Pharmacokinetics lecture notes pharmacology


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Pharmacokinetics lecture notes pharmacology

  1. 1. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 1 PHARMACOKINETICS Pharmacokinetic is the study of the movement of drugs in the body. Processes of Pharmacokinetics (i) Absorption (ii) Distribution (iii) Metabolism (Bio-transformation) (iv) Elimination Commonly used Pharmacokinetic Parameters (i) Bio-availability (ii) Volume of distribution (iii) Half-Life (iv) Clearance All the processes of Pharmacokinetics involve the passage of the drug across the cell Mb. Cell Mb: Consists of a bilayer of Amphipathic lipids with the hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase and their hydrophilic head is oriented outward. Drugs cross the membrane either by passive processes or by mechanism involving active participation of components of the Mb. A. Passive Transport (i) Simple diffusion-most common-usually lipid soluble drug. e.g Propranolol, Diazepam, Thiopentone Na….. (ii) Paracellular transport. B. Active Transport (i) Facilitated diffusion e.g BI2, folic acid (ii) Drug transporters Facilitated transport: Describes a carrier-mediated transport process in which there is no input of energy.
  2. 2. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 2 Absorption It is the movement of a drug from its site of administration into the central compartment and the extent to which this occurs. Factors affecting Absorption A. Pharmaceutical factors (Extrinsic factors)-Drug related factors 1. Physical state of the drug: Drug given in aqueous/ liquid dosage are more rapidly absorbed. e.g colloids are slowly absorbed(dextran, albumin), compared to crystalloid (saline, glucose). 2. Water/Lipid solubility Drug given in aqueous solution mix more readily with the aqueous phase of the absorbing the surface than when given in solution. Aqueous solution more easily absorbed. 3. Particle size Solid dosage forms containing smaller particles-microfine crystals are better absorbed from the gut. e.g Aspirin , Warfarin ,Griseofulvin. Solid dosage containing larger particles are little absorbed e.g Neomycin. 4. Ionisation of the drug Non-ionised drugs are better absorbed from the GIT, e.g Aspirin in stomach and morphine in intestine. 5. Disintegration-time of the drug It is the time taken for solid dosage form (e.g tablet) of a drug to break down into finer particles in the gut completely. Longer the disintegration time, the slower will be the rate of absorption. 6. Dissolution-Time of a drug Time taken for a solid dosage form e.g tablet to go into the solution form in the gut after it has disintegrated. Shorter dissolution time, higher will be the rate of absorption. 7. Enteric-coated tablet They are made-enteric coated by means of cellulose/Phthalate. They resist disintegration & dissolution by gastric juice, but permits disintegration & dissolution in alkaline medium of the gut. They have prolonged action- e.g S.R Tablet-Prolonged action. B. Human factors/other factors 1. Concentration of the drug Passive diffusion depends on the concentration gradient. Higher concentration of the drug, faster will be the rate of absorption. 2. Area of the absorbing surface Larger the surface area, more is theabsorption.
  3. 3. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 3 3. Vascularity of the absorbing surface The higher the blood flow, the more and faster is the absorption. 4. Route of absorption Factors affecting absorption from oral route: 1. Epithelial lining of GIT is lipoidal; lipid soluble drug are better absorbed. 2. Gastric juice is acidic; therefore acidic drugs are readily absorbed from the stomach as they are non- ionised. e.g Aspirin /ethanol. 3. Acid labile drug e.g Insulin is destroyed by this route 4. Ionised drug e.g basic drug-Morphine are better absorbed in duodenum. 5. Presence of food in the stomach (other drugs)  In general food in stomach retards absorption e.g Rifampicin, Ampicicillin, Iron, Isonicinil. Rifampicin is best given on empty stomach.  Fatty food increases the absorption of: Ribavirin Albendazole /Mebendazole Effavirenz Atovaquone  Vitamin C increases absorption of Iron.  Phytates /oxalates decreases absorption of iron  Iron & Tetracycline (tetracycline chelates iron)  Phenytoin &sucralfate (sucralfate decreases the absorption of phenytoin). 6. Rate of absorption increases with increasing rate of gastric emptying. Pregnancy delays gastric emptying: decreases absorption by oral route. Migraine also cause gastro-paresis PCM + Metoclopramide Rabeprazole + Domperidone in Gastroparesis 7. Pathological state CCF→Mucosal oedema delays absorption GIT→Malabsorption B. Parenteral :Intramuscular / subcutaneous Route  Heat / muscular exercise / massage causes vasodilation and hence increases the absorption of the drug.  Vasoconstrictors e.g Epinephrine decrease absorption and prolonged duration action of such drug in local site Lignocaine + Epinephrine.
