phenomenon is called ion trapping
- 6. 𝒑𝒌𝒂 𝒂𝒄𝒊𝒅= 𝒑𝑯 + 𝐥𝐨𝐠 𝒏𝒐𝒏𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒂𝒄𝒊𝒅 𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒂𝒄𝒊𝒅 𝒑𝒌𝒂 𝒃𝒂𝒔𝒆 = 𝒑𝒉 + 𝐥𝐨𝐠 𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒃𝒂𝒔𝒆 𝒏𝒐𝒏𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒃𝒂𝒔𝒆 Stronger the acid / weaker the base lower will be the pka value Weakly basic drugs are non ionised in basic media and weakly acidic drugs non ionised in acidic media If 𝑝𝑘𝑎 = 𝑝𝐻 it would remain 50% ionised and 50% non ionised If pH increases or decreases by 1 unit there is a 10 fold increase or decrease in the ratio of the ionised and non ionised fraction of the drug Strongly acidic / basic drugs remain predominantly ionised at all pH therefore poorly absorbed
- 7. Carrier mediated transport 1. FACILITATEDDIFFUSION 2. ACTIVE TRANSPORT
- 8. Facilitated diffusion Carriercan move a drug substrate along its concentration gradient only No energy required Rate of diffusion depends on the binding ability of the drugs to its carrier Two drugs having similar physico-chemical characteristics can compete for the same transfer mechanism thus interfere with each other E.g. amino acids in brain, antimetabolite anticancer drugs, antiviral drugs
- 9. Active transport Energydependent carrier mediated transport taking place against the electrochemical gradient Energy generated by membrane ATPase Process can be blocked by inhibiting cell metabolism or by reducing ATP levels Drugs having same characteristics can compete
- 10. Primary active transport Bio transportation of drugs directly coupled with ATP hydrolysis ATP binding cassette (ABC) carry out the process E.g. antibiotics, anticancer drugs
- 11. Secondary active transport One ion/solute supplies driving force for the transport of other ion/solute Symporter/co-transporter – in the same direction. Na+/K+/2Cl- symporter Antiporter/counter-transporter – in opposite direction. Na+-H+ exchanger Not directly linked with ATP hydrolysis
- 12. ABC family ofsuper transporters 7 subclasses (ABC A to ABC G) Encoded by 49 genes Most important example is P–glycoprotein (ABCB1 or MDR-1)
- 13. Solute linked carrier(SLC) Facilitated diffusion or secondary active transport 43 SLC families encoded by different genes Neuronal – serotonin, NE, dopamine Non neuronal – GLUT, cholesterol
- 14. Pinocytosis Pinocytosis –process where a cell engulfs a fluid or a drug in solution This is applicable to proteins and other big molecules, and contributes little to transport of most drugs
- 15. Filtration Free orunbound drug of small molecular size pass through pore or spaces between cells E.g. urea, alcohol, glucose
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- 18. From GIT Mainlyby passive diffusion Sugar and other nutrients by active transport Gut is more permeable to non-ionised lipid soluble form of drug Ability of a drug to be absorbed is compromised by P-glycoprotein efflux by enterocytes Metabolism in these cells and liver Diseases that may affect absorption
- 19. From mouth SalivapH is slightly acidic When stimulated by sublingual drugs it becomes alkaline (~7.4) Lipid soluble non-ionised basic drugs are absorbed Drug goes directly into circulation bypassing the first pass metabolism E.g. isosorbide dinitrate
- 20. From stomach pHis acidic Lipid soluble acidic or neutral drugs are absorbed Undergoes first pass metabolism
- 21. From intestine AlkalinepH Lipid soluble non-ionised basic or neutral drugs are absorbed Chances of first pass metabolism Enterohepatic circulation maybe seen
- 22. From large intestineto colon Alkaline pH Absorption through external haemorrhoidal vein Minimal first pass effect
- 23. Absorption via parenteralsites Intravenous – completely absorbed and rapidly distributed reach the blood stream directly without crossing any membrane Intramuscular and subcutaneous – absorbed mainly by passive diffusion from the injection site to the plasma or lymph IM absorption more rapid than SC because of high vascularity of muscles
- 24. Absorption via lungs Lipid soluble drugs are absorbed Vaporised form – general anaesthetics Aqueous solution – salbutamol Spray of suspended micro fined particles – disodium cromoglycate Absorbed by simple diffusion From pulmonary epithelium and mucous membrane of trachea and lungs Absorption rapid – large surface area and high vascularity First pass metabolism avoided
- 25. Absorption via topicalsites Poor absorption through intact skin Underlying dermis permeable to lipid soluble drugs Transdermal application – nitro-glycerine, scopolamine, clonidine Mucous membrane application - thin and highly vascular absorbing surface. Oxytocin and vasopressin as nasal spray Eye drops and ointments absorbed through cornea
- 26. Bioavailability Fractional extentto which an administered dose of drug reaches its site of action or a biological fluid (usually the systemic circulation) from which the drug has access to its site of action It is an absolute term which requires measurement of both true rate and total amount of drug that reaches the general circulation from an administered dosage form Equivalence – comparison of two different brand products of the same drug with a set of established standards Different brands of the same drug can be chemically equivalent but may not be biologically or therapeutically equivalent
