Drugs used in management of pain

Objectives:Ø Revisehowpainisperceivedandmodulated,emphasizingonneurotransmitters,receptors,

channelsinvolved

Ø ClassifydrugsusedinmanagementofpainØ Expandonpharmacologyofopiates,patternsofclassification,mechanismofaction,

indications,ADR,…etc.detailingonmorphine asanexample&itssyntheticderivatives.

Ø Hintsontheproperties&clinicalusesofmorphineantagonists.Ø Compareinbriefactionsandindicationsofotheropiateagonistsandantagonists.

extrainformationandfurtherexplanation

important

doctorsnotes

Drugsnames

Mnemonics

color index:

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Checkoutthemnemonicsfile:

Drugsu

sedinm

anagem

ento

fpain

NSAIDs

•1stclassofdrugsused.

•workatthesiteoftissue(actperipherally)•sodecreasingopioid-relatedsideeffects.

•Neithercausetoleranceordependence.

•Hasaceilingeffecttoanalgesia.

NSAIDSare antiinflammatorythereforetheypreventformationofthe

chemicalmediatorsassociatedwithnociceptoractivation

Adjuvantdrugs

modifytheperceptionofpainandremovethe

concomitantsofpainsuchasanxiety,fear,

depression.

They don’treallystopthepainrathertheyworkonmanagingitviacontrollingsymptoms

Primarilyindicatedforclinicalconditionsother

thanpain

Antiepileptics

Antidepressants

neuroleptic

anxiolytics

Opioids

Receptors(gprotein

coupledr)

1.Mu(µ).

2.Kappa(ĸ)3.Delta(δ)4.ORL-1.

classification

accordingto

theirsource

1.Natural→

Morphine,Codeine2.Semisynthetic→

Heroin3.Synthetic→

Pethidine,Methadone

agonistic/antagonisti

caction

Agonists Morphine,Codeine,Pethidine,

Methadone

Mixedagonist\antagonist

Pentazocine

PureantagonistNalaxone,Naltraxone

theirspecificityof

actiononreceptors

µreceptor.agonists→

Morphine,codeine,heroinagonistatkreceptor.&

antagonistatµreceptor.→

Pentazocine

-The5thvitalsignsuggeststhatassessmentofpainshouldbeasautomaticastakingaclient’sBP

andpulse

-Isanunpleasantsensoryandemotionalexperienceassociatedwithactualandpotentialtissue

damage,ordescribedintermsofsuchdamage

Whatispain?

• Painisamiserableexperience.

• Painisthemostcommonreasonpatientseekmedicaladvice.

• Impairsthepatientfunctionalability&psychologicalwellbeing.

• Painincreases:

- sympatheticoutput.

- Increasesmyocardialoxygendemand.

- IncreasesBP,HR.

• Painlimitsmobility.

• IncreasesriskforDVT(Deepveinthrombosis)andPE(Pulmonaryembolism)

•Maymodifytheperceptionofpain(by↓AP)andremovetheconcomitantsofpainsuchasanxiety,

fear,depression.

•Primarilyindicatedforclinical conditionsotherthanpain.They’reindicatedforanxiety-epilepsy-depression.

•e.g.Anxiolytics,Neuroleptics,Antidepressants,Antiepileptics.Usedinsever+chronicpains•Usefulinneuropathicpain

Adjuvant

drugs

•Opiumisderivedfromthejuiceoftheopiumpoppy,Papaversomniferum

•Thenaturalproductsincludemorphine,codeine,papaverineandthebaine•Opiatesaredrugsderivedfromopiumandsemisyntheticandsyntheticderivatives

•OpioidsrefertoopiatesandEndogenousopioidpeptides,e.g.β−Endorphins,enkephalins&dynorphins.•Opioidsarenatural,semi- synthetic,orsyntheticcompoundsthatproducemorphine-likeeffects.

•Uses:Theirprimaryuseistorelieveintensepain,whetherthatpainresultsfromsurgery,injury,or

chronicdisease.

Opioids

•Generallythefirstclassofdrugsusedforcontrollingpain.•WorkatsiteoftissueinjurytopreventtheformationofthenociceptivemediatorsAshistamineand

prostaglandin.