  4. 4. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 4 C. Topical Inflamed, Denuded areas has increased vascularity such that absorption of the given drug increases drastically to such an extent that toxicity can easily occurs. Contact time of the site of absorption: If a drug moves through the GIT very quickly as in severe diarrhea, it will not be absorbed. N.B: Anything that delays the transport of drug from stomach →Intestine → delays rate of absorption. e,gDicyclomine
  5. 5. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 5 Bio-availability It is defined as the fraction of the drug dose that reaches the systemic circulation in unchanged form after pre-systemic elimination and is available for action. Relative Bio-availability= Amount of Drug absorption Amount of drug administered by any route Bio-availability IV route : 100% Oral: 0- 100% Incomplete Bio-availability may be due to (i) Incomplete absorption (ii) First-pass metabolism Absolute Bio-availability is calculated by AUC after oral dose x 100 AUC after IV dose Factors modifying / affecting Bio-availability (i) Route of administration (ii) Presence of food / Drug in GIT (iii) Effect of Pre-systemic elimination (iv)Entero-hepatic recycling (vi) Drug distribution / Plasma protein binding (vi) Pharmaceutical factors. e.g ( Physical& chemical properties of the drug Dosage form, particle size ,Disintegration / Dissolution).
  6. 6. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 6 Entero-hepatic Recycling It is the process of re-circulation of drugs whereby the drug enters the liver from intestine by portal vein and back to the intestine via Bile-duct. β-Glucoronidase is needed for entero-hepatic recycling to occur. Hydrolysis is needed such that reabsorption can occur. Example of Drugs undergoing EHR All NSAIDs except Nabumetone (PCM, Indomethacin /Diclofenac) Opioids: Morphine, Buprenorphin, Methadone.. Diazepam, OCP, Amoxycillin, Ampicillin, Sulfonamides, Tamoxifen, Digoxin. Endogeneous subs: Vit D3, Oestrogen, Progesterone, Vit B12, Thyroxine. Significance 1. Help in prolongation of action of the drug but however decreases its potency. 2. Certain drugs inhibit EHC and are useful in the treatment of toxicities of drugs that are capable of undergoing entero-hepatic recycling. e.g Activated charcoal Anion exchange resin for Digoxin Drug Distribution It refers to the reversible transfer of a drug between the blood and the extravascular fluids and Tissues of the body (e.g fat, muscle & brain tissue). Distribution is a passive process:  The driving force is the concentration gradient between blood and the tissues.  The process occurs by the diffusion of free drug until equilibrium is established. Distribution of a drug is not uniform throughout the body because different tissues receive the drug from plasma at different rates and to different extents. Following absorption or systemic administration into the blood stream, a drug distributes into interstitial and intracellular fluids. First Distribution Phase Initially well perfused organ-Liver /Heart / Kidney /Brain receive the blood.
