Dr. RAGHU PRASADA M SMBBS, MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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PHARMACOKINETICS:Pharmacokinetics is the science of the kinetics of drug absorption,distribution, and elimination (i.e, excretion and metabolism).PHARMACODYNAMICS:Pharmacodynamics refers to the relationship between the drugconcentration at the site of action (receptor) and pharmacologicresponse.

ABSORPTION:“The process of movement of unchanged drug from the site ofadministration to systemic circulation is called as absorption”.It can also be defined as the process of movement of unchangeddrug from the site of administration to the site of measurement i.eplasma.

The process whereby drug moves from the muscle,digestive tract or other site of entry into the bodytowards the circulatory system

Drugs are administered away from their site of action .To reach their site of action they are permeate fromone compartment to another by crossing the differentbarriers.So the drugs have to cross the cell membranes.

Fluid bi-layer of phospholipids.Scattered membrane protein molecules embedded inbi-layer serve as

Receptors--- selective targets for drug actionIon channelsTransporters

Lipid molecules are capable of lateral movement.It is flexibleHas high electrical resistanceRelatively impermeable to highly polar moleculesHighly permeable to lipid soluble drug molecules

1. Passive diffusionLipid diffusionAqueous diffusion

2. Carrier mediated transportActive transportFacilitated diffusion

3. PinocytosisEndocytosisExocytosis

Pores of about 10 nm and 50 to 70 nm were inferred tobe present in membranes based on capillary membranetransport studies. These small pores provide a channelthrough which water, ions, and dissolved solutes such asurea may move across the membrane.Passive Diffusion: Passive diffusion is theprocess by which molecules spontaneouslydiffuse from a region of higher concentrationto a region of lower concentration. This process ispassive because no external energy isexpended

Important for drug molecules too large or too insolublein lipid to diffuse passively through membranes.Carriers are trans-membrane proteins.The drug molecules chemically related to naturallyoccurring peptides, amino-acids, or sugars can usethese carriers.Carrier binds one or more molecules or ions, changesconformation & releases them on the other site ofmembrane.

Main sites:Renal tubule.Biliary tract.Blood brain barrier. (BBB)Gastrointestinal tract. (GIT)

Types:Active TransportFacilitated Diffusion:

Active transport: The characteristics are:Against the concentration gradientEnergy dependent , obtained from hydrolysis of ATPCarrier is requiredSelectiveSaturableCompetitive inhibition by another drug binding to samecarrier.

Reverse transporters: Carriers specialized in expellingforeign molecules as the enter the cells.

One large family is ABC (ATP binding cassette ) familyIt includes P-glycoprotein or multidrug resistance type1 (MDR1) transporter, found in the brain, testis &other tissues and in some drug resistant neoplasticcells

It can be inhibited by grape fruit juice & certaindrugs i.e VERAPAMIL.2. Multidrug resistance –associated protein (MRP)transporters play important role in excretion of drug orits metabolites into urine or bile.

Facilitated Diffusion: A mechanism to enhancediffusion of drugs with low lipid solubility.Along a concentration gradientCarrier mediated: Carrier increases lipid solubility ofdrug →↑rate of diffusionNot energy dependentSaturableCompetitive inhibitione.g. Glucose entry into the cell by Glucose transporters-GLUT1-GLUT5

Specific receptors for transport proteins must bepresent for this process to work.Endocytosis: Drugs which have very large molecules(macromolecules) can be engulfed by the cellmembrane in a vesicle & carried into the cell &released within the cell by pinching off the vesicle &breakdown of its membrane.Examples:Transport of vitamin B12 with a binding protein (intrinsic factor) across gut wall.Iron is transported into hemoglobin synthesizing RBCsprecursors with transferrin.

Exocytosis is the reverse of endocytosis.It isresponsible for secretion of many substances fromcells. e.g. Expulsion of neurotransmitters into thesynaptic cleft.

The neurotransmitter substances are stored inmembrane bound vesicles in nerve endings toprotect them from metabolic destruction .

Appropriate activation of nerve ending causesexpulsion of its contents in to the synaptic cleft.

Solid dosage form

Granules oraggregates

Fine particles

Drug in solutionAt absorption site

Ionic drug Ionic drug

Non-ionic drugNon-ionic drug1

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3

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BloodGI Lumen GI Barrier

Sequence of events in the absorption of drugs from orally administeredsolid dosage forms

Physicochemical/ Pharmaceutical factors:Drug solubility & dissolution rateParticle size & effective surface areaPolymorphism & amorphismPseudoploymorphism (hydrates/solvates)Salt form of the drugLipophilicity of the drug pH- Partition-hypothesispKa of drug & gastrointestinal pHDrug stability

Physicochemical/ Pharmaceutical factors :Disintegration time (tablets/capsules)Dissolution timeManufacturing variablesPharmaceutical ingredients (excipients/adjuvants)Nature & type of dosage formProduct age & storage condition

Pharmacokinetic factors :Route of administrationMembrane physiology

a) Nature of cell membraneb) Transport processes

AgeGastric emptying time and Intestinal transit time

Gastrointestinal pHDisease statesBlood flow through the GITGastrointestinal contents: a) Food- drug interactions

b) Fluids c) Other normal GI contentsPresystemic metabolism by: (first pass metabolism)

a) Luminal enzymes b) Gut wall enzymes

PHYSICOCHEMICAL/PHARMACEUT-ICAL FACTORS

1) Drug solubility & dissolution rate :The rate determining steps in absorption of orallyadministered drugs are:1. Rate of dissolution2. Rate of drug permeation through the biomembrane.Dissolution is rate determining step for hydrophobic &poorly aqueous soluble drugs.