•Candecreaseopioiduseby~30%thereforedecreasingopioid-relatedsideeffects.

•Theyneithercausetoleranceordependence•Hasaceilingeffecttoanalgesia.TheyhavealimitthenifthepainincreasethanthislimitNSAID

produceNoeffecttoreliefthepainevenifweincreasethedose.

NSAIDs

Whyshouldwetreatpain?

Drugsusedinmanagementofpain:

Acaseofoverdose:

SigmundFreud,thefatherofpsychoanalysis.Hiscancerofthejawwascausinghimincreasingly

severePAIN &agony.Hebeggedhisfriendanddoctor,MaxSchurtorelievehim.Hisdoctor

administeredincreasingdosesofMORPHINEthatresultedinFreud'sdeathon23September1939.

WhateffectofmorphinecausedthedeathofSigmundFreud?Euthenasia

Maycausemyocardialinfraction.

WeuseAdjuvantdrugsandNSAIDsinordertorelieve.

WHOPainLadder: Whydoweusemorethan1drug?→Combinationofdrugslowers

theADRs

Opioidsexerttheirpharmacologicalreceptorsthrough4typesofreceptors: ThesereceptormainlyfoundintheCNSandlessinperipheral

- Allofthe4receptorsaretypicalG-proteincoupledreceptors.

- Anatomicaldistributioninbrain,spinalcord,&theperiphery.

Classification:

Ifthesedrugsfailedto

controlpainthenwehaveto

addmildorweakOpioid.

Ifthecombinationfailed

becauseofincreasinginthe

severityofthepainthenwe

addstrongOpioid.

What’stheadvantagesanddisadvantagesforthiscombination?

Advantages:NSAIDs,they’renotaddictiveandtheyaren’tcausetolerance.

Disadvantages:theycanonlyrelievemildtomoderatepaintheycan’trelieveseverepaine.g.painoftrauma– painofcancer.

435team

Analgesia

Sideeffects

كل شيء لھ ثمن، فإذا أبغى أقضي أو أقلل األلم راح أضطر أزود األدویة

وجرعاتھا فبالتالي زدت معھا اآلثار الجانبیة

A- Accordingtotheirsource:

1- Natural:

MorphineCodeine

2- Semi-synthetic:

Heroin→(Diacetylmorphine,synthesized

formmorphine)

3- Synthetic:

Pethidine,Methadone.

B- Accordingtotheirspecificityofactiononreceptors:

Morphine,codeine,heroin→µ-receptoragonists Pentazocine→ agonistatk–receptors

→ antagonistatµ-receptors

C- Accordingtoagonistic/antagonistic actions:

1- Agonists;

Morphine,Codeine,Pethidine,Methadone

2- Mixedagonists/antagonists;

Pentazocine3- Pureantagonist;

Nalaxone,Naltraxone

Drug

morphine

Mech.

ofaction 1. Bindingtopresynaptic opioidreceptorscoupledtoGi(inhibitoryGprotein)→↓ AC(adenylate

cyclase) &cAMP→↓ N-type voltage-gatedCa2+channels(inhibitinfluxofCa2+,→ reducereleaseofneurotransmitter)→↓ excitatorytransmitter.

2. Bindingtopostsynaptic receptors→ opening ofKchannels. (↑postsynapticK+efflux(hyperpolarization)→↓ neuronalexcitability.Decreasereleaseofneurotransmitterfrom

presynapticanddecreasetheneuronalactivityofpostsynapticleadingdecreaseinaction

potentialsignalsofpain.

Pharmacod

ynam

icsActions

- Analgesia [inacute&chronicpain]moreeffectiveonvisceral&skeletalpain.- Euphoria&sedation.à relievesanxietyofpatient.→ that’swhytheymayaddictit.- Respiratorydepression→byreductionofthesensitivityofrespiratorycenterneuronstocarbon

di- oxide.Main causeofdeathinaddicted people- Depressionofcoughreflexes→treatmentofnon-reproductivecough.Drycough.- Nausea&vomiting→ ↑excitationCRTZ.- Pinpointpupil(miosis)→Diagnosticfeatureofopioidaddiction.- How?ItexcitestheEWN→enhanceparasympatheticeffect→constrictpupil.

- Releaseshistaminefrommastcells→causing:hypotension,bronchoconstriction,itchingofskin→contraindicatedw\ asthmaticpts.

- EffectsonGIT:- •↑intoneofcontraction,↓motilityofintestine→severeconstipation →InGITreducesmotility(peristalsis)byreducingreleaseofAch→usedtotreatdiarrhea.

•↑biliarytractpressureandbiliary colicduetocontractionofthegallbladderandconstrictionofthebiliarysphincter→contraindicatedinbiliarycolic. increasetheintra-biliarypressuresoforthisreasonwecan’tuseitforgallbladdercolic.- Depressrenalfunctions

Tolerance - Toleranceoccurswhenthepersontakesahigherdoseofthedrugtoachievethesamelevelof

responseachievedinitially- Occursrapidlywithopioids(e.g.morphine 12–24hours)- Developsto(reduce) respiratorydepression,analgesia,euphoriaandsedation.No tolerancefor

miosissoit’sgoodindicatorforaddictpeople.

Depe

nden

ce

- Dependencedevelopswhentheneuronsadapttotherepeateddrugexposureandonlyfunctionnormallyinthepresenceofthedrug

- Physicaldependence(abstinence)→withdrawalmanifestationsdevelopuponstoppage.Orgivingopioidsantagonist.

- Lastsforafewdays(8-10days)informof↑bodyache,insomnia,diarrhea,gooseflesh,lacrimation.

- Psychological dependencelastingformonths/years→craving.Thisisverydifficulttotreat.- Dependencedevelopedmainlywithmorphine.

Pharmacokinetics

- T1⁄2is2-3h- Itisslowlyanderraticallyabsorbedorally(bioavailability10-40%) →

GivenSC,IM,orIVinjection.- MetabolizedbyconjugationwithglucuronicacidItgoestotheintestine

(undergorecycling)thenitgoesbacktothebloodcirculation.- Undergoesenterohepaticrecycling→ CrossesBBB.- CrossesPlacenta→Infantsbornofaddictedmothersshowphysical

dependenceonopiatesandexhibitwithdrawalsymptomsifopioidsarenotadministeredif themothergotaddictivetomorphine,thenewbornbabywillalsobeaddictivetomorphine.

Thisisthevomitingcenterinthebrain.(Stimulatevomiting).

Mechanismofaction(opioids) Pharmacologicalactionofmorphine

Drug

morphine

ClinicalIn

dicatio

ns 1. PainControl:

cancerpain,severeburns,trauma,Severevisceralpain(notrenalcolics(becauseitconstrictstheureter)/biliarycolics,acutepancreatitis becausethegallbladder&pancreashassimilarsphincterconstrictedbymorphine)

2. MyocardialIschemiaandAcutePulmonaryEdema3. Relief: distress:

e.g.heartfailure(nonpainfulconditions)4. Pre- anestheticmedication

AdverseEffects

- Constipation- RespiratoryDepression- Itching- Nausea/Vomiting- ConstrictedPupil- Sedation

Ø (CRINCS) Contraindicatio

ns- HeadInjurydilationincranialbloodvessels >intra-cranialPressure>bleeding- BronchialasthmaorImpairedPulmonaryFunction- Biliarycolic→itincreasethepressureofbiliarytract.- Elderly: moresensitivedueto→↓Metabolism,leanbodymass&

Renalfunction- Pancreatic pain- PtstakeMAOIs(Monoamineoxidaseinhibitors)àbcdepressant

actionsofmorphineareenhanced- Infants,neonates,orduringchildbirth→decrease conjugatingcapacity

→accumulate→respiratorydepression

*morphinereleasehistamine,soitcancause

bronchoconstrictionandcentrallydepressesrespiration.

Drug CodeineCharacteristics • µAgonist

• Dependenceless than morphine

Indication • Usedinmild&moderatepain(systemic)

• Dry cough

• Diarrhea

Drug

TRAMADOL PETHIDINE(meperidine) FENTANYL

Mecha

nism

ofa

ction

• Synthetic,μ agonist.

• lesspotentthan

Morphine.àsoitis

weakAnalgesic.

• inhibitsNEand5HT(serotonin)reuptake.

Synthetic,moreeffectivek(kappa)agonist. • Synthetic,μ agonist,

• morepotentthanPethidine andMorphine

Pharmacodynamics

- Lessanalgesic,constipating,depressant

onfetalrespirationthanmorphine.- Nocoughsuppressanteffect.

- Doesnotcausepinpointpupilsbut,rather,

causesthepupilstodilatebecauseofan

anticholinergicaction.

P.K Canbegivenorallyàmore

oralbioavailability____

• Highlylipophilic.

• ShortDuration.

Indicatio

ns

• Mildtomoderateacute

andchronicvisceral

pain.

• Duringlaboràbecauseitdoesnot

inhibitrespiration.

• AsinMorphine butnotincoughanddiarrhea.

• Betteràpreanaetheticmedication.

• Usedinobstetricanalgesia(nodecrease

inrespiration)

• Usedinseverevisceralpain;renaland

biliarycolics (smoothmusclesrelaxant).

- Usedforacutepain.

Pethidine ismetabolizedbydealkylationforthis

reasonitdoesn’taccumulateinthebodyofthe

fetusso,itwon’tcauserespiratorydepressionin

thefetus.

• Hasatropine-like action(smooth

musclerelaxant)sowecanuseitwith

biliarycolicandpancreatitis.

• Analgesicsupplementduring

anesthesia(IVorintrathecal=injectionintothespinalcanal).

• Induceandmaintainanesthesiain

poor-riskpts(stabilizingheart)

• Usedincombinationwith DroperidolasNEUROLEPTANALGESIA.- Incancer

painandseverepostoperativepain;

(transdermalpatchchangedevery72

hrs)

ADRs

- Seizures(notusewith

epileptics)

- Nausea

- Drymouth

- Dizziness

- Sedation

- LessADRson respiratory

andCVS

- Tremors,convulsionsisduetothe

serotonininthebrain,hyperthermia,

hypotension.

- Blurredvision,drymouth,urine

retention(atropine-likeeffects)

- Toleranceandaddiction.

- Respiratorydepression(mostserious)

- CVeffectsareless. Soitisgoodforptswithheartproblems.- Bradycardiamaystilloccur

Opioiddrugs:

OpioidAgonists:

و الجسم لصقھ تخدر كل أیام ٣كل یتم تغییرھا

Drug Opioidagonists OpioidAntagonists

METHADONE NALOXONE NALTREXONE

Actio

n/Mech.

ofaction

- Weakersyntheticμagonist.

- antagonistoftheN-methyl- D-

aspartate(NMDA)receptor.

- Pureopioidantagonist

- Competitiveantagonisttoμ,κ,

andδ.

Verysimilarto

Naloxone

P.D

Innon-addicts,itcausestolerance

anddependencebutnotassevere

asthatofMorphine.___ ___

P.K

T1/2=55hrs Effectslastsonlyfor2-4hrs.Longerdurationofaction.

T1/2=10hrs

Indicatio

ns

Usedtotreatandcontrolopioidwithdrawal(inpeoplewhohavebecomeaddictedtoopiatessuch

asheroin)

neurogenicpainàNMDA

antagonist.

• Usedtotreatandreverserespiratorydepressioncausedbyopioid

overdose.

• Reversetheeffectofanalgesiaontherespirationofthenewborn

baby.

• Precipitateswithdrawalsyndromeinaddicts.

OPIOIDANTAGONISTS

Withaddictionofopioid:

Withmethadone:

Morphine NaloxoneNalorphineAnADDICT

methadone

After72

hours

Useforoverdoseof

morphine(antidote)

ItisbettertobepureeitherAgonistorAntagonist

:قادة فريق علم األدوية

عبدالرحمن ذكري &لي التميمي : الشكر موصول ألعضاء الفريق املتميزين

غادة املزروع

ري الشثريالشمرانيساره

شذا الغيهب سمر القحطاني

رميا العتيبي روان سعد القحطاني

References:

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2- 435team’swork

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