  7. 7. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 7 Second Distribution Phase  May require minutes to several hours before the concentration of the drug in tissues is in equilibrium with that of blood.  Involves larger fraction of the body  Delivery to less well-perfused organ e.g Adipose tissue,muscles, Skin. Apparent volume of Distribution, Vd. It is the volume that would accommodate all the drug in the body if the concentration throughout was same as in plasma i.e the body was behaving as a single homogeneous compartment. Vd = Amount of drug in body Conc of drug in blood /Plasma Redistribution  Highly lipid soluble drugs when given by IV or inhalational route initially gets distributed to organs of high blood flow such as brain /heart /Kidney.  If site of action of the drug was in one of those highly perfused organ; the onset of action will be very rapid (e.g thiopental –IV GA)  Later less vascular but more bulky tissues (muscles /fat) take up the drug & plasma concentration falls and the drug is withdrawn from these sites.  In the above case, redistribution leads to terminate of action of the drug. N.B: Greater the lipid solubility of the drug, faster is its rate of redistribution. However, when the same drug is given repeatedly /continuously over longer periods , the low perfusion, high capacity sites gets progressively filled up & the drug becomes longer acting. Example Nitrazepam sedative action lasting 6-8 hrs initially but after prolonged use the t1/2 becomes 30 hours. The real volume of distribution has physiological meaning and is related to body water (total 42L). Factors affecting Distribution of drug 1. Tissue permeability of the drugs  Lipid solubility & transmembrane pH gradient.  PKa of the drug. ( especially for drugs that are weak acids /bases)  Molecular wt  Partition coefficient  Physiological barriers to diffusion of the drugs  Ionisation (Unionized drug promotes more easily) 2. Relative binding to plasma protein. Limit concentration of the free drug. N.B: Drugs that are extensively bound to PPB are largely restricted to the vascular compartment Therefore they have a low volume of distribution. e.g Warfarin 99% PPB Vd: 9.8 L/70kg
  8. 8. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 8 3. Sequestration in tissues Vd of such drugs are much more than the total body water or even body mass. Morphine: 230L/70kg Digoxin: 500L/70kg Chloroquine: 13000L/70kg 4. Presence of specific tissue transporters e.g P-gP Organ / Tissue size and perfusion rate 5. Pathological states CCF / Cirrhosis /anaemia / Obesity Alternate of distribution of water Permeability of Mb altered 6. Drug-interaction /Pregnancy Clinical Significance 1. Drugs with very high volume of distribution have much higher concentration in extravascular tissue than in vascular compartment. Therefore, they are not homogenously distributed. Drugs with small volume of distribution are homogeneously distribution. 2. In case of Poisoning with drugs low Vd, in general Haemodialysis can be of use e.g these drugs are confined to the vascular compartment. N.B: Drugs that remain confined in (i) Blood /Plasma : small Vd 5-10 L (II) Drugs going beyond vasc comp (e.g tissue) Vd =10-20L (iii) Drugs sequestered in tissues, Vd 500-50,000L When Vd exceeds total body water (<42L), it means that there is sequestration of the drug in tissues. Plasma Protein Binding Many drugs circulate in the blood stream bound to Plasma Protein. The binding is usually reversible. Covalent binding with reactive drugs such as alkylating agent occurs occasionally. Albumin-major carrier for acidic drugs. Examples of drugs that bind to albumin: NSAIDs Warfarin Barbiturates Benzodiazepines Sulfonamides
  9. 9. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 9 α -1 acid Glycoprotein binds basic drugs Examples of drugs that bind to α -1 acid Glycoprotein: β-Blockers Imipramine Verapamil Methadone Non specific binding to other plasma Proteins occurs to a much smaller extent. e.g certain drugs bind to proteins that function as specific hormone carrier protein. E.g Thyroid hormone-Thyroxine binding globulin. Kinetics of Protein Drug binding The kinetics of reversible drug-protein binding for a protein with one simple binding site can be described by the low of mass action: Protein + Drug Drug Protein complex. The function of total drugs in Plasma that is bound is determined by: (i) Drug concentration (ii) Affinity for the binding sites (iii) Number of binding sites Therefore Plasma Protein binding is non-linear & saturable process. (iv) Disease related factors: e.g Hypoalbuminaemia secondary to liver disease / Nephrolic syndrome decrease PPB and increases the unbound fraction. Condition leading to ↑ Acute Phase response: Cancer /Crohn’s Disease /MI leads to an increase in α1 –Acid glycoprotein and enhanced binding of basic drugs. (v) Drug-Drug interaction. Implication of PPB 1. Highly Plasma protein bound drugs are largely restricted to the vascular compartment, therefore they have a low Vd. 2. Bound fraction is not available for action  Acts as drug reservoir  They are in equilibrium with free drug in Plasma and dissociate when conc of the water is reduced. 3. Makes the drug longer acting.  Not available for metabolism /excrete unless they are actively extracted by liver /kidney tubules.  Limits the drug Glomeruler filtration N.B: PPB generally does not limit renal tubular secretion / biotransformation as when the free drug concentration decreases, dissociation will occur. 4. One drug can bind to many sites of albumin molecule and also more than one drug can bind to the same drug. 5. Drug-Drug interaction.  Drugs having higher affinity will displace the one with lower affinity. If the drug is having high affinity for different sites-no interaction occurs.  Acidic drug will not displace basic drug
  10. 10. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 10  Important displacement Reactions: Salicylates with Sulfonylureas Phenytoin with Warfarin Aspirin & Warfarin Tissue Binding Many drugs accumulates in tissues at high concentration rather than ECF e.g Quinacrine-Liver Chloroquine-Relina Iodine-thyroid Thiopentone-Adipose tissue Tetracycline –Bone / teeth Tissue binding occurs through cellular constituent such as: Protein Phospholipids ------- generally reversible Nuclear protein It serves as reservoir and prolongs the duration of action of the drug. Consequence: Such as accumulation of drug & tissue Binding – local toxicity e.g Chloroquine –retinopathy Gentamicin—ototoxicity /Nephotoxicity. CNS & Cerebrospinal fluid Distribution of drugs into CNS from Blood is unique. Brain capillary endothelial cells have continuous tight junction, therefore drug penetration into the brain depends on transcellular rather than paracellular transport. This unique characteristic of brain capillary endothetial cells & capillary cells constitute the Blood Brain Barrier. At choroid Plexus →Blood-CSF barrier (epithelial cells joined by height junctions rather than endothelial cells) N.B: Only lipid-soluble drugs are able to penetrate and have action on CNS. Other mechanism to prevent entry drugs in brain. (i) Efflux transporters P-gP, organic anion transporter Polypeptide ( OATP) control the drug. (ii) Enzymatic BBB MAO, Cholinesterase and other enzymes Prevent entry of cathecholines, 5HT ,ACH to enter the brain in their active form. Blood Brain Barrier is deficient at CTZ ( floor of 4th ventricle) (Even Lipid insoluble drugs are emetics) N.B: Inflammation of meninges or brain increase permeability of these barriers. Significance: Important for designing drugs e.g 2nd generate Anti-histaminics Less sedating as less lipid solution.
  11. 11. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 11 Placental transfer of drugs. General determinants in drug transfer across the placenta. (i) Lipid solubility (ii) Extent of Plasma protein binding (iii) Degree of ionisation of weak acids or bases Fetal plasma is slightly more acidic than that of the mother ( PH 7.0-7.2 v/s 7.4) Therefore iron trapping of basic drugs occurs. Here also, P-Gp + other export transporters are present which limit the exposure of the fetus to potentially dangerous agents. N.B: Placental barrier is not an absolute barrier. The fetus is to some extent exposed to all drugs taken by the mother. Drug metabolism Drugs are most often eliminated by bio-transformation/ and or excreted into urine or bile. Liver is the major site of drug metabolism; Other tissues involves the kidney, intestine, lung. Half –life Plasma half life It is the time taken for the plasma concentration of a drug to fall to one half of its value during elimination (during a constant infusion). T1/2 = ln 2 x Vd CL Note: Most drugs have an alpha T1/2 and remain in plasma; due to distribution. Some drugs have beta- T1/2: they have 2 T1/2; one in plasma and one in tissues; due to elimination.
  12. 12. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 12 Examples of half-life of some drugs: Adenosine: 10 seconds Esmolol: 10 minutes Aspirin: 15 minutes Digoxin: 4 hours Digitoxin: 40 hours Amiodarone: 100 days In first T1/2: 50% of drug is eliminated In second T1/2: 75% of drug is eliminated In third T1/2: 87.5% of drug is eliminated In fourth T1/2: 93.75% of drug is eliminated In fifth T1/2: 97% of drug is eliminated Thus almost complete elimination occurs in about 4-5 T1/2. Factors affecting T1/2 1. Clearance 2. Volume of distribution 3. Plasma-protein binding 4. Types of elimination kinetics (zero/first order) 5. Pathological states 6. Active metabolites 7. Entero-hepatic recycling. Clinical significance of knowing the plasma T1/2 1. Duration of action of the drug can be determined. 2. Effective dose and dosage schedule can be planned more easily. 3. Time to reach steady state concentration and time for complete elimination of the drug from the body can be calculated. Clinical situation where plasma T1/2 is increased: 1. Decrease renal plasma flow eg CCF, cardigenic shock, haemorrhage 2. Increase volume of distribution 3. Decreased excretion of the drug, eg renal disease. 4. Decrease metabolism of the drug, eg cirrhosis. Biological T1/2 It is the time in which the pharmacological effect of a drug or its active metabolite is reduced to half. It is applicable to drugs whose effects persists long after the drug has been eliminated. Eg anti-cancer drugs.
  13. 13. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 13 Accumulation factor Whenever drug doses are repeated, the drug will accumulate in the body until dosing is stopped. This is because in theory, it will take an infinitely long time to eliminate all of a given drug from the body. In practice, if dosing interval is shorter than 4 T1/2, accumulation will be detectable. Accumulation factor = 1 Fraction lost in one dosing interval Example For a drug given once every T1/2, Accumulation factor = 1/0.5=2. Plateau principle and steady state plasma concentration, Cpss Cpss is said to be achieved when the rate of absorption of a drug and its elimination are equal such that subsequent administration of the same dose have no effect on the plasma conc. Cpss is achieved after 5 T1/2. Cpss = dose rate Clearance Note: drugs with shorter T1/2 reaches Cpss faster.
  14. 14. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 14 Target level strategy It is meant for drug whose margin of safety is small and their effects are not quantifiable. Eg Anti-arrythmic drugs Anti-epileptics In such cases, it is best to a chieve a certain plasma conc within the therapeutic range. Loading dose It is a single or quickly repeated dose given in the beginning of treatment to achieve the target conc rapidly. It is governed by the bio-availability and volume of distribution. Loading dose = target Cpss x Vd F Eg: insulin in diabetic ketoacidosis Digitalis in rapid digitalization Maintenance dose These are doses that are administered at regular interval of time to keep the steady state plasma concentration. It balances elimination. MD = CL x target plasma conc Clearance It is the fraction of the theoretical volume of fluid( plasma) that is completely cleared of the drug/unit time. CL = rate of elimination Plasma conc of the drug Significance For knowing proper dosing regimen and to maintain steady state concentration. Dosing rate = CL x Cpss
  15. 15. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 15 Kinetic of elimination First order kinetics (linear kinetics) It is the kinetic characteristic of a drug such that the rate of elimination of the drug is directly proportional to the drug concentration; clearance remains constant. 95% of drugs in use at therapeutic concentration are eliminated by first order kinetics. Examples: paracetamol, diclofenac, amoxicillin, dexamethasone, diazepam… Zero-order kinetics ( Non-linear) It is the kinetic characteristic of a drug whereby the rate of elimination of the drug remains constant irrespective of the drug concentration; clearance decreases with increase in concentration.
  16. 16. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 16 Hardly few drugs follows zero-order kinetics. Examples: alcohol, paclitaxel, azlocillin First order kinetic Zero order kinetic Constant fraction of drug is eliminated. Constant amount of drug is eliminated. Rate of elimination is directly proportional to plasma conc of the drug. Rate of elimination is independent of plasma conc of the drug. Clearance is constant. Clearance is more at low conc and less at high conc. T1/2 is constant T1/2 is less at low conc and increases with increase in plasma conc of the drug. Michaelis Menten kinetics (mixed-order kinetics/dose dependent kinetics) Examples: Aspirin, phenytoin, digoxin, warfarin, tolbutamide, theophylline.. At low doses, the drug is being handled by first order kinetics and as plasma conc of the drug rises, the kinetic of elimination changes from first order to zero-order. It may be due to: 1. Saturation of the metabolizing enzyme . 2. Saturation of the elimination process Significance The clinical use of such drugs needs proper monitoring and maintenance of their plasma concentration because small increase in their concentration may result in drug toxicity.
  17. 17. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 17 Elimination of Drugs Drugs are eliminated from the body either in unchanged by the process of excretion or converted to metabolism. N.B: Lipid soluble drugs are not readily eliminated. They have to be metabolized to more polar. Kidney most important organ for excretion of drugs Renal excretion  Glomerular filtration  Active tubular secretion  Passive tubular reabsorption Glomerular filtration depends on: (i) GFR (N 110-130 ml/min) (ii) Extent of Plasma binding. Only unbound drug is filtered. Tubular secretion  Active Process  The process requires a carrier and supply of energy  They are also subjected to competitive inhibition e.g( Penicillin + Probenecid) e.g substance secreted para-amino hippuric acid.  The Process is saturable. Tubular Reabsorption  Passive reabsorption of lipid-soluble drugs take place in distal tubule.  Very few drugs undergo reabsorption actively, e.g electrocytes /Glucose /Vitamin. N.B: Drugs which are present in Glomerular filtrate can be reabsorbed in the tubules.  In proximal and distal tubules, the non-ionised form of weak acids and bases undergo net passive reabsorption.  When tubular urine is made more alkaline, weak acids are largely ionized such that they are excreted more rapidly and to a greater extent. Eg: Aspirin + NaHCO3 N.B: Whether alteration PH results in significance change in drug elimination depends on the extent & (i) Persistance of pH change and (ii) Contribution of pH dependent passive reabsorption to total drug elimination. This effect is greater for weak acids and bases with pKa values in range of urinary pH 5-8 Biliary & fecal excretion These are applicable for substances that are principally unabsorbed orally ingested drugs or drug metabolites which are excreted either in bile or secreted into the intestinal tract and is not reabsorbed. e.g Cromoglygate, Morphine glucoronide, Chloramphenicol, Erythromycin, moxifloxacin….
  18. 18. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 18 Exhaled Air Lung is the major organ of excretion for gaseous & volatile substance e.g Anaesthetic gases. Salivary excretion Not really a method of drug excretion as the drug is swallowed again and reabsorbed. The concentration of some drugs in plasma parallels that in plasma. Therefore, saliva is a useful biological fluid to determine drug concentration when it is inconvenienced to obtain blood e.g Lithium , Rifampicin. Other ways In sweat / tear / hair/ Skin Sensitive method of detection of drugs in these tissues; have forensic significance. Examples of drugs excreted by these routes: lithium KI Clofazimine Rifampicin Breast milk Milk is more acidic than plasma. Basic lipids may be slightly more concentrated in milk e.g β-Blockers
  19. 19. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 19 Methods of Prolongation of Drug Action Advantages of prolonging the duration of action of drug. i. Frequency of administration is reduced ii. Improved patient compliance (less disturbing and less likely to forget) iii. Large fluctuations in plasma is avoided ( therefore side-effect related to peak plasma level just after dosing is minimized) Note: Drugs needed for brief therapeutics effect need not be made long-acting e.g hypnotics / headache remedy. Methods of prolonging the duration of action of Drugs 1. Retarding drug absorption 2. Retarding drug metabolism ( from liver) 3. Retarding renal excretion of the drug 4. Using compound which are highly plasma protein bound 5. Modifying the molecular structure of the drug. Retarding drug absorption 1. Oral absorption can be retarded by: (i) Giving the drug on full stomach. (ii) Giving the drug in form of SR-tablet, Spansules , Capsules. Drug with t1/2 ≤ 4hr are suitable for SR formulation. If t1/2 ≥ 12hr, there is no need for such formulation. Controlled release tablet (semi-permeable Mb to control release of drug from the dosage form); Prolong the action by (4-8hrs). 2. Parenteral absorption is retarded by: (i) Decrease vascularity of the absorption surface e.g Epinephrine with lignocaine (LA), (1:50,000-1:`00,000) Epinephrine decreases the rate of entry of LA from Local site to systemic circulation and prolongs duration of action and decrease systemic toxicity of bloodless field.
  20. 20. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 20 (ii) Reduction in solubility of the drug. Achieved by combining the drug with a compound having poor liquid lipid solubility or by giving the drug in suspension form. e.g Insulin + Zinc suspension (20-24hr) Penicillin + Procaine 12-24 hrly Benzathine penicillin 2-4 weekly. (iii) Administration of the drug in oily solution or along with water-repellent substance. e.g Aluminium monosterate delays absorption of water repellent. (iv) Combination of the drug with protein from which it is slowly released. e.g Protamine-zinc-insulin (really used now)-24-36 hrs. (v) Depot preparation e.g DMPA ( Depo-Medroxyprogestone Acetate) → 1-3 mth Give drugs in form of pellet implantation / sialistic & Bio-degradable implants. 2. Modification of their chemical structure  Esterification Steroidal sex hormone:testosterone / oestrogen ↓ When esterified with carboxylic acids ↓ Give like propiorate /Benzoate ↓ Slowly absorbed.  Pegylation (combination with polyethylene glycol) Interferon → usually administered thrice weekly Interferon + Polyethylene glycol ↓ Absorb more slowly →permitting weekly dosing.  Transdermal Delivery system e.g Fentanyl patch, Nitroglycerine patch
  21. 21. PHARMACOKINETICS LECTURE NOTES JAN/FEB 2014 21 3. Retarding drug Metabolism. Hepatic microsomal enzyme required for bio-transformation ↓ Inhibited by certain enzyme e.g MAO inhibitors  Levodopa; Duration of action increased by combining with peripheral dopa-decarboxylase inhibitor, carbidopa.  Allopurinol increased duration of action of Mercaptopurine; 6- Mercaptopurine is degraded by xanthine oxidase and allopurinol inhibits xanthine oxidase. Note: Depression of bio-transformation may alter the interior of the body by delaying the inactivation of endogenous products like steroid hormone. 4. Retarding the renal excretion of drug. Renal excretion-  Glomerular filtration  Tubular reabsorption  Tubular secretion (Active process) Excretion by glomerular filtration cannot be blocked / slowed ↓ Harmful effect on kidney But tubular secretion of certain lipid can be blocked by employing agents that shares the same tubular secretory pathway. e.g: Probenecid is used to decrease penicillin excretion /Ampicillin ↓ Prolongation of duration of action 5. Increased Protein binding of the drug in Plasma Long acting sulfonamides e.g Sulfadoxine is more highly bound to plasma protein than shorter acting sulfonamide e.g sulfadiazine (50%) Suramin- drug used in trypanosomiasis; Extensive PPB →long duration of action. 6. Drug sequesterd in Adipose tissue e.gQuinesterol ( cyclopentylester of estradiol) ↓ Prolonged duration of action. References BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12th ed. US: Mc Graw Hill. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12th ed. US: Mc Graw Hill. ROYAL PHARMACEUTICAL SOCIETY., 2012. BNF. London: BNF publication. Lippincott’s illustrated 4th edition