Pharmacology of opioid analgesics

7/28/2019 Pharmacology of opioid analgesics

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Pharmacology of

Opioid AnalgesicsDr.Rathnakar U.P.

MD.DIH.PGDHM

MBBS. 5th Sem

2nd July 2013


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Pain

Unpleasant sensory and emotional experience

associated with actual or potential tissue damage

Subjective experience

Difficult to quantify

Warning signal

Can be pointless and contribute to discomfort

Demands instant relief-highly impresses layman


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Pain-Types

Superficial-cutaneous

Somatic

Deep non-visceral[muscles, joints]

Deep visceral

Referred

Psychogenic or functional pain


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Pain-characteristics

Superficial

Well defined

Skin-[pricking]

Inflammation

Neuralgia

Migraine-ishemia

TAO

Non visceral

Dull

BP, pulse-

normal

Visceral

Diffuse

Autonomicresponse

Renal colic, MI,

peptic ulcer


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Pain-characteristics

Referred

Deep pain can be

referred

To the cutaneous

area supplied by

the same segment

Heart- L.arm

Diaphragm-

shoulder

Psychogenic

Vague

No anatomicalpattern

Does not

disturb sleep

Followsexhaustion


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Pain pathways

Pain

receptors

Afferent-

fibres

SG-dorsal horn

Gate control

Spinothalamic tract

Thalamus & postcentral

gyrus & limbic system

Inhibitory pathways


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[Depress CNS]

[Do not depress CNS]


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Opioids

Opiates

[Products from opium

poppy]

Opioids

[Natural, synthetic &

semisynthetic drugs

with morphine like

action]

Opium -dried latex obtained from opiumpoppies Opium contains up to 12%morphine, - which is most frequentlyprocessed chemically to produce heroin.

The latex includes-

-Codeine-non-narcotic alkaloids, such aspapaverine, thebaine and noscapine .

The latex is obtained bylacerating the immaturefruits -the latex leaks out

and dries to a sticky brownresidue. This is scraped offthe fruit.

Papaver somniferum


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Opioids act on

endogenous opioidreceptors

Why should there be receptors in our

body for a substance found inPapaver somniferum???


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Endogenous opioids

[Peptides in CNS with opioid like action]

Beta-Endorphin

Enkephalin

Dynorphins Nociceptin/orphanin Endomorphins

Role: Endogenous analgesics, neurotransmittors, behavior modulators

OpioidReceptors

Mu, kappa, delta

Opioids

[Natural, synth, semisynth][Endogenous]


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Opioids-Classification[Agonists & Mixed action opioids & antagonists]

Natural

Morphine Codeine

Semisynthetic

Heroin Pholcodeine

Synthetic

Pethidine Fentanyl

Methadone

Tramadol

Classification-Chemical structure??????

Agonists


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Opioids- Receptors

Mu

.

Kappa

Others

Nociceptin/Orphanin

FQ

Delta


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MECHANISM OF ACTION

Ascending pathways

Block

Open

13


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MECHANISM OF ACTION

Descending pathways

Promote Inhibition of pain impulses


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Opioid-MOA

Inhibit

Inhibit pain impulse transmission

Inhibit pain perception

Modifies emotional component

3

5

5. Promotes descending inhibition

4

5


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Inhibition of pain

[Gate control]

Pain

Touch

Why when we bang our head, it feels better when we rub it.

16


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Morphine-prototypePharmacological actions-CNS

CNS-Depressant effects

Analgesia

Sedation

Euphoria

Resp.depression

Depress cough center

Temp reg.center

Vasomotor center

CNS-stimulant effects

CTZ

E.W.Nucleus

Vagal center

Truncal rigidity


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Morphine-prototypeOther-Pharmacological actions

Endocrine-ADH

CVS-Vasodilation

GIT-constipation Biliary tract-spasm of

Oddi

UB-urgency and

difficulty

RS-bronchospasm ANS-Symp.stim-

hyperglycemia


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Morphine-prototype

ADEs

Sedation, lethargy, dysphoria

Vomiting

Allergy Apnoea

Poisoning

Tolerance & Dependence


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Morphine-prototype Pharmacologicalactions CNS - depressant

Analgesia

Very strong

Dull, deep visceral pain

Peripheral and central

Anxiety, fear, apprehension,

autonomic [emotional

components]

Pain is no longer unpleasant-ignores

No proportionate CNS

dep.[unlike GA]

