CLASS OPIODS

Stimulus Nociceptors Ascending afferent pathways Fast A delta fibres

▪ Sharp, well-localised pain Slow C fibres

▪ Dull, poorly localised pain Spinothalamic and spinoreticular tracts ascend to

brain

Mu ()- Endomorphins- 1&2 Located at supraspinal and spinal sites Analgesia and respiratory depression Mioisis, euphoria, reduced GI motility Morphine and pure agonists affinity Naloxone –blocks action

Kappa ()- Dynorphin-A Dorsal horn of spinal cord and brain stem Analgesia, miosis, sedation Mixed agonist and antagonist affinity

Delta ()- Enkephalins Binding sites for endogenous peptides Spinal analgesia, dysphoria, delusions,

hallucinations, rewardNOP-Nociceptin Opiod Receptor-nociceptinBiphasic hyperalgesic analgesic responseReward and reinforcement

Opium is a dark brown resinous materialobtained from poppy (papaver somniferum)capsule.Phenanthrene derivatives-Morphine, codeine,Thebaine

Benzisoquinoline derivatives- Papaverine,Noscapine

Morphine analoguesAgonists -Morphine, Codeine, Diamorpine( Heroin),Pholcodine, LevorphanolPartial Agonists- Nalorphine, LevallorphanAntagonists – Naloxone, Naltrexone, NalmefeneSemi-synthetic Opiates: Hydromorphone,Hydrocodone, Oxycodone, Oxymorphone,Desomorphine, Diacetylmorphine (Heroin)

Classification of opiates

Synthetic Opioids:Agonist-fentanyl, Pethidine, Alfentanil, Remifentanil,Oxycodone, Etorphine, Methadone, TramadolDextropropoxyphenePartial Agonists- Pentazocine, Cyclazocine,Buprenorphine, Nalbuphine, ButorphanolOther Mode Of Action- TramadolOther Than Analgesic- Loperamide, Noscapine,Diphenoxlylate, Dextromethorphan

Similar to GPCR µ, δ-Inhibition of adenylate cyclasedecrease in

cAMP Activation of K channels hyperpolarisationdecrease in excitability

Inhibition of Ca conductance by suppressing voltage-gated N-type Ca channels

Analgesia-Pain relief occurs both by raising thethreshold for pain perception and by increasing paintolerance

Release of glutamate from the primary painafferents in spinal cord and its post synaptic actionon dorsla horn neuron is inhibited

Respiratory depression-Neurogenic (RAS), Chemical(hypercapnoeic), Hypoxic,

sensitivity of the respiratory center to CO2 Analgesia and respiratory depression are inseparable

and increase with dose in parallel -coughsuppression

Euphoria Relaxed and dreamy state, Mental clouding Dysphoria may occur in place of euphoria

Sedation- different to that produced by hypnoticsDrowsiness and indifference to surrounding as well as toown body occurs without motar inco-ordination, ataxia More likely to occur in the elderly Less likely to occur with synthetic opioids Additive with other CNS depressants

Gastrointestinal tract- nausea, vomiting, High densityof opioid receptors in GI tractConstricts sphincters-Constipation due to spasticimmobility of the bowelCardiovascular-therapeutic dosedirect vasodilationand inhibition of baroreceptor reflexesHigh doseMild bradycardia and hypotension due tohistamine release and decreased sympathetic tone Nosignificant effects on the heart, on cardiac rhythm oron blood pressure

Biliary tract- it causes spasm of spincter of oddiraise in intra biliary pressure aggravate biliary colic

Action partly countered by atropine, completely bynaloxone and also by smooth muscle relaxants likenitrates

Urinary bladder-tone of both detrusor and spincteris increased urinary urgency and difficulty inmicturition can occur.

Bronchi-histamine release bronchoconstriction ANS-mild hyperglycemia due to central sympathetic

stimulation

Histamine release-Can cause bronchospasm andhypotension, Rash, pruritusCentral cortical areas and hippocampal cells arestimulated at high IV dosesMuscle rigidity andimmobility resemble catalepsy in ratsVagal centre- stimulation can cause bradycardiaConvulsions may occurpro-convulsive action dueto inhbtn of GABA release by hippocampalinterneurons

CTZ- morphine stimulates and causes nausea,vomiting larger doses depress vomiting centredirectly, emetics should not be tried in poisoning

Meiosis-Stimulation of Edinger-Westphal nucleusis a central action, and no effect on topical action

Endocrine-Inhibits release of ACTH, prolactin andgonadotrophic hormones Increased ADH – impaired water excretion and

hyponatremia Urinary-Increased tone of bladder detrusor and

vesicle sphincter – urinary retention

Primary constituent of crude opium

Strong agonist and prototypical narcotic analgesic

Used in the treatment of moderate-severe pain

t½ range: 1-6 hours

Bioavailability 30%Hepatic first pass metabolism

Intramuscular0.1-0.2 mg.kg-1 q4hrSubcutaneous

Liver – Conjugation and enterohepatic circulation Morphine-3-glucuronide – 80% Morphine-6-glucuronide – 10%

