Medwiki.students.jh.edu



PharmacokineticsPharmacokinetics vs. pharmacodynamicsPharmacodynamics deals withWhat the drug does to the bodyVarying the drug effects by varying the drug amountChoosing between effective concentration and acceptable toxicityA concentration responseDeciding on the targetPharmacokinetics deals withWhat the body does to a drugVarying the drug concentration with space and timeHitting the targetThings that influence drugs crossing membranesSizeLarge molecules with MW > 500 (like proteins) don’t move well across membranesPolarityWith low polarity (less charge), there’s more movement across membranesWith high polarity (more charge), there’s less movement across membranesAqueous to organic ratioDrugs with both aqueous and organic components can move the best across membranesProtein bindingUnbound drugs can move across membranes and react with targetsDrugs bound to proteins can’t move across membranes and can’t react with targetsHigh protein binding isn’t necessarily bad—you just need to have enough free drug for an effect to be observedThings that change protein bindingAltered protein production (more/less)Altered affinityDisplacement by another drugpHAcids are uncharged when pH << pKa (because there are lots of H+)Bases are uncharged when pH >> pKa (because there are few H+)Normal pHOf blood, 7.4Of urine, 4.5-7.5Of gastric fluid, 1.5-7.0Only uncharged drugs move freely across membranesMembrane transportersP-glycoprotein pumps substrates into the stomach lumen; inhibition will improve oral bioavailabilityOrganic anion transporters take substrates from the blood to the stomach lumen; inhibition will allow a longer t1/2Pharmacokinetic parametersArea under the curve = AUCA measure of drug exposure that takes [drug] and time into accountUnits = mg*hoursmLBioavailability = FFraction of a dose of drug that reaches blood after an extravascular dose (i.e., orally, intramuscularly)Has no units; is a fraction or percent that’s less than 1.0 because ofFailure to enter solutionShort exposure to be absorbedHard time crossing membranesMetabolized before it gets to systemic circulationSystemic dose=administered dose*FYou can break down F into all the fractions that reflect barriers to entryMeasurement of bioavailabilityF=exposure in blood after EV dose Xexposure in blood after IV dose XF=AUCEVAUCIVEV dose on top because F is a fraction, so you have to give more orally to compensate when switching from IVYou need to use F when you’re choosing an oral loading doseIf you’re increasing/decreasing an oral dose, then you just make a proportional change; you don’t need to worry about FIf you’re choosing an IV loading dose, then you don’t need to worry about FIt gets more complicated with saltsSome IV drugs are given as the salt of the active drugS is the fraction of active drug that’s given relative to the total amount given in salt formS=amount of active drug givenamount of total given in salt formSalt dose*S=Nonsalt doseCase example of theophylline/aminophyllineSwitching from oral theophylline to IV aminophylline, you need to multiply the oral theophylline dose by FSSwitching from IV aminophylline to oral theophylline, you need to multiply the IV aminophylline dose by SFVolume of distribution = VdVolume into which a dose appears to be uniformly distributedUnits = LAffected byHow easily the drug stays/leaves the designated VdIf the drug can move easily across membranes, then Vd can be larger if it’s equally distributedVd can also be smaller if the drug moves in one direction across a membrane very easily but not backPatient’s body sizeProtein binding, which decreases VdSite and method of drug measurementVd isn’t necessarily a physiologic spaceVd of a population can be used to calculate the Vd for a patient by multiplying by the patient’s massLoading doseYou do this when you want toStart a new drug and don’t want to wait a while to get up to the correct concentrationImprove the effect of an existing drugAssumes instantaneous uniform distribution (which isn’t true)Dose?drug*VdF for oral loading dose?drug*VdF with F = 1.0 for normal IV loading dose ?drug*VdS for IV loading dose of a salt drugVd is the slope on a curve of