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, reward
NOP-Nociceptin Opiod Receptor-nociceptin
Biphasic hyperalgesic analgesic response
Reward and reinforcement

Opium is a dark brown resinous material
obtained from poppy (papaver somniferum)
capsule.
Phenanthrene derivatives-Morphine, codeine,
Thebaine
Benzisoquinoline derivatives- Papaverine,
Noscapine

Morphine analogues
Agonists -Morphine, Codeine, Diamorpine( Heroin),
Pholcodine, Levorphanol
Partial Agonists- Nalorphine, Levallorphan
Antagonists – Naloxone, Naltrexone, Nalmefene
Semi-synthetic Opiates: Hydromorphone,
Hydrocodone, Oxycodone, Oxymorphone,
Desomorphine, Diacetylmorphine (Heroin)
Classification of opiates

Synthetic Opioids:
Agonist-fentanyl, Pethidine, Alfentanil, Remifentanil,
Oxycodone, Etorphine, Methadone, Tramadol
Dextropropoxyphene
Partial Agonists- Pentazocine, Cyclazocine,
Buprenorphine, Nalbuphine, Butorphanol
Other Mode Of Action- Tramadol
Other Than Analgesic- Loperamide, Noscapine,
Diphenoxlylate, Dextromethorphan

 Similar to GPCR
 µ, δ-Inhibition of adenylate cyclase decrease in
cAMP
 Activation of K channels hyperpolarisation
decrease in excitability
 Inhibition of Ca conductance by suppressing voltage-
gated N-type Ca channels

 Analgesia-Pain relief occurs both by raising the
threshold for pain perception and by increasing pain
tolerance
 Release of glutamate from the primary pain
afferents in spinal cord and its post synaptic action
on 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 -cough
suppression

 Euphoria
 Relaxed and dreamy state, Mental clouding
 Dysphoria may occur in place of euphoria
Sedation- different to that produced by hypnotics
Drowsiness and indifference to surrounding as well as to
own 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 density
of opioid receptors in GI tract
Constricts sphincters-Constipation due to spastic
immobility of the bowel
Cardiovascular-therapeutic dose direct vasodilation
and inhibition of baroreceptor reflexes
High doseMild bradycardia and hypotension due to
histamine release and decreased sympathetic tone No
significant effects on the heart, on cardiac rhythm or
on blood pressure

 Biliary tract- it causes spasm of spincter of oddi
raise in intra biliary pressure aggravate biliary colic
 Action partly countered by atropine, completely by
naloxone and also by smooth muscle relaxants like
nitrates
 Urinary bladder-tone of both detrusor and spincter
is increased urinary urgency and difficulty in
micturition can occur.
 Bronchi-histamine release bronchoconstriction
 ANS-mild hyperglycemia due to central sympathetic
stimulation

Histamine release-Can cause bronchospasm and
hypotension, Rash, pruritus
Central cortical areas and hippocampal cells are
stimulated at high IV dosesMuscle rigidity and
immobility resemble catalepsy in rats
Vagal centre- stimulation can cause bradycardia
Convulsions may occurpro-convulsive action due
to inhbtn of GABA release by hippocampal
interneurons

 CTZ- morphine stimulates and causes nausea,
vomiting larger doses depress vomiting centre
directly, emetics should not be tried in poisoning
 Meiosis-Stimulation of Edinger-Westphal nucleus
is a central action, and no effect on topical action
 Endocrine-Inhibits release of ACTH, prolactin and
gonadotrophic 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
Intramuscular
0.1-0.2 mg.kg-1 q4hr
Subcutaneous

 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 with
opioid receptor, actions blocked by naloxone
 1/10 analgesic potency
 IM –rapid onset and shorter duration
 Tachycardia, dry mouth and blurring of
visionantimuscarinic 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 and
chronic pain.
 Requires metabolism to become analgesic
 Maximal dose 400-600 mg/day
 Post-operative, neuropathic, labour pain

 Supplied as a racemic mixture L methadone is mu
agonist and D methadone is NMDA receptor
antagonist
 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 analgesia
ADR- 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, indistinct
euphoria and dependence.
 Dysphoria, hallucinations and hypertension in high
dose
 Used for moderate or chronic pain.

Naloxone, Naltrexone
Used to reverse respiratory depression
Used as a diagnostic test in opioid addicts
Used to treat addiction after withdrawal
Caution: Naloxone t½ is 1– 2 hours
Naltrexone t½ is approximately 10 hours

 Competative antagonist
 Pure antagonist
 Withdrawal syndrome
 Morphine addicts
 Given IV
Uses –morphine overdose
Neonatal asphyxia
Diagnosis of opioid dependence

 Naltrexone is different in that it is orally
administered and has a longer duration of
effectiveness.
 Naltrexone is indicated for use in the treatment of
alcohol abuse.

Addiction (also dependence, abuse)
Loss of control over drug use
Compulsive drug use
Continued use despite harm
Physical Dependence
Stopping the drug leads to a withdrawal syndrome
Tolerance
Less effect after prolonged use; dose escalation
required 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, bowel
action
 Nausea, vomiting
 Increased pain
 Agitation, insomnia
 Dysphoria
 Dilated pupils
 Increased BP, PR, RR
 hyperventilation
 Sweaty, urine
 Diarrhoea, abdominal
cramps, hyperthermia
 Nausea, vomiting
Opioid effects
Opioid withdrawal
(Abstinence Syndrome)

Opioid agonists which does not cross BBB
• Loperamide and Racecadotril
MOA: Activation of mu-receptors decreases peristaltic
movements. Activation of delta-receptors contributes to
their antisecretory effects.
Loperamide directly stimulates mu- and delta-receptors.
Racecadotril blocks enzyme encephalinase and increases
local concentration of enkephalins in intestinal mucosa
which then stimulate mu- and delta-receptors. This drug
can be used orally from children under 5 years old (including
babies), 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

Class opiods

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Class opiods