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DefinitionPharmacology (Pcology) is the science of drugsOswald Schmiedeberg regarded as the father of pharmacologyDivided in several branches likePharmacokineticsPharmacodynamicsPharmacotherapeuticsChemotherapy and toxicology etc.The two main division for our study are Pharmacodynamics and Pharmacokinetics

PCODYNAMICS

PKINETICS

Routes of drug administration (R.O.A.)IV:Intravenous, IM:Intramuscular, SC:Subcutaneous, SL:Sublingual, TD:Transdermal

R.O.A., Some IMP. Points ContdLocal Routes:Very low or no systemic absorptionSystemic Routes:Oral: Safer and Economical, some drugs are ineffective because of High first Pass Metabolism (eg. nitrates, lignocaine, propranolol, ), Degradation (Insulin, penicillin G)Sublingual: Avoids First Pass Metabolism , Used in Emergencies, Only lipid soluble and non irritating drugs (eg. of drugs administered by this route Nitroglycerine, isosorbidedinitrate etc.)Transdermal: Only for drugs Highly lipid solubleNasal: eg. Nafarelin (GnRH agonist), calcitonin and desmopressinInhalational: Rate of drug delivery can be controlled like I.V. Infusion, antiasthmatic and inhalational anaesthetic agentsRectal: Avoids first pass metabolism upto 50% (Diazepam in febrile seizures)Intravenous: Bolus(Dose injected at once) or Infusion(Continuous delivery over a period of time)Intradermal: Through Bleb, Vaccines

PHARMACOKINETICSADME study: Absorption, Distribution, Metabolism, ExcretionABSORPTION:

1. Absorption contdSo, for absorption of drug from biological membrane it should be present in unionised lipid soluble formIonisation depends on pH of surrounding medium and pKa of drugLets make it simple, ABSORPTION WILL OCCUR WHEN MEDIUM IS SAME, Means acidic drugs will remain unionised in acidic environment and get absorbed while basic drugs will remain unionised in basic environment and get absorbedIonisation of a drug is neither 100% nor 0% (Weak acids or bases), therefore a drug should never be 100% lipid or water soluble

Absorption (contd)pH-pka relationship pka is the pH at which drug is 50% ionised and 50% unionisedAcidic drug will remain unionised in acidic medium but will ionise in basic medium and basic drug will remain unionised in basic medium and ionise in acidic mediumSuppose an acidic drug having pKa of 4 was placed in pH 4, it will be 50 % ionised and 50% unionised, NOW same drug is kept in medium of pH 3 (acidic), it remains lipid soluble. But, if it is kept in pH 2 what will happen, obviously it becomes more lipid soluble because more of the drug is un-ionised, But Numerically HOW MUCH???Concepts:If the pH of the medium is less than pKa (Medium becomes acidic)For Acidic drugs, unionised form increases and ionised form decreasesFor Basic drugs, ionised form increases and unionised form decreasesIf the pH of the medium is more than pKa (Medium becomes basic), opposite happens

Ionised or Unionised fraction depends upon difference (d, only magnitude) between pH and pKaWhen pH=pKa, d=0, 50% ionised 50% unionisedWhen pH-pKa=1, d=1, one form is 90% and other is 10%When pH-pKa=2, d=2, one form is 99% and other is 1%When pH-pKa=3, d=3, one form is 99.9% and other form is 0.1%Example: (Acidic drug, pKa=3)

Absorption (contd)pH of medium(pH-pKa)Ionised from %Unionised form %3.0050504.0190105.029916.0399.90.1

BioavailabilityFraction of administered drug that reaches into the systemic circulation in the unchanged form

By IV route it is 100%

Presystemic or first pass metabolism

Bioavail. (contd)

Fig. Plot between plasma conc. and time to calculate bioavailabilityIt can be calculated by comparing AUC (Area under the curve) for I.V. route and for the desired route or can also be calculated by comparing excretion in urineAUC tells about extent of absorptionTmax tells about rate of absorptionCmax is max conc. obtained in plasmaBioequivalence = 20% bioavailability

MEC: Min. effective conc., MTC: Max therapeutic conc.

2. DistributionAfter drug reaches to the blood it is distributed to many tissues, which is determined by a hypothetical parameter Volume of Distribution (Vd)It is the volume that would be required to contain the administered dose if that dose was evenly distributed at the at the conc. measured in plasmaHigher Vd means more amount of drug was entering in tissueDepends on lipid solubility and protein bindingLipid soluble drug crosses blood vessel easily and thus have high VdIf a drug is highly bound to plasma protein it behaves like a large molecule and unable to cross the blood vessel, thus goes less into the circulation and have low Vd Only free form (not bound to plasma protein) of drug is responsible for action as well as metabolism of a drug. Thus, Plasma protein binding makes drug long acting by reducing its metabolism

Distribution (contd)

Distribution (Contd)After a drug reaches plasma there are four possibilities:

IonisationMolecular WeightDescriptionVdHighly ionised (Water soluble)HighNot able to cross blood vessel Low (around 3 L, Vol. of plasma)Highly ionised Low Some of it can reach interstitial fluidAround 14 L (Vol. of plasma + Vol. of Interstitial fluid)Un-ionised (lipid soluble)LowEnter in cell alsoHigh 42 (plasma+ISF+ICF)Un-ionisedLowHigh affinity for tissuesVd even greater than total body water (>42 L)

3. Metabolism (Biotransformation)Chemical alteration of the drug in the bodyNeeded to render the nonpolar (lipid soluble) compounds into polar (lipid-insoluble) to excrete them outside the bodyPrimary site is liver, others are kidney, intestine lungs and plasmaBiotransformation of drug may lead to following three events:

1. InactivationMost drugs render inactive or less active metabolites

2. Active metabolite from an active drugMany drugs are partially converted to one or more active metabolites;

Active DrugActive MetaboliteChloral hydrateTrichloroethanolMorphineMorphine-6-GlucoronideCefotaximeDesacetyl cefotaximeAllopurinolAlloxanthineProcainamideN-acetyl procainamidePrimidonePhenobarbitoneDiazepamOxazepamDigitoxinDigoxinImipramineDesipramineAmitriptylineNortriptylineCodeineMorphineSpironolactoneCanrenone

Metabolism (Contd)3. Activation of inactive drugProdrug concept

ProdrugActive formLevodopaDopamineEnalaprilEnalaprilatDipivefrineEpinephrineProguanilCycloguanilPrednisonePrednisoloneBacampicillinAmoxicillinSulfasalazine5-Aminosalicylic acid

Metabolism (Contd)Biotransformation reactions are of two types:

1. Nonsynthetic/Phase I/Functionalisation reactions:Functional group is generated or exposedMetabolite may be active or inactiveMajor reactions involved are:Oxidation (Major), Reduction, Hydrolysis, Cyclisation, De-cyclisation

2. Synthetic reaction/Phase II Conjugation by endogenous substrate to form a highly polar water soluble compound which is easily excretedMajor reactions involved are:Glucuronide conjugation (Major), Acetylation, Methylation, sulphate, glycine, or glutathione conjugation

Metabolism (Contd)Metabolism may occur with the help of:

Microsomal enzyme: present in smooth endoplasmic reticulumEx; monooxygenases, cytochrome P450, and glucoronyl transferasesMay be induced or inhibited by other drug

Non microsomal enzyme: present in cytoplasm and mitochondriaEx; flavoprotein oxidases, esterases, amidases and conjugasesNot inducible by other drugs but shows genetic polymorphism

Metabolism (Contd)Drug metabolising by microsomal enzyme is called as substrate and chemical increasing or decreasing that enzyme is called as inducer or inhibitor respectively

Enzyme Inducers

Enzyme inducerGGriseofulvinPPhenytoinRRifampicinSSmokingCell CarbamazepinePhonePhenobarbitone

Enzyme inhibitorsEnzyme inhibitorsVitamin ValproateKKetoconazoleCannotCimetidineCauseCiprofloxacinEnzymeErythromycinInhibitionIsoniazid

Cytochrome P-450450 denotes their strong absorbance at450nmSuperfamily of microsomesCYP3A4 is involved in metabolism of 50% drugsRoot wordFamilySub-familyGene numberCYP3A4

Nomenclature

Hoffman eliminationInactivation of the drug in the body fluids by spontaneous molecular rearrangement without the agency of any enyme, eg; Atracurium

4. ExcretionPassage out of systemically absorbed drugMajor route is kidney; involves glomerular filtration, tubular reabsorption and tubular secretion1. Glomerular filtration: Depends on plasma protein binding and renal blood flow. Does not depends upon lipid solubility because all substances crosses the fenestrated glomerular membrane2. Tubular reabsorption: Depends on lipid solubility

Lipid solubility depends on ionisation, ionised drug will be excreted

Barbiturates, salicylateSodiumbicarbonateAcidic drug in basic mediumMorphine, amphetamineAmmonium chloride

Excretion (contd)3. Tubular secretion: Does not depend on lipid solubility or plasma protein binding. Separate pump for acidic and basic drugs are present in nephron; drug utilising same pump may show drug interaction; eg. Probenecid decreases excretion of penicillin

Kinetics of elimination

Pharmacokinetics model may be one or two compartmentOne compartment Model:Drug having less or no distribution in tissues, elimination is continuous and the log plasma conc. vs time curve is linear (frst order kinetics)

One compartment model

Log scaleSlope of this curve is k (rate constant)Clearance = k * Vd k = 0.693/t1/2 CoExtrapolation of this curve on y-axis is Co used to calculate Vd

Vd= Dose/Co

Some imp formulaRenal clearance:Renal cl.= uv/p

Total body clearance = rate of elimination/pu = urine conc. of drugv = rate of urine flowp = plasma drug conc.

Order of kineticsDrug may follow zero or first order kineticsRate of elimination (plasma conc.)orderFor zero order kinetics, (plasma conc.)0 is equal to one, it means rate of elimination is independent of plasma conc. or it is constantFor first order kinetics rate of elimination is proportional to plasma conc.

First order kinetics (linear)Zero order kinetics (Non linear)Constant fraction of drug is eliminated per unit timeConstant amount of drug is eliminated per unit timeROE proportional to CoROE independent of CoClearance (Cl) remains const.Cl is more at low conc. and less at high conc.Half life (T1/2)remains const.T1/2 less at low conc. and more at high conc. Most drugs follow first order kineticsVery few drugs eg; Alcohol

Half life (t1/2)Time required to reduce the plasma conc. half to its original valueIt is a secondary Pkinetic parameter derived from two primary Pkinetic parameter Vd and clearance (Cl)Determines dosing interval and time required to reach steady state conc. Does not affect dose of the drug t1/2 = (0.693 * Vd)/Cl

ReferencesGarg GR, Gupta S. Review of Pharmacology, sixth edition, 2012, Jaypee publishers, New DelhiTripathi KD. Essentials of medical pharmacology, sixth edition, 2008, Jaypee publishers, New Delhi

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