- 27. Bioequivalence Two ormore similar dosage forms of the same drug reach the blood circulation at the same relative rate and to the same relative extent Difference in bioavailability are primarily seen with oral dosage forms Differences of less than 25% will not have a significant effect on clinical outcome – bioequivalent Differences of bioavailability assume much greater concern with drugs having narrow margin of safety
- 28. Measurement of bioavailability The absorption pattern of two brand products is plotted against time Peak plasma concentration{C max} Time to attain peak plasma concentration{t max} Area under the curve{AUC} The first 2 parameters are simple indicators for the rate of absorption AUC reflects the extent of absorption For the product to be considered bio equivalent C max, t max and AUC should not be significantly different AUC is a better indicator for bioavailability of drugs to be given for longer period
- 30. 𝑫𝒓𝒖𝒈 𝒃𝒊𝒐𝒂𝒗𝒂𝒍𝒂𝒃𝒊𝒍𝒊𝒕𝒚(%) = 𝑨𝑼𝑪𝒐𝒓𝒂𝒍 𝑨𝑼𝑪 𝑰𝑽 × 𝟏𝟎𝟎 NB: same dose is given orally and intravenously
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- 32. Pharmaceutical factors Particlesize – dissolves more rapidly when surface area is increased by decreasing particle size. e.g. micro-fined aspirin, spironolactone Salt form – salt dissolves better than their parent compounds. E.g. phenytoin sodium Crystal form – e.g. amorphous novobiocin have better bioavailability compared to their crystalline form Water of hydration – many drugs associates with water to form hydrates. E.g. anhydrous forms of ampicillin have better bioavailability than their hydrous forms Nature of excipients and adjuvants – these are pharmacologically inert substances used as filling material or binding agent. With a drug which obeys zero or mixed order kinetics change from one brand to other may lead to therapeutic failure or drug intoxication due to different excipients/adjuvants Degree of ionisation – non ionised lipid soluble drugs are better absorbed
- 33. Pharmacological factors Gastricemptying and gastrointestinal motility – gastric emptying increases absorption as it reaches larger surface area. Promoted by fasting, anxiety, lying on right side, hypothyroidism and gastro- kinetic drugs Gastro-intestinal disease – in coeliac disease amoxicillin shows decreased absorption while cephalexin shows increased absorption ampicillin shows no change. Food and other substances – empty stomach increases absorption First-pass effect – drug degradation occurring before drug entering the systemic circulation for drugs taken orally therefore there is decreased bioavailability and diminished therapeutic response
- 34. Cont. Drug-drug interactions– e.g. paraffin decreases bioavailability of fat soluble vitamins as it emulsifies fats Pharmacogenetic factors – e.g. slow acetylators of isoniazid show increased bioavailability in American whites leading to isoniazid toxicity Miscellaneous factors – route of administration, area of absorbing surface, state of circulation at the site of absorption
- 35. Drug distribution Patternof scattering of the specific amount of drug among various locations within the body Distributed into all organs including non relevant to its pharmacological effect After absorption the drugs may not only get reversibly associated with its site of action but may bind to plasma proteins and may accumulate in various storage sites Distribution, metabolism and excretion termed as drug disposition
- 36. Factors affecting drugdistribution Lipid solubility Ionisation at physiological pH ( a function of pKa) Extent of binding to plasma and tissue proteins Presence of tissue specific transporters Differences in regional blood flow
- 38. Volume of distribution Volume of the plasma that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma 𝒂𝑽𝒅 = 𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒕𝒉𝒆 𝒃𝒐𝒅𝒚 𝒎𝒈 𝒌𝒈 𝒄𝒐𝒏𝒄 𝒐𝒇 𝒕𝒉𝒆 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒕𝒉𝒆 𝒑𝒍𝒂𝒔𝒎𝒂( 𝒎𝒈 𝑳 ) aVd = apparent volume of distribution Expressed in L/kg
- 39. If thedrug does not cross capillary walls aVd = plasma water i.e. 3L. Seen in drugs with high molecular weight or lesser lipid soluble drugs Drugs highly bound to plasma proteins have a low aVd value and vice versa aVd for many drugs may be much more than the actual body volume which means that they are widely distributed and are difficult to be removed by haemodialysis. If a drug is having smaller aVd have less protein binding also , it is easier to be removed by haemodialysis aVd<5L – drug is retained within the vascular compartment. e.g. heparin, insulin aVd~15L – drug is restricted to the extracellular fluid. e.g. aspirin, amoxycillin aVd>20l – indicates distribution throughout the total body water. e.g. phenytoin, methyldopa