concentration on x-axis and dose on y-axisClearance = ClRate at which volume of fluid is cleared of drugCl=Vd*k=Vd*0.7t12Depends onFlowExtraction ratio = the fraction of a drug that’s removedDrugs with high extraction rates depend a lot on blood flow to the organs of elimination (liver and kidneys)When blood flow increases, Cl goes up and drug amount goes downNote: flow and extraction ratio increase during pregnancyTotal clearance is a function of hepatic clearance and renal clearanceContinuous infusionAt steady state, input rate = elimination ratedoseτ=continuous infusion rate=Cl*CssF, and usually you don’t have to worry about FTime to steady state is 4-5 half-livesElimination rate constant = keCt=C0e-ketFraction of a drug in the body that’s eliminated per unit of timeUnits = 1hrElimination rate is measured in mghrIncreases early on as [drug] increasesBut can only increase to a point, when organs of elimination are saturatedFirst order elimination[drug] decreases by the same fraction for each unit of timeSeen at first when the capacity of organs of elimination hasn’t been met/exceededke doesn’t change during first order (i.e., the slope is linear)Rate = keA1Zero order eliminationSeen later when you get a lot of drug and exceed the capacity of the organs of eliminationRate = keA0Half-life = t1/2Time required for [drug] to drop by halfOnly works for first order eliminationt12=0.7keNumber of half-lives elapsed is n=?tt12Number of half-lives in the dosing interval, τ, is n'=τt12Peak to trough ratio is CmaxCmin=2n'After 4 to 5 half-lives, 95% (essentially all) of the drug is eliminatedThe quickest way to lower [drug] in the body is to stop giving it (not lowering the dose); you can estimate how long it’ll take to lower [drug] to the desired concentration by seeing what fraction you need and how many half-lives that’ll take to get thereDosing regimensLoading doseContinuous infusion rateIntermittent dosingGiving a smaller dose more frequently can move peaks and troughs closer together while keeping the same average concentrationCl determines CssHalf-life determines CmaxCminAccumulation index = RACDepending on the half-life of the drug, it might take a long or short amount of time to reach the desired [drug]If there is exactly one half-life in the dosing interval, then RAC will be 2Concentration constrained dosingRate of dosing is determined by the ratio of target concentrations, CmaxCmin=2n, where n is the number of half-lives per dosing intervalDose is determined by the difference in target concentrations, Cmax-Cmin*VdF=DDrugs with mixed order eliminationAlcoholAspirinPhenytoinFluoxetineDelavirdineNiacinAutonomic pharmacologyParasympathetic nervous systemAnatomyPresynaptic fibers come from midbrain, medulla, and sacral spinal cordLong presynaptic fibersShort postsynaptic fibersNicotinic ACh receptors on gangliaMuscarinic ACh receptors on targetsPhysiologyOpposes sympathetic activityUsually constricts smooth muscles and increases secretion from glandsLocalized effects of signalingNotable actionsPupillary constrictionConstriction of bronchial muscle in lungsDecreased heart rateIncreased digestionBladder contractionCholinergic synapseStepsACh synthesisCatalyzed by cholineInhibited by NVPCa2+-dependent release of ACh in vesicles into synaptic cleftPromoted by β-bungarotoxinInhibited by botulinum toxinBinding to muscarinic ACh receptor on target neuronA normal GPCR with 7 transmembrane domainsM1, M3, M5 receptor subtypes interact with Gq proteinsM2, M4 receptor subtypes interact with Gi proteinsM2 is cardiac selectiveBreakdown of ACh by acetylcholinesterase in the synaptic cleftAcetylcholinesterase is a serine proteaseACh is converted into acetate and cholineThis is the turnoff mechanism for the synapseThere are neuronal and serum types of acetylcholinesteraseCholine taken up into presynaptic neuronNot the turnoff mechanismMuscarinic agonistsBethanecholResistant to cholinesterasesEffectsIncreased peristalsis and secretionDecreases bladder capacity, relaxes external sphincterTreatment for neurogenic bladder (lacking bladder control)PilocarpineComes from leaves of a shrub in South AmericaEffectsPupillary constrictionFall in IOPTreatment for glaucomaMetoclopramideEffectsIncreases gastric emptyingAnti-emetic (prevents vomiting and nausea)Treatment for gastroparesis (when stomach can’t empty itself) and nauseaMuscarinic antagonistsAtropineCompetitive antagonist of AChEffectsDry mouthConstipationUrinary retentionBronchodilationTachycardiaPupillary dilationDeliriumTreatment for cardiac arrest, diarrheaScopolamineTreatment for motion sicknessIpratropium bromideCauses bronchodilationTreatment for COPD, asthmaBenztropineTreatment for Parkinsonian side effects of antipsychoticsOxybutyninTreatment for urinary incontinence, muscle spasmsDiphenhydramine (benedryl)Antihistamine with anti-cholinergic side effectsUsed as a sedativeAcetylcholinesterase inhibitorsCan beTherapeutics (e.g., physostigmine)Antidotes to poison (e.g., pyridostigmine)Toxins (e.g., sarin), which can causeBronchial spasmsSalivationLacrimationDefecationUrinationBradycardiaHypotensionDeathNeostigmine used to treat myasthenia gravisSarin used in Tokyo subway attacks, and can be treated withAtropine (muscarinic antagonist)Pralidoxime, which can rescue the inactive acetylcholinesterase via nucleophilic attackSympathetic nervous systemAnatomyPresynaptic fibers come from thoracolumbar spinal cordGanglia are in paravertebral chains alongside spinal cordShort presynaptic fibersLong postsynaptic fibersNicotinic ACh receptors on gangliaMost target receptors are adrenergic (use epinephrine), but sweat glands are cholinergicAdrenal medulla releases epinephrinePhysiologyOpposes parasympathetic activityCan relax or constrict smooth musclesWidespread effects of signalingNotable actionsDilation of bronchial muscles in lungsIncrease glucose mobilization in liver so there’s more energy availableIncrease heart rate and stroke volumeIncrease blood flow to skeletal muscleDecreased motility of GI systemAdrenergic synapseStepsNorepinephrine (NE) synthesisStart with tyrosineTyrosine hydroxylase catalyzes tyrosine DOPAThe rate-limiting stepInhibited by α-methyltyrosine to treat pheochromacytomaAromatic acid decarboxylase catalyzes DOPA dopamineInhibited by α-methyldopa to treat hypertensionDopamine hydroxylase catalyzes dopamine NEAdrenal glands convert NE to epinephrine using phenylethanolamine N methyltransferaseCa2+-dependent release of NE in vesicles into synaptic cleftBinding to adrenergic receptor on target neuronBretylium, guanethidine, α-methylnorepinephrine act as false neurotransmitters by taking the place of NE in vesicles, so not as much NE is releasedNE transporter moves NE back into presynaptic cellThe turnoff mechanism of signalingInhibited by tricyclic antidepressantsMAO breaks down NENot the turnoff mechanism of signalingInhibited by pargylineSympathomimetic drugsEnhance NE secretionExamples: amphetamine, ephedrine, tyramineSome adrenergic receptor signaling facts3 known subtypes of α1 receptors, α1A, α1B, α1C, α2 receptors, α2A, α2B, α2C, and β receptors, β1, β2, β3D1 dopamine receptor is present in the vascular bedDopamine can also bind to the α-receptorα receptorsNon-selective for α1 or α2 antagonistsPhenoxybenzamine to treat pheochromacytomaPhentolamineα1 adrenergic receptorsAgonistsGeneral effects are arteriole and venous constriction in skin, GI tract, kidneys, brainPhenylephrine to treat hypotension, nasal congestionAntagonistsPrazosin to treat hypertension, enhance urine flow in prostatic hyperplasiaα2 adrenergic receptorsAgonistsGeneral effects are negative feedback at synapse, blocking NE release presynapticallyClonidine to treat hypertension, withdrawal in substance abuseAntagonistsYohimbine as an aphrodisiac (questionable if this actually does anything)β receptorsNon-selective for β1 or β2 agonists that stimulate cardiac output and dilate bronchial smooth muscleIsoproterenolEpinephrine (which is also an agonist for α receptors)Non-selective for β1 or β2 antagonists that treat hypertension, angina, anxiety, vasovagal syncope, arrhythmiasPropranololβ1 receptorAgonistsGeneral effects are increasing heart rate, force of cardiac contractions, and cardiac conduction velocityDobutamine increases heart rate and force of contractions; given via IV to treat congestive heart failureAntagonistsMetoprolol