Pharmacokinetics 1&2 - Absorption & Bioavailability PDF

Pharmacokinetics 1&2 Absorption& Bioavailability Dr.Bindu Susan Varghese  Session Learning Outcomes(SLO) At the end of the lecture the student should be able to: Recall the mechanism of transport across membranes and factors affecting transport. Elaborate on passive diffusion and...

Pharmacokinetics 1&2 Absorption& Bioavailability Dr.Bindu Susan Varghese  Session Learning Outcomes(SLO) At the end of the lecture the student should be able to: Recall the mechanism of transport across membranes and factors affecting transport. Elaborate on passive diffusion and factors affecting it. Explain the principles of absorption of a drug. Define bioavailability and bioequivalence. List the factors affecting absorption and bioavailability. Describe first pass effect/pre systemic elimination. Explain pharmacokinetic interactions and variations in What happens to the drug in the body OR what the body does to the drug. drugreachtocirculation  Membrane transport Passive diffusion Facilitated diffusion Carrier mediated Active transport Endocytosis Filtration  Passive diffusion notrequireEnergy HIGHER LOWER  mostofdrug Passive diffusion is weakacid weak electrolyte Higher concentration to lower No energy required Alipidsoluble nonchargeddrug crossing Nonelectrolytes; depends on lipophilicity Weak electrolytes: Partially ionized, depends on fractionblwionizedronionized lipid solubility, degree of ionization; pH of surrounding; pKa(dissociation constant). Henderson Hasselbach’s equation ; 4084160Wh pH = pKa + log ionised fraction (eg:weak ACID) nonionised fraction pKa is constant for any drug. From Henderson Hasselbalch’s equation OWN conc of nonionized acid(AH) pKa (Acid) = pH + log conc of ionized acid (A-) conc of ionized base(HB+) pKa (Base) = pH + log conc of nonionized base(B) * pKa values remain constant for a drug.  factor affect TAMIA theionization ofthedrug pad d pka Degree of ionization is altered in opposite gggentiestine directions for weak acids and bases as pH varies. mostofdragonionized apitsdragaionized Gatpito stomachis acidicwhen whentheyco Pkap 4 yourakewake toAcidicpH Weak acid acidicthe drug Weak base theywillbee gotofdrug absorption ionized ionizedunionized whengoutakeweak baserthestomachisacidic ionizedin basicdrug thesoy thearagwinbeionizedcannotcross basicmedium whengotoacidic themembranegoestointestinewhichisbasic intestine environmentthey andnepinonoizedthedrug y 9Absorption haveavilabilityt blueheightted whenthedrug is impinfo completelyunionized Implications Orionized Generally stronger the acid, the lower the pKa value. Stronger the base, higher the pKa value. When pKa equals the pH of the surrounding, 50% is ionized and 50% is nonionized. For every upward or downward shift in pH, there is 10 fold increase or decrease in the ratio. Weak acids are mostly nonionized in acidic pH and weak bases are nonionized in basic pH and vice versa.(cross membranes by diffusion in similar pH) Strong acids, bases and quartenary compounds remain mostly ionized at standard pH.(do not cross easily)  lessionized ionization MoisthentighedAbsorption acid in Acidicstomach conionzed Yggk medium Ion trapping Pigneimerdafekhentgocrgsthesmanintestinecbasicstructres Acidic drugs are ion trapped in basic pH and basic drugs in acidic pH. Hence cannot cross membranes by diffusion. Examples are:- The nonionized form of weakly acidic drug allowed Aspirinnot instomac be of aspirin(pKa 3.5) crosses the gastric mucosa (pH2), cannotfurthermore reaches the cell (pH 7) and becomes ionized. This do till Cdistrubtion contributes to gastric mucosa damage by aspirin. Barbiturates(weak acid) normally when they toprev reach acidic urine they are reabsorbed. But are Mhow poisni write ion-trapped in alkaline urine. Hence are excreted.become Acidifytheorineinbasicdrug I Akal  Carrier mediated-Facilitated diffusion notrequireenergy HIGHER LOWER Carrier mediated- Active transport LOWER HIGHER  Carrier mediated Facilitated diffusion Active transport Higher concentration to Lower concentration to lower higher No energy required Energy required as ATP Carrier usually a protein Carrier usually a protein Separate for