Routes of Drug AdministrationOralTopical (Percutaneous)Rectal or VaginalPulmonalParenteralTypes of Orally Administered DrugsPills (single dose)TabletsCoated Tablets (shell)Matrix Tablets (carrier meshwork)Capsules (gelatin shell)Troches/LozengesSolutionsPercutaneous Drug AdministrationOintment + Lipophilic creamPasteLotionGelsCan be single or multilayer, orcontained in a reservoirOther TopicalsEye DropsNose DropsPulmonary FormulationsSuppositoriesParenteral Drug AdministrationAmpulesVialsCartridge AmpulesInfusionsAdvantage: 100% Absorption,enters circulation without hepaticelim, better bioavailability ofhydrophilic drugsTypes of Barriers for DrugDistribution/AbsorptionExternal Absorption Barriers:(epithelial layer on skin, lung,intestine—Lipophilic barrier)Internal Blood-Tissue Barriers:Cardiac muscle, endocrine glands,gut, liver, CNSDrug DistributionPassive DiffusionActive TransportReceptor-mediated Endocytosis[DRUG] IS A FUNCTION OFABSORBTION ANDELIMINATION!BioavailabilityThe AUC of the administered drugdivided by the AUC of theintraveneously administered drugIV>TD>IM=SC>Rectal>Oral=InhalVolume of DistributionRate of EliminationVd=Amt of drug in the mody/[drug]R of E: Via kidney (filtration) orliver (metabolism)Usually first order kinetics3 drugs have zero-order kineticsClearanceRate of Elim/[Drug]Rate of Elim= k*Cp*VdK= ln2/T ½CL= K*VdPhase I ReactionsConvert parent compound into morepolar metaboliteAdd/unmask functional group:OH, SH, NH2, COOH, etcOxidation, Reduction, hydrolyticcleavage, Alkylation, Dealkylation,etc…Phase II ReactionsConjugation with endogenoussubstrate (increase aq solubility)Conjugation with gucoronide,sulfate, acetate, amino acidMFOMixed Function OxidasesRequire reducing agent andmolecular oxygenTwo enzymes: 1) Flavoprotein,NADPH-cytochrome c reductase2) Cytochrome P450 (electronacceptor); CYPP450 EnzymesPPAR ligands, CYP1, CYP2E,CYP2BPolymorphisms cause changes indrug metab: CYP2C19, CYP2B,CYP2D6Induction of P450enzymes=metabolize drugConjugation ReactionsGlucoronidationSulfationAcetylationAmino acid ConjGlutathione ConjFatty acid ConjCondensation ReactionMonoamine Oxidases (MAO)Catalyze oxidative deamination ofendogenous catecholamines(epinephrine)Lacated in never terminals andperipheral tissuesMany drug/food interactions!(cheese, wine)Inhib by MAO inhib Therapeutic IndexMaximum non-toxic dose/Mineffective doseDoesn’t take into account variabilitybtw indivsLD50/ED50AgonistCan be drugs or endogenous ligandsfor the receptorIncreasing [agonist] will produceincrease in biological responseFull:evokes 100% max possible effectPartial: not 100%AntagonistBlock or reverse effect of agonistNo effect on their ownCompetitive, Non-competitive,inverse agonist (triggers negresponse)Four major drug targetsReceptorEnzymeIon ChannelTransporterCa++ as a Second MessengerRegulates many cellular and phys.ResponsesGradient btw extracellular andintracellular (high:low) creates manyopportunities for regulationStored in ER and otherCa ChannelsVoltage mediated: L, N, TLigand gatedStore operated Sesnsors: Annexins, EF-handproteins, Calmodulin, ProponinCTarget of many drugs!G-Protein-coupled ReceptorsGPCR: transmembrane Bind GTP and GDP GAPS, GEFS, RGSs important inthis regulationMain Targets: Phospholipase C,Adenylate cyclaseG-ProteinsG-Proteins: Guanine nucleotidebinding proteins2 groups: Small GTP bindingHeterotrimeric G proteinsPKA Target of cAMPFour subunits (2 reg, 2 catalytic)Phosphorylates transcription factorsex: CREBRegulation of ReceptorsHeterologous desensitization(Incoming signal from differentreceptor) Homologous desensitization (onlyoccurs on receptor which has alreadybeen stimulated)Nuclear ReceptorsGC, Mineralcorticoids, RetinoidsPPARsLipid soluble ligands that penetratecell membrane, Receptors containDNA-binding domains(transcriptionalactivators/suppressors)Takes longer to act—requirespenetration and protein synth firstPhospholipidsPhospholipasesCommon fatty acid chain+glycerolbackbone+phosphor-residuePLA2 (reg through Ca++ and phos),PLC (Beta: Reg through GPCR,Gamma: EGFR or TCR, activatedthrough tyrosine phosphorylationPhospholipases…DAG: membrane bound, acts as asubstrate for PLA2IP3: Ca++ regulatedArachidonic Acid MetabolismEicosanoids: derivative ofarachadonice acidRapidly metab by COX into PG andLTs1st reaction: cyclic ring structure(COX), 2nd reaction: oxidation(Peroxidase)Function of PGsVascular tone (relaxation,constriction)Platelet agg (Inc and Dec)Uterus tone (Inc)Bronchial Muscle (Contriction,relaxation)Gastric secretion (Inib), temp/pain LeukotrienesLTC4, D4 and E4 mediate allergicrxn (SRS-A)Mediate anaphylactic shock, 10,000more postent than histamineConstricts bronchi, dilates bvLTB4 strong chemattractant formacrophageNervous SystemDivided into CNS and PNSPNS div into Somatic andAutonomousAuto: Sypmathetic andParasympatheticCholinergic ReceptorsMuscarinic Receptors:Heterotrimeric G protein coupled,CNS, gastric mucosa M1Cardiac=M2, Glandular=M3Nicotinic Receptors: Ion channelcoupled Muscle type, Ganglion type,CNS typeCholinomimetics=ParasympathomimeticsDirect Parasympathomimetics:Affinity for M or N receptors (mimicAch)Inderect Parasympathometics:Inhibit activity of Achesterase (Achincreased)To affect Paraympathetic…To Treat associated diseases….1. Mimic Input2. Block Input3. Promote Parasymp4. Block SympPilocarpineMuscarineMuscarinic Parasymp, does notactivate N rec, treates glaucoma(local! Eyedrops)Muscarine has no therapeuticapplication!CarbamateQuaternary AlcoholsAchestease Inhibitors, raise Ach Physiostigmine (topical only)NeostigmineEdrophonium (diagnose MyastheniaGravis)Horny Goat WeedAcCh-ase inhibActs as AcCh-ase inhib but activeingredient unkownIndirect stimulation of M3 receptor(vascular), triggers NOproduction=vasodilationAction similar to Viagra (dangerous)OgranophosphatesNerve GassesAcCh-ase inhibitors (irreversible) No medical applicationAtropineHyoscineMuscarinic ParasympathomimeticAtropine (antagonist of cholinergicsystem): CNS stimulant, beforeanesth. Prevent hypersecretion ofbronchial mucus, treats bradycardy..Hyoscine=CNS depressant,antiemetic,Nicotinic ParasympatholyticsCompetitive Antagonists: Competewith AcCh for N rec, preventdepolarization, reversibleAgonists: Depolarizing blockers,AcCh mimetics not hydrolyzed byAcCh-ase, trigger a sustaineddepolarization, irreversibleSuccinocholine/SuxamethoniumDimeric AcCh, Acts as agonist likeAcCh, not hydrolyzed by AcCh-ase(only plasma esterase)Depolarization
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