reduces cardiac output to treat hypertension and anginaβ2 receptorAgonistsGeneral effects are relaxing bronchial smooth muscle, arterioles in skeletal muscle, uterine smooth muscle, and increasing liver glycogen breakdownAlbuterol dilates bronchial smooth muscle and uterine smooth muscle without many cardiac side effects to treat asthma, stop premature labor, promote glycogen breakdown in liverAntagonists aren’t clinically usefulβ3 receptor agonists may reduce adipose tissue in obesitySpecial considerations of epinephrine, NE, and dopamineEpinephrinePredominantly a β agonistIncreases cardiac output, BP, and consumption of O2 and blood glucoseUsed to stop anaphylactic responses and cardiac arrestNEPredominantly an α agonistIncreases BP with less of an effect on cardiac output and metabolismUsed to treat hypotensive shock, but it’s been replaced by phenylephrineDopamineGiven via IVLow doses act on D1 receptor to treat renal failure patients with low perfusionMedium and high doses have effects on α and β receptors to increase BP during shockDrugs and receptorsOccupancy theorySays that the magnitude of the biological effect is proportional to the concentration of the receptor-ligand complexγ=% of total R bound with L=RL[RT]=EEmax=LKD+[L]Kd is the concentration needed to reach half of VmaxThe smaller the KD, the more potent the drug, because KD describes dissociation, so a low KD means the drug doesn’t dissociate very easily and stays around longer to have an effectShifting the log dose response curve to the right means the drug is less potent because KD will be higherUpon ligand binding to a receptor, there’s a conformational change in the receptor-ligand complexReceptor analysisEffect of a drug is dependent onLigand concentration, [L]Receptor concentration, [R]Affinity between L and RNature of the cellular response after bindingCurvesThe shape of a curve plotting [L] on the x-axis and EEmax on the y-axis will show a rectangular hyperbolaThe ED50 is the [L] needed for a 50% effect to be observed; this is an observed value in an experimentED50 = KD if occupancy theory holdsOn a log dose response curve, the curve is sigmoidal and the KD (ED50) is at the inflection pointLigand classesAgonistLigand binds to receptor to give an effectGives 100% of full effectAntagonistFills receptor site so ligand can’t bindCan only observe the effects if you start with the receptor working because you can then see the effect dropKi is like KD, but for inhibitors; the smaller the Ki, the more potent the inhibitorPartial agonistWorks like an agonist, but has a partial effect less than 100%Ligand bindingYou can measure ligand binding by using radiolabeled drugsRL=Rt*[L]KD+[L], where [Rt] is the asymptote of specific bindingOn a Scatchard plot, the slope is -1KD, and the x-intercept is RtThe more negative the slope, the more potent the drugDrug metabolismWhat is it?Converting a drug from (usually) a lipid soluble form to a water soluble form that can be excretedBiotransformation = metabolismPhase I metabolismIntroduces or reveals a functional group (such as –OH, –NH2, –SH) making the product (i.e., the metabolite) more polarMetabolite may or may not be pharmacologically activeProdrugs require metabolism before they’re activeHappens mostly in the liverIntestines, kidney, brain, lung, and skin are some popular locations of extrahepatic metabolismEnzymes are usually in the ER or cytosolCan happen before phase II, but doesn’t always need to happenTypes of reactionsOxidationOxygen can be incorporated onto the moleculeOxidation can cause a loss of part of the moleculeMicrosomal mixed function oxidases = monooxygenases require O2 and NADPHCytochrome P450s = CYPs catalyze lots of oxidation reactionsMost common phase I metabolism pathwayThere are different ones for prokaryotes and eukaryotesContains hemeDifferent P450s can insert oxygen into various positions and act on the same drugThe same drug can be modified in different waysMetabolism by P450s isn’t always good; metabolites can beInactive, and then they’re excretedActiveReactive, which can lead to toxicity or detoxicityP450s catalyze lots of reactions, but aromatic hydroxylation is the most