acidic and Separate for acidic and basic drugs. basic drugs. a wi Capacity limited of incarrier a Capacity limited drug w shin carriers 61swam 1 a Two drugs can compete Two drugs can compete for the same carrier. for the same carrier. Aminoacids in brain, P glycoprotein is an active vitamins like B12. transporter*. forcarrieracidicdrug Albumin isImp  Primary and Secondary: Active transport UNIPORTER SYMPORTER ANTIPORTER Endocytosis  Pharmacokinetics ABSORPTION EXCRETION DISTRIBUTION METABOLISM  Absorption When the drug moves from the site of administration into the blood stream; it is said to be absorbed. GI tract Absorption Parenteral(im,iv,sc) Lungs Skin Exceptions are: sublingual and rectal Iftdirectyintosucby portalsystem Passtheportalsystem bypass  Gastrointestinal absorption Sublingual Blood Bypassing liver vessel Lipophilic, neutral and basic (very little) not muchabsorpedfromthemouth Lipophilic, neutral and acidic stomach mostofdrugabsorpin Acidic drugbestabsorpedinacidicuedium Lipophilic, neutral and Rectal basic drugs along with Bypassing liver some acidic drugs most basicdruggorointestinebczitisbasica whereisthebasicdrugabsorb Intestinehaversurfaceareasoitcanabsorpacid stomach draginintestinemostlybutlithenotas smallintestine wheretheacidicdrugabsorp stomacassomerineinsman Very little basic and intestine gastroinvestialroutefor neutral drugs waterabsorp orallydrugs colon  Parenteral absorption Intravenous - completely absorbed Intramuscular and subcutaneous enter plasma or lymph by diffusion. May enter capillaries directly through endothelial cells. Absorption from muscle is much superior to subcutaneous as muscle is highly vascular. Skin  Lungs/Alveolar General anesthetics Aqueous form of drugs like salbutamol Suspended microfine particles by inhaler Simple diffusion occurs Large surface area and vascularity contribute to good absorption. intestine MAbsorption is asurface inintestine Area  Skin Intact skin does not allow drugs to permeate easily. Abraded skin enhances absorption. Dermis allows absorption of lipid soluble drugs. Eg: Drugs given as transdermal patches. doesnot Epidermis allowed absorp to anything the if drug 4reachtodermiswillbe absorped site tothe givingcloser treat youwantto that  Methods to enhance absorption theat Hot fomentation,massaging.(only highly lipid soluble) Mbreakdownfibroustissuetot Absorption Hyaluronidase an enzyme breaks down intercellular matrix, increases rate of diffusion and in turn absorption; mainly incorporated in i/m injection preparations.  Methods to delay Absorption Using different formulations like slow release, ofdrug wehavemultiplelayer sustained release depot and subcutaneous implants. Physical characteristic of the drug. Eg: Amorphous form is rapidly absorbed, while the crystalline form is slowly absorbed. Adding a vasoconstrictor Adding epinephrine to lidocaine a Intensifying Constriction Adrenaline local anesthetic, retards systemic absorption and thus 1. prolongs duration of action 2. minimizes systemic toxicity(lidocaine can cause arrhythmias and seizures.  AfterItakenthe drughowmuchof Bioavailability (F) thedrugisreachtoblood Usef todetermine Alwaysto thedosage 100t isreachthe blood The fraction of a drug reaching systemic circulation in unchanged/active form. It determines the rate and extent of absorption. Bioavailability after IV = 100% or Bioavailability factor is 1 Other routes < 1 ◦ Incomplete absorption from site of administration ◦ Partial destruction in GIT ◦ Metabolism in liver  theconccurve Areaunder Bioavailability (F)  Bioavailability (F) AUC (oral)= amount of drug in the plasma after oral. AUC (iv) is amount of drug in the plasma after i/v AUC is expressed as mg hr/L. Bioavailability on i/v is 100% Other route will1001fthan have Bioavailability(oral)= AUC (oral) x 100 www.w MY AUC (i/v) When doses are same for oral and i/v  Bioequivalence pipewas61 BE W Two drugs are bioequivalent if they show comparable bioavailability and similar time to achieve peak plasma concentrations. Data on bioequivalence of a drug formulation, helps avoid complications arising from product substitution. The FDA does not recommend substituting drugs that have not been determined to be bioequivalent.  