E.g. Griseofulvin & Spironolactone.Permeation is the rate determining step for hydrophilic& high aqueous soluble drugs.

E.g. cromolyn sodium OR Neomycin.

2) Particle size and effective surface area:Particle size may play a major role in drug absorption.Dissolution rate of solid particles is proportional tosurface areaSmaller particle size, greater surface area then higherwill be dissolution rate, because dissolution is thought totake place at the surface area of the solute( Drug).Particle size reduction has been used to increase theabsorption of a large number of poorly soluble drugsE.g. Bishydroxycoumarin, digoxin, griseofulvin

We have to reduce the size of particles up to 0.1 micronto increase surface area of absorption. So these can beachieved by “micronisation process’’.a) HYDROPHILIC OR b) HYDROPHOBICa) HYDROPHILIC DRUGS:In hydrophilic drugs the small particles have higherenergy than the bulk of the solid resulting in anincreased interaction with the solvent. Examples,1.Griesiofulvin – Dose reduced to half due tomicronisation.2.Spironolactone – the dose was decreased to 20 times

3.Digoxin – the bioavailability was found to be 100% inmicronized tablets.After micronisation it was found that the absorptionefficiency was highly increasedb) HYDROPHOBIC DRUGS:In this micronisation techniquies results in decreasedeffective surface area & thus fall in dissolution rate.

The hydrophobic surface of the drugs adsorbs airon to their surface which inhibits their wettability.Ex Cyclosporin

Drug stability:A drug for oral use may destabilize either during its shelflife or in the GIT.Two major reasons for poor bioavailability

-Degradation of the drug into inactive form and-Interaction with one or more different component(s)either of the dosage form or those present in the GIT toform a complex that is poorly soluble or is not absorbable

Many drugs are weak acids/basesCan be ionized, unionizedVaries with pH of environment

Acids release H+Strong: All H+ releasedWeak: Some H+ released

Ka quantitates strength of acid

Oral – 5<100% bioavailabilityFirst pass effect is significantAbsorption in small intestine is primarily dependent onphysico-chemical propertiesNon ionised compounds –ethyl alcohol and Low molecularweight substances –urea readily cross cell membraneRectal -30<100% bioavailabilityOnly about 50% of the rectal dose may pass through liver(external haemorrhoidal veins).Barriers here are colonial mucosa, anaerobic organismsand enzymatic activity E.g. Metoclopramide, ergotamine,

lidocaine

Absorption of Drugs Lung – gases, liquid droplets5<100% bioavailabilityThe drug can have local effects - Epinephrine for asthma.The drug can have systemic effects - general anesthetics.

Large surface area, limited thickness of pulmonarymembrane and high blood flow allow for almost instantabsorption by diffusion Avoid first pass effect

Lungs are also site of first pass excretion

Bioavailability characteristics withdifferent routes

Intra-arterial: nearly 100% bioavailableIntra-arterial injection is used to deliver drugs directly to organs, forexample, in cancer chemotherapy, and in the use of vasopressin for GIbleeding.Intrathecal: nearly 100% bioavailableInjection directly into the cerebrospinal fluid (CFS) ensures completeCNS bioavailability for drugs that can not cross the blood-brain barrier.E.g. Mepivacaine and prilocaine for spinal anesthesia.Intravenous (IV): nearly 100% bioavailabeIV administration introduces drug directly into the venous circulation.IV bolus is used for immediate therapeutic effect, typically for generalanesthesia and for treatment of cardiac arrhythmia.

Intramuscular (IM): nearly 100% bioavailableFor drugs and vaccines that are not absorbed orally, forexample, aminoglycosides, insulin and hepatitis vaccine.The IM route is often used for sustained medication andspecialized vehicles, such as aqueous suspensions, oilyvehiclesTopical route:Transdermal: 80<100 % bioavailableContinuous release of drug over a specified period, lowpresystemic clearance, and easy drug withdrawal by simplyremoving the device, and good patient convenience andcompliance.

Intranasal:Intranasal administration may be used for local or systemiceffects. Local effects include treatment of nasal allergies,rhinitis, and nasal congestion. Nasal delivery for systemiceffects is established for a small number of drugsE.g. Vasopressin analogues and oxytocin are commerciallyavailable for intranasal dosage.Vaginal: vaginal absorption can give rise to rapid andefficient systemic delivery.E.g. vaginal rings and biodegradable microspheres

Sublingual/Buccal:Drugs can be absorbed from the oral cavity itself orsublingually. Absorption from either route is rapid,sublingual more so apparently because of greaterpermeability of sublingual membranes and rich bloodsupply.E.g. organic nitrates, barbiturates, papaverine,prochlorperazine, benzodiazepines.

Bioavailability is defined as the fraction ofunchanged drug reaching the systemiccirculation following administration byany routeFactors influencing bioavailability

First pass metabolismSolubility of drugChemical instabilityDrug formulationEnzyme inductionIndividual variation

The tmax is independent of dose and is dependent on the rateconstants for absorption (ka) and elimination (k)

At Cmax, sometimes called peak concentration, the rate of drugabsorbed is equal to the rate of drug eliminated. Therefore, thenet rate of concentration change is equal to zeroAUC is a measure of the body’s exposure to a drug

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The AUC-Area Under Curve is expressed in the units ofmg-hr/mlPlanimeter –an instrument for measurement of area ofplane figuresCut and weigh method- that means to cut out the areaunder the entire curve on rectilinear graph paper andweigh it on analytical balanceMathematical –using trapezhoid rule

When drug is absorbed across the GI tract, it enters theportal circulation before entering the systemic circulation.Here some part of drug gets metabolized and amount ofunchanged drug that gains access to the systemic circulationis decreased. Ex- lidocaine, morphine, nitroglycerine,propranolol

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