commonCYP families1-3 usually work on exogenous drugs; CYP3A4 works on >50% of drugs; CYP3A5 also works on lots of drugs4 and on usually work on endogenous stuffOxidation reactions not catalyzed by CYPsFlavin-containing monoxygenase (FMO) systemMostly in the liver, some in the intestine and lungOxidizes compounds with S and NUses NADH and NADPH cofactorsEpoxide hydrolases (EH) catalyze trans addition of water to alkene epoxides and arene oxidesAlcohol metabolismAlcohol dehydrogenase (ADH)Mostly expressed in liver, some in stomachCatalyzes conversion of ethanol into acetaldehyde, which is associated with flushing and hangover symptomsGets saturated at low [alcohol]CYP2E1 helps with alcohol metabolism when ADH gets saturated (this is a protective measure)Aldehyde dehydrogenase (ALDH)Catalyzes conversion of acetaldehyde into acetic acidGenetic polymorphisms existDisulfiram inhibits ALDH in treating alcoholism, so people feel sick when they drinkXanthine oxidasesAmine oxidasesReductionHydrolytic cleavageAlkylation = methylationDealkylationRing cyclizationN-carboxylationDimerizationTransamidationIsomerizationDecarboxylationPhase II metabolismWhat is it?Conjugation reactions where you add stuff to drugsMajor organs where it happens = liver, kidneys, intestinesNeeds an available polar functional group, so phase I might have to proceed first to add thatPhase II metabolites are usually inactiveException: morphine 6-glucuronideProducts are very polar and charged, so they’re excreted in bile, urine, or fecesNot very inducibleGlucuronidationMost important phase II metabolism pathwayThe transfer of glucuronic acid from UDPGA (a necessary cofactor that’s found in all tissues) to the drugCatalyzed by UGT enzymesA low affinity, high capacity enzymeSite of glucuronidation is S, O, or NDeficiency of UGT1A1 (which metabolizes bilirubin) is associated with Gilbert’s Syndrome and Crigler-Najjar syndrome type IPolymorphismsUGT1A1*28 homozygotes have increased risk of neutropenia after taking irinotecanLow UGT1A9 variants have increased GI toxicityProducts are excreted in bileMorphine metabolized by UGT2B7 to morphine 3-glucuronide (which is inactive) and morphine 6-glucuronide (which is active—this is unusual)SulfationMostly for phenols, but also for alcohols, amines, and thiolsPAPS = a necessary energy-rich donorSULT1 and SULT2 families catalyze transfer of sulfate to the drugSULTs are mildly inducibleCompetes with glucuronidation pathwaySulfation wins at low [substrate]Glucuronidation wins at high [substrate]Metabolites are usually inactiveException: minoxidil sulfate is activeMetabolites are usually excreted by kidneys, but larger ones are via bileGlutathione conjugationGlutathione S-transferase (GST) catalyzes addition of glutathione to a drug[glutathione] in liver is very highGST substrates areHydrophobicElectrophilicReact non-enzymatically with glutathioneGlutathione conjugates can be metabolized further or excreted directlyAcetylationRequires acetyl CoAEnzyme is NATResults in a more lipophilic metabolite that can be very reactiveCan cause renal toxicity after sulfonamide metabolismMethylationA minor pathwaySAM is a cofactorResults in a more lipophilic metaboliteNicotine is N-methylated to form a very toxic metaboliteEnterohepatic recyclingDrugs can circulate from the liver to bile, then to the small intestine to be absorbed by enterocytes, and then back to the liverCommon in phase II metabolismThis delays elimination of drugs, and can lead to more toxicityCan happen with glucuronidation and sulfationBioactivation = transformation of a drug into a more toxic metaboliteCan be a single reaction or a sequence that leads to a toxic metaboliteAcetaminophen toxicityCan cause liver failure and deathTreatment uses antioxidant N-acetyl cysteine, which leads to more glutathione production; glutathione reduces NAPQI Acetanilide and phenacetin are kind of like prodrugs that are metabolized to make acetaminophen3 main pathways of acetaminophen metabolism2 of them occur 95% of the time via phase II metabolism, and produce safe metabolitesCYP2E1 catalyzes the reaction of acetaminophen to NAPQINAPQI is an oxidizing agent and can do bad stuff, such as