Bioequivalence Two formulations of a drug given orally Rate of absorption- not similar (Cmax and Tmax are different and there is a significant difference of more than 20% in AUC of both. Then the formulations are not bioequivalent and are said to be Bioinequivalent  Factors affecting absorption and bioavailability Pharmaceutical Particle size Tablet/ capsule Disintegration Fine particles (powder) Dissolution Drug in solution Absorbed Quick absorption when given as a solution.orpowder  Factors affecting absorption and bioavailability  Crystal form- crystalline form takes more time, while amorphous dissolutes faster because it is easier to break intermolecular bonds.  Water of hydration: anhydrous dissolutes quicker. notcontainwatermolecule  Properties of excipient/ additivesC Italia am out I dm 066  Degree of ionization/lipophilicity  Factors affecting absorption & bioavailability Pharmacological  First pass effect/presystemic elimination  Gastrointestinal emptying time  Gastrointestinal diseases  Presence of food/interaction with food  Pharmacogenetic factors  First pass effect/Presystemic toliver elimination thedrug reducethefirst will pass livernotfunctiont mostdrugreachthe After the drug enters probly blood morebioavilabilyB Toxcityoccur patienthave Alcholic hypertension thentBP moreblood GI tract: reachthesystemiccirculation  Drug undergoes Adrughave afirstpass metabolism in: willnotgive Orallybozdrug Intestinal lumen willnotfunction well Intestinal epithelium Portal vein Hepatocytes  As a result Bioavailability reduces.  Factors affecting bioavailability contd how much thingsismorefrom stomachtointestine Gastric emptying time & GI motility longertimeinstomach  Slow gastric emptying (longer time in the stomach)enhances absorption of weak acids from stomach and vice versa.  Enhanced gastric emptying facilitates absorption of mostly all bases and few acids from the intestine.  Enhanced intestinal motility reduces absorption from intestine and vice versa. Constipation and diarrhea can alter bioavailability of most of the drugs absorbed from the intestine. Speed of gastric emptying is inversely proportional to gastric emptying time. at108 W W M 08 W  Factors affecting bioavailability-contd Gastrointestinal diseases Achlorhydria: gastric pH increases; absorption is altered Malabsorption syndrome/ coeliac disease; bioavailability varies for different drugs. Pharmacogenetic factors from totheepithelium intestial M INH is an anti tuberculous drug which is metabolised by acetylation even before it reaches the systemic circulation. In slow acetylators, the bioavailability is high compared to fast acetylators in whom the concentration of the drug falls rapidly.  Not Rememberthedrug Interaction with food Rate and extent of absorption of rifampicin is reduced in the presence of food. Absorption of tetracycline is reduced in the presence of milk. Absorption of griseofulvin is enhanced in the presence of fatty food. Absorption of phenytoin is enhanced after food due to bile secretion. Pharmacokinetics 3 Distribution Dr Bindu Susan Varghese  Session Learning Outcomes(SLO) At the end of the lecture student should be able to: Describe the phenomenon of distribution. Explain plasma protein binding of a drug and its clinical significance. Define apparent Volume of distribution(aVd). Explain the factors modifying Apparent volume of distribution.  Distribution Once a drug reaches circulation, it gets distributed to regions which are relevant as well as irrelevant EMINE to its therapeutic TEHAN effect. 2 2 1IN Drugs may be evenly, unevenly or selectively distributed. Central compartment consists of blood(plasma) and highly vascular organs. Peripheral compartment may be single/multiple. poutsidesheblood Eg: ECF, ICF and tissue reservoirs like muscle, adipose tissue, bone etc. Retina CT Drugs obey one, two or multiple compartment models  Absorption Peripheral compartment 1 Central Peripheral compartment 2 compartment Elimination Everythingback toCc thendominated only this occurs from  ONE COMPARTMENT drugonlyincc theneleminated Absorption TWO COMPARTMENT centralt aperipherale Peripheral compartment 1 Central Peripheral compartment 2 