▪ Active - 13x potency of morphine

Metabolites are renally excreted Chronic Kidney Disease is a relative

contraindication to use

Synthetic Morphine derivative (diacetylmorphine,

diamorphine) penetration of the blood-brain barrier t½ approximately 5 minutes 6-MAM(6-

MonoAcetyl Morphine) Banned in most countries

Minor constituent of opium First-pass effect < morphine Used in the treatment of mild-moderate pain t½ range: 2 – 4 hours 1/10th – 1/6th analgesic potency of morphine Used in combination with other analgesics Antitussive action > morphine Good activity by oral route-(1:2) Lesser constipation and lesser respiratory depression

Not an analgesic unless metabolized to morphine Up to 10% of population are poor metabolizers –

little or no analgesia from codeine Rapid metabolizers also may have little analgesia Ceiling dose: 360mg/day

Chemically unrelated to morphine, interacts withopioid receptor, actions blocked by naloxone

1/10 analgesic potency IM –rapid onset and shorter duration Tachycardia, dry mouth and blurring of

visionantimuscarinic action Has sedative and euphoriant action Nor-pethidine-CNS stimulation, tremors,

restlessness and convulsions Uses –analgesis, labour and preanaesthetic

Metabolite of trazadone weak receptor agonist, inhibits uptake of NA and

5-HT, effective on moderate to severe acute andchronic pain.

Requires metabolism to become analgesic Maximal dose 400-600 mg/day Post-operative, neuropathic, labour pain

Supplied as a racemic mixtureL methadone is muagonist and D methadone is NMDA receptorantagonist

Synthetic, Long acting—13-47 hrs Half life variable but average is 24 hours – needs

slow titration Highly lipophilic – good in renal dialysis Oral/ rectal/ sc/iv Neuropathic and cancer pain No active metabolites

Synthetic phenylpiperidine derivative (pethidine) µ- and κ-receptor agonist 100 times potent than morphine Highy lipid soluble, safer in cardiovascular surgeries Used as a pre-medicant before surgery and in the

treatment of moderate-severe pain Not a histamine liberator and does not increase ICT t½ range: 3 – 12 hours Neurolept analgesia, obstetric analgesiaADR- muscle rigidity, respiratory depression

Synthetic phenylpiperidine derivative µ-receptor agonist pKa 6.5 89% un-ionised at pH 7.4 Lipid solubility ~90x morphine Comparison with fentanyl Less lipid soluble Lower pKa, greater percentage is un-ionised at

physiologic pH▪ Faster onset of action

An agonist on receptor, but a weak antagonist at and receptors (partial agonist).

Actions (less potent compared with morphine):analgesia and respiratory depression, indistincteuphoria and dependence.

Dysphoria, hallucinations and hypertension in highdose

Used for moderate or chronic pain.

Naloxone, NaltrexoneUsed to reverse respiratory depressionUsed as a diagnostic test in opioid addictsUsed to treat addiction after withdrawal

Caution: Naloxone t½ is 1– 2 hoursNaltrexone t½ is approximately 10 hours

Competative antagonist Pure antagonist Withdrawal syndrome Morphine addicts Given IVUses –morphine overdoseNeonatal asphyxiaDiagnosis of opioid dependence

Naltrexone is different in that it is orallyadministered and has a longer duration ofeffectiveness.

Naltrexone is indicated for use in the treatment ofalcohol abuse.

Addiction (also dependence, abuse)Loss of control over drug useCompulsive drug useContinued use despite harm

Physical DependenceStopping the drug leads to a withdrawal syndrome

ToleranceLess effect after prolonged use; dose escalationrequired to maintain effect

Negligible tolerance to miosis and constipation High degree of tolerance develops to the central

nervous system effects of opioids: Analgesia, Euphoria, Sedation, Respiratory

depression Requires increased dosages in long-term users survivability at high blood concentrations Conclusions about toxicity of opioids cannot be

drawn on measurement of blood levels alone

Analgesia Sedation Euphoria Pinpoint pupils Low BP, PR, RR Dry skin, mouth,urine

Constipation, bowelaction

Nausea, vomiting

Increased pain Agitation, insomnia Dysphoria Dilated pupils Increased BP, PR, RR hyperventilation Sweaty,urine Diarrhoea, abdominal

cramps, hyperthermia Nausea, vomiting

Opioid effectsOpioid withdrawal(Abstinence Syndrome)

Opioid agonists which does not cross BBB• Loperamide and Racecadotril

MOA: Activation of mu-receptors decreases peristalticmovements. Activation of delta-receptors contributes totheir antisecretory effects.Loperamide directly stimulates mu- and delta-receptors.Racecadotril blocks enzyme encephalinase and increaseslocal concentration of enkephalins in intestinal mucosawhich then stimulate mu- and delta-receptors. This drugcan be used orally from children under 5 years old (includingbabies), but

Loperamide is contraindicated in children < 5 years old.

Analgesia Severe diarrhea Cough suppressant Maintenance of opioid dependence

Methadone & buprenorphine / naloxone

Long-term administration

Blocks effects of opioids↓illicit use