No ceiling effect

Sedation

Different from hypnotics

No ataxia, motor in-

cordination or excitement Not anitconvulsant

[epileptogenic]

Mood

Euphoria [dysphoria-rare]

rush Kick =orgasm


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Morphine-prototype Pharmacologicalactions CNS - depressant

Respiration

Dose dependent dep.-Resp

center

Indifference to breathing In morphine poisoning hypoxic

drive maintains respiration

Dangerous to give 100%

continuous oxygen in poisoning Resp arrest - cause of death in

poisoning

Cough

Depressed

Temperature

Hypothermia

VMC

Fall of BP


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Morphine-prototypePharmacological actions-CNS

CNS-Depressant effects

Analgesia

Sedation

Euphoria

Resp.depression

Depress cough center

Temp reg.center

Vasomotor center

CNS-stimulant effects

CTZ-

E.W.Nucleus

Vagal center

Truncal rigidity


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Morphine-prototype Pharmacological actionsCNS-StimulantCTZ

Vomiting

E.W.Nucleus [

Miosis [No tolerance]

Not topical-central action

Some cats-mydriasis!

Vagal center

Bradycardia

Cortical areas, hippocapus

Truncal rigidity

Proconvulsant [No tolerance]


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Morphine-prototype Pharmacologicalactions Other actions

CVS-Vasodilation

1. Histamine release

2. VMC depressed

3. Direct on BV

Shifts bloodpulmonary-

systemic=acute LVF

Decreases cardiac load=MI

CO2=Cerebral vasodilation=

ICT= CI in head injuries

GIT-constipation [No tolerance]

1. Movement

2. Spasm of sphincters

3. Decreases secretions

4. Inattention to defecation reflex

Neuroendocrine

ADH -reduce urine

FSH, LH, ACTH-Impotence,

libido, infertility


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Morphine-prototype Pharmacologicalactions On Other Smooth muscles

Biliary

1. Spasm of ODDI

U.Bladder Tone-detrusor and sphincter-

urgency & difficulty

Uterus

1. May prolong labour

Bronchi

Spasm-histamine

ANS

Mild Symp.stimulation-

hyperglycemia


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Receptor ORL1Analgesia

Supraspinal +++ -? - Antiopioid

Spinal ++ ++ + ++

Peripheral ++ - ++ -

Respiratory depression +++ ++ - -

Pupil constriction ++ - + -

Reduced GI motility ++ ++ + -

Euphoria +++ - - -

Dysphoria & hallucinations - - +++ -

Sedation ++ - ++ -Physical dependence +++ - - -


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Morphine

PK

Oral- BA to 1/6 of parenteral

Rectal, s.c, i.m, i.v.

Spinal-less resp.dep. Route is chosen depending upon the

condition

Crosses placenta Metabolized in liver[first pass]

Duration of action-4-6 hours


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Morphine ADEs

Th.doses[side effects]

Resp.dep

Idiosyncratic

Hypotension

Bronchospasm

Allergic

Constipation

Toxic doses

Acute morphine poisoning

Prolonged use

Tolerance

Physical dependenceHistamine

Morphine


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Morphine

Adverse effectsTolerance and dependence

Tolerance

Repeated use

PK and PD

For all actions except-Miosis, Constipation,

proconvulsant

Constipated & pin point pupils

Cross tolerance with opioids and other CNSdepressants

Cross tolerance incomplete- opioid rotation

Addicts tolerate grams


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Tolerance

Morphine


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Morphine

Adverse effectsTolerance and dependence

Dependence Psychological & physical-state of addiction

Dependence leads to abuse [more among medical personnel]

Withdrawal: Drug seeking behaviour, lacrimation, sweating, yawning,

anxiety, fear, mydriasis, insomnia, tremors, diarrhoea, colic,

dehydration, rise in BP, wt.loss, convulsions, CV collapse.

Treatment of dependence Acute [Detoxification]- Clonidine orLofexidine [reduce NA effects]

Chronic-[substitution] therapy with methadone


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Morphine

Adverse effects

Side effects[Th.doses]: Sedation, mental

clouding, dysphoria, vomiting,

constipation, resp.depression, blurred

vision, urinary retention, fall of BP

idiosyncrasy and allergy; Urticaria, itching,

swelling of lips

A local reaction at injection site,generalized itching may occur due to

histamine release.


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Morphine

Adverse effects

Apnoea of new born-

When morphine is given to the mother

during labour.

Naloxone 10 g/kg injected into

umbilical cord is the treatment of choice


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Morphine

Adverse effects

Acute morphine poisoning

Accidental, suicidal, overdose in abusers

Toxicity-50mg. Lethal-250mg Respiratory support

Gastric lavage- KMno4even when injected

[highly basic drug] Antidote-Naloxone 0.4 to 0.8 mg i.v. every

2mts-till resp.normal

Repeated every 1-4 hours[short duration


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Morphine

Precautions

Infants, elderly, with

resp.insufficiency[emphysema]

Bronchia asthma- histamine release

Hypotensive states

Urinary retension-elderly

Hypothyroidism, liver or renal failure-moresensitive

Unstable personalities-likely to be addicted


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Morphine

Precautions

Head injury-Contraindicated

1. Retained CO2- raises ICT2. Therapeutic doses-resp.depression

3. Vomiting, miosis, mental clouding by

morphine interferes with head injuryassesment [Glasgow scale???]

Drug interactions

Tripathi VIIth ed. Page 474

Morphine Respiratorydepression

CO2retention

Celebral

vasodilatation

Intracranialtension


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Morphine-CIs

Head Injury Bronchial asthma

Undiagnosed abdominal pain


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Morphine

Dose

Oral-10-50mg

S.c or I,m-10-15mg

i.v.-2-3 mg Epidural,

Preparations:Tablets, slow release tablets,

ampoules[10mg/ml]


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Morphine

Uses

To relieve severe visceral pain

MI, Burns, Post op.pain, fracture of long bones

Acute LVF

Relieves pulm.congestion

Preanesthetic

Analgesic & antianxiety[not in surgical anesthesia]

Frightening situations

RTA without head injury Not to be used as antitussive & antidiarrhoeal though effective


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Opioids-Classification

Natural

Morphine

Codeine

Semisynthetic

Heroin

Pholcodeine

Synthetic

Pethidine

Fentanyl

Methadone

Tramadol


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Opioids

Pethidine[meperidine]

1. 1/10th analgesic potency of morphine

2. Rapid onset-short duration

3. Not anti-tussive

4. Action on smooth muscles [, ]

5. Resp dep=morphine

6. Abuse=morphine

7. Tachycardia [anticholinergic]

8. Less histamine release[safe in asthmatics]

9. LA action

10.Orally better absorbed


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Opioids

Pethidine [Metabolism]

Pethidine

Meperidinic acid[Major metabolite]

Norpethidine[Minor metabolite]

Hydrolysis

DemethylationExcitatory

symptoms in

over dosage

MAO

inhibitors

interfere


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Opioids

Pethidine [ADEs]

Similar to morphine

Atropinic like[dry mouth, blurred vision]

Tolerance and physical dependence slow

Interaction with

MAO inhibitors[block hydrolysis]

And SSRIs [Pethidine blocks uptake of 5HT]


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Opioids

Pethidine [Uses]

Analgesic [Substitute to morphine]

Preanesthetic

Shivering during anesthesia & i.v. infusion [2action ADEs-CNS stimulation-norpethidine [accumulates]

Preferred during labour [not absolute]-does not delay labour

Dose: 50-100mg-i.m. , s.c.


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How pethidine differs from

morphine?

1. Less potent[1/10]

2. Rapid onset/ short duration

3. Less histamine

4. Anticholinergic-tachycardia5. Less sedation

6. Less antitussive

7. Less constipation

8. Less retention of urine9. Does not delay labour, less resp dep. In neonates

10. LA action


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Diphenoxylate & loperamide

Pethidine congeners

Not analgesics

Antimotility action on GIT

Symptomatic treatment of diarrhea


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Opioids

Codeine

Less potent analgesic

[CodeineMorphine]

Selective antitussive-own action [Linctus

codeine]

Orally effective

Abuse liability is low.


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Fentanyl[Sufentanyl, Alfentanyl, Remfentanyl]

Pethidine congener

100 times potent than morphine

Highly lipid soluble

i.v-in anesthesia[TIVA]

Transdermal patch-cancer analgesia

Anesthetic adjunct Epidural & spinal routes


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Methadone

Synthetic

Similar to morphine

Orally effective, longer acting

Accumulates

Less euphoria, no kick

Withdrawal symptoms are mild Used as substitute in morphine

dependence [1mg=4mg of morphine, 2mg

of heroin, 20mg of pethidine]


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Tramadol

Weak agonist at receptors

Inhibitor of reuptake of noradrenaline / 5-HT

Naloxone blocks resp.dep, not analgesia

Orally effective, metabolite is also analgesic

Better side effect profile than most opioids

Preferred in mild to moderate pain-not effective in severe pain

Caution in epileptics

Do not use along with MAOI

Tapentadol

U


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Uses

Morphine and congeners

Severe pain [any pain with care]

Preanaesthetic

Balanced anaesthesia

Relief of anxiety/apprehension

Acute LVF

Cough [Codeine-not morphine!] Diarrhoea [loperamide, diphenoxylate]

U


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Uses

Morphine and congeners

Severe pain

Mild pain-morphine or Pethidine not used

Abuse potential should be considered

Severe pain opioids should not be

withheld


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O i id t


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Opioid receptors

1. - Most of the analgesic effects of opioids, and for some majorunwanted effects (e.g. respiratory depression, euphoria, sedation and

dependence). Most of the analgesic opioids are -receptor agonists.

2. - Receptor activation results in analgesia but also can beproconvulsant.

3. - Analgesia at the spinal level -sedation, dysphoria andhallucinations. Some analgesics are mixed agonists/ antagonists.

4. ORL15.


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Opioids[Functional classification]

Agonists [,, k] [natural, semi synth.,synth]

Strong [Morphine] Mild [Codeine]

Mixed[agonist & antagonist]

Nalorphine, pentazocine, butorphanol,

Buprenorphine [Partial agonist]

Antagonists [,, k]

[Naloxone, Naltrexone, Nalmiphene]

Mi d[ g i t & t g i t]


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Pentazocine

[antagonist]k [agonist]

Analgesia at spinal level

Withdrawal symptoms in morphine addicts

Dysphoria

Weak analgesic & less ADEs

Raise in BP & tachycardia- CI in ischemia Tolerance & dependence+

Mi ed[agonist & antagonist]


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Butorphanol

[antagonist]k [agonist]

Similar to pentazocine

Three times more potent -morphine

Moderate painful conditions

Can be given by nasal route

Levorphanol



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Buprenorphine

[Partial]k [antagonist]

More potent than morphine, lower analgesic

Effective sublingually

Orally absorbed-First pass-not effective

Actions not completely reversed by

Naloxone [tight binding to receptors] CI-in labour

Pure antagonist


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Pure antagonist

Naloxone

Blocks all opioid receptors[more effectively ]

In the absence of opioids-

Increases pituitary hormonal levels

In the presence of opioids-

Injected i.v. All actions of morphine are reversed

Also antagonizes the actions of mixed action opioids

[Buprenorphine less]

Precipitates withdrawal effects in morphine addicts Blocks actions of endogenous opioids [no hyperalgesia!]

Blocks effects of acupuncture, placebo [?endogenous opioids

are involved]

Pure antagonist


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Pure antagonist

Naloxone-uses

Drug of choice for morphine poisoning-i.v. dose???

To reverse neonatal asphyxia-morphine induced

Overdose of mixed action opioids[except

buprenorphine] Adjunct in intraspinal anesthesia[low dose has no

effect on analgesia]-respiratory depression

Diagnosis of opium addicts Partly reverses alcohol intoxication

To raise BP in shock-increases cortisol levels

Other pure antagonists


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Other pure antagonists

Naltrxeone:

More potent than naloxone-long acting

Orally effective

To block the effects of opioids in addicts in deaddicted

To reduce alcohol craving

Hepatotoxic

Nalmefene-orally effective. No hepatotoxicitry

Alvimopan, Methyl naltrexone:

Does not cross BBB-no withdrawal symptoms in addicts

Used to reverse peripheral actions of morphine[eg.

constipation in cancer pts. on opioids]


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Differences


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NSAIDs OPIOIDS

Source Synthetic Natural alkaoids/semisynthetic/ syntheticderivatives

MOA Inhibition of PGsynthesisActs on opioid receptors(, , , , )

CNS Does not depress CNS Depress CNS

Effect on painRaises pain threshold +Also alters painperceptionOther actions Most are

antiinflammatory andantipyretic

No such action

ADEs GIT and othersNo dependence &tolerance

Dependence & tolerancemost important

Availability Many are OTC drugs Very strictly controlled

Pharmacology of opioid analgesics

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