compartment Elimination MULTIPLE COMPARTMENT Distribution α phase α distribution alyfalls Rapid β phase β elimination exeterykinatic Metabolism Excreation IV Route  Distribution One compartment Two/multi compartment (no α phase) Nodistrubtion fordrug  Drugdistributed146 insideECF more Distribution fromtheplasma Thevolumeofdrugis45 wherethedruggone towholebody drughasgoneto3000lit be it isexcessively distrustedtoourtiss  Storage Distribution-drug reservoirs Cellular / tissue reservoirs 81boow X SW Digoxin and emetine in sk.muscles,heart, liver and kidney Chloroquine in fat, liver, retina Fat Thiopentone, DDT Bones and connective tissue Tetracycline, arsenic, cisplatin form complexes with bone salts. Plasma protein binding drugnotcross theplasma become theblood inbleed resiroverinside  Plasma protein binding Drugs bind to plasma proteins in a reversible manner and dynamic equilibrium. Free drug + protein Drug protein complex Excessive plasma protein binding serves as a circulating drug reservoir. Cannot cross membranes. Remain withintheplasmabutas astorageform But when free drug levels fall, bound drug dissociates to become free drug. Albumin and α1 Acid glycoprotein are major plasma proteins Acidic drugs generally bind to albumin Basic drugs bind to α1acid glycoprotein.  Plasma protein binding ja HE PP binding is capacity limited and saturable. Highly PP bound drugs are restricted to the Freedrug binding Cannotcross protien dialysisM you vascular compartment. cannotremovethe drugthatisbindtopp Highly PP bound drugs do not cross membranes; are not removed by dialysis, hence special techniques required in poisoning.  Clinical significance of PP binding UricacidRelatedtoprotienmetabolism Aurea kidneydiseas 1. In liver disease and uremia, albumin is low, so free drug concentration of weak acids can be high. pinflamenatrypouldisease 2. In crohn’s disease, inflammation and physiological stress, acute phase reactants like α1 acid glycoprotein are elevated. So plasma protein binding for some basic drugs increases; free drug decreases.  Clinical significance of PP binding- contd 3. Two drugs can bind to albumin and compete for the albumin. This can lead to displacement interactions leading to toxicity of either. bag wartime outalbumias.eeW wgwarfintoxcirypa2na Eg: salicylates and phenytoin displace warfarin from Thighyppbound protein binding site. If a drug is 99% PP bound, 1% is free. If 1% is displaced, 99% becomes 98.01% and 1% free becomes 1.99%( doubled).  Apparent volume of distribution(aVd) The volume of fluid that would accommodate all the drug in the body, if the drug was distributed equally throughout and the concentration anywhere was same as that of plasma. Because Vd is not a real volume, it is referred to as an apparent volume(aVd). Distrubted ofdrugtobody to I inplasmaofdrag 9,9 jiggygdney Ickes thatmeanthedrughas win15 distrusted extensively Vd = Amount of drug in the body Drugalmostinplasmathat is thedrugnot mean distrabel Plasma concentration Lower the aVd means drug is less distributed and pasmanofblood vice versa. Apparent volume of distribution(aVd/Vd) Heparin 4 L plasma Tolbutamide 7 L mpgfromplasma Aspirin 11 L btwECF Prazosin 42 L Totalbw Digoxin 500 L Chloroquine 13000 L i aVd is expressed as L/70 kg we11LNWADI Is AE ta DD ECEnNUM 291  Factors modifying Volume of Distribution Physiological In pregnancy aVd is increased due to increase in plasma volume. Pathological - aVd may be increased in renal failure(water retention) - In liver disease aVd increases due to less albumin synthesis, leading to more unbound drug. - aVd decreases in severe dehydration. t 2 litreducedvolumedistrubeted toyole distrubtionof42now plasmac 9thanwhat youException  Summary aVd = total drug given/plasma conc aVd is inversely proportional to plasma concentration. If plasma conc is very low, it means the drug is extensively distributed. If plasma conc is high(includes pl protein bound drugs), then aVd is minimum.  IV IM got youall Absorption Bioavilability CmaxTmax Area in CurveAUC Absorptionistin IU oralhastheleastbioavilabity Age Genetic Routeofdrug pct and Extinsevelydistrusted to thetissue cholroquine Jj in retina liver we go 0665p wow own I