cause oxidative stress, protein adducts, and toxicityDrinking alcohol causes upregulation of CYP2E1, which means formation of NAPQI from acetaminophen is favoredBenzo[a]pyrene = BaPFound in charbroiled meat, tobacco smoke, and coal tarIs a carcinogen after bioactivationCan also be metabolized to harmless thingsAflatoxinFound on moldy peanuts, rice, and cornAflatoxin B1 is a liver carcinogenThings that influence drug metabolismGenetic variationPolymorphisms, often related to ethnicityCYP2D6 is a highly polymorphic geneThere are high, intermediate, or low metabolizersCYP2D6 metabolizes codeine to morphine, so poor metabolizers don’t benefit from codeinePregnant high metabolizers on codeine can pass on toxic breast milk to babies who aren’t high metabolizersAgeExpression of drug-metabolizing enzymes varies with ageBabies metabolize drugs at a slower rate than adultsFolks over age 70 have decreased first-pass metabolismSexSome sexual dimorphisms in expression and activity of drug-metabolizing enzymesPregnancy causes differential expression of drug-metabolizing enzymesDietGrapefruit juice (see later for more info)Alcohol induces expression of more CYP2E1St. John’s wort can increase expression of CYPs (similar to alcohol)Other drugsDiseaseCirrhosis, alcoholic liver disease, jaundice, and carcinoma slow down drug metabolismFirst-pass metabolism is decreasedF is increasedEnvironmental factorsPesticides and industrial chemicalsSmoking; cigarette smoke increases clearance of theophyllineInduction of drug metabolismSome drugs can increase the metabolism of other co-administered drugs; this is the basis of drug-drug interactionsUsually occurs at transcriptional level by increasing expression of drug-metabolizing enzymesClinical consequencesHigher rate of biotransformation and first-pass metabolismDecrease in plasma [drug]Reduced F of drugPotential increased activity or toxicity of a drug if the metabolite is active or toxicPotential decreased efficacy of drug if the metabolite is inactiveEnzymatic inhibitionP450s show reversible and irreversible inhibitionIrreversible inhibition is usually due to a reactive metabolite covalently binding to active site or heme, and this usually stimulates drug-drug interactionsReversible inhibition is due to substrate competition for the active site, and is less common in drug-drug interactionsClinical consequencesLower rate of metabolism and first-pass metabolismIncreased [parent compound]Prolonged effects of the parent compoundFewer (if any) effects of the metabolitesCan increase or decrease toxicity depending on whether the parent compound is toxic or notGrapefruit juiceHas a compound that irreversibly inhibits CYP3A4 and CYP2B6Causes high [drug] if the drug is metabolized by those CYPsBecause inhibition is irreversible, recovery requires new CYPs to be synthesizedDrug developmentPhase studiesPre-clinical studies look atEfficacy and mechanism of actionToxicologyPharmacokineticsPharmaceuticsPhase I trialsObjectivesShort-term safety and tolerabilityPharmacokineticsSubjects = healthy volunteersSample size = tensDuration = days to weeksPhase II trialsObjectivesMedium-term safety and tolerabilityEvidence of beneficial activitySubjects = patientsSample size = hundredsDuration = weeks to monthsPhase III trials (also called registrational trials)ObjectivesLong-term safety and tolerabilityClinical efficacySubjects = patientsSample size = thousandsDuration = yearsPhase IV trialsTake place after the drug hits the marketObjectivesPost-marketing surveillanceDevelop new usesLook at special patient populationsLook at real world toxicity and effectivenessSubjects = patientsSample size = thousandsDuration = retrospectiveINDs and NDAs in drug developmentIND required forInvestigational new drugsApproved drugs ifThe label changesAdvertising claims changeThere are new routes of administration, formulations, doses, or patient populations with increased riskThe IRB requires itNDAData submitted to support marketing of a new drugReviewed by advisory committee that can make a recommendation to approve or disapproveFDA not obligated to follow the recommendation ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download