- 40. Redistribution Highly lipidsoluble drugs get initially distributed to organs with high blood flow Then to less vascular but more bulky tissues Plasma concentration falls and the drug is withdrawn from the highly perfused sites If the site of action was in one of the highly perfused organs , redistribution results in termination of drug action E.g. anaesthetic action of thiopentone sodium injected IV is terminated in few minutes due to redistribution
- 42. Physiological barriers to drug distribution 1.BLOOD-BRAIN BARRIER 2. BLOOD-CSF BARRIER 3. CSF-BRAIN BARRIER 4. PLACENTAL BARRIER
- 43. Blood-brain barrier(BBB) Endothelialcells of brain capillaries are tightly joined and lack intercellular pores Glial cells envelope these capillaries which are less permeable Anatomically there exists a dual barrier in CNS ; blood-brain barrier and the blood- CSF barrier(located in the choroid plexus) Efflux transporters – molecular barrier. P-glycoprotein and ABCC1 Protects brain tissue from toxic substances and some neurotransmitters Only lipid soluble non-ionised form of drugs penetrate Inflammatory conditions like meningitis increases penetration to penicillins
- 45. Regions of thebrain which are relatively permeable 1. Pituitary gland 2. Pineal body 3. Median eminence 4. Choroid plexus 5. Area postrema near floor of fourth ventricle
- 46. Blood-CSF and CSF-brainbarrier CSF is secreted by epithelial cells of choroid plexus which are lined by occluding zonulae CSF-brain barrier there is no occluding zonulae. CSF brain barrier is extremely permeable toto drug molecules. In cases of brain abscess drugs can be given intrathecally which easily cross CSF- brain barrier
- 47. Placental barrier Placentalmembrane lipid in nature – passive diffusion of non-ionised lipid soluble substances Active transport and pinocytosis are also operative Drug administration during pregnancy severely restricted Hypoxia increases permeability of drugs
- 48. Reservoirs Cellular reservoir- tissue affinity could be due to binding to tissue proteins or nucleoproteins. E.g. digoxin and emetine in skeletal muscles, heart, kidney Fat as reservoir – highly lipid soluble drugs get selectively accumulated in fat and adipose tissue. E.g. thiopentone Transcellular reservoir – aqueous humour, CSF, endolymph, joint fluid, pleural, pericardial and peritoneal sacs Bones and connective tissue as reservoir – e.g. tetracyclines, cisplatin, lead
- 49. Important proteins thatcontribute to drug binding 1. Plasma proteins – albumin. Most of the acidic drugs bind. E.g. warfarin 2. α1-Acid glycoprotein - lipophilic basic drugs bind. E.g. quinidine . It is an acute phase reactant protein, its plasma concentration increases in physiological and pathological stress 3. Tissue proteins and nucleoproteins – drugs having high apparent volume of distribution bind. E.g. digoxin 4. Miscellaneous binding proteins – steroids bind to corticosteroid binding globulin, thyroxine to α-globulins, antigens to gamma globulins
- 50. Plasma protein binding Drugs usually bind to plasma and cellular proteins in a reversible manner and in dynamic equilibrium 𝑭𝒓𝒆𝒆 𝒅𝒓𝒖𝒈 + 𝑷𝒓𝒐𝒕𝒆𝒊𝒏 ↔ 𝑫𝒓𝒖𝒈𝑷𝒓𝒐𝒕𝒆𝒊𝒏 𝒄𝒐𝒎𝒑𝒍𝒆𝒙 As the free or unbound drug is eliminated from the body more drug dissociates from the drug plasma protein complex Extensive protein binding does not prevent the drug from reaching its site of action but only prolongs the drug availability and duration of action
- 51. Clinically important aspectsof plasma protein binding High plasma protein bound drugs remain largely restricted to the vascular compartment and have lower volumes of distribution Bound fraction is not available for action High degree of binding makes the drug long action High protein bound drugs are difficult to be removed by dialysis Binding of drugs to plasma proteins is a capacity-limited and saturable process More than one drug can bind to the same site of albumin leads to displacement interaction. Drug with high affinity displaces that with low affinity. If just 1% of a drug which is 99% bound is displaced the concentration of free form will be doubled
- 52. Displacement reactions Phenylbutazonedisplaces tolbutamide from its binding sites leading to hypoglycaemia Tolbutamide displaces warfarin resulting in increased risk of haemorrhage Sulphonamides displaces bilirubin leading to kernicterus in neonates Salicylates displaces methotrexate
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Editor's Notes
- #42 Curves depict the distribution of the barbiturate anesthetic thiopental into different body compartments following a single rapid intravenous dose. Note breaks and changes of scale on both axes. The drug level at thiopental’s site of action in the brain closely mirrors the plasma level of the drug. The rate of accumulation in the various body compartments depends on regional blood flow; the extent of accumulation reflects the differing capacities of the compartments and the steady but slow effect of elimination to reduce the amount of drug available. Emergence from the anesthetic influence of this single dose of thiopental relies on redistribution, not on metabolism. The drug will partition out of tissue depots as metabolism and elimination take their course. Depletion of compartments will follow the same order as accumulation, as a function of their perfusion.