OPIOIDS

DR. SURAJ KURMI (INTERN)DEPARTMENT OF ANESTHESIOLOGY

“Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”

OBJECTIVES

• INTRODUCTION/ TERMINOLOGY• HISTORY• CLASSIFICATION• OPIOIDS RECEPTORS AND ITS DISTRIBUTION• MECHANISM OF ACTIONS• SYSTEMIC EFFECTS• USES IN ANESTHESIA• IMPORTANT OPIOIDS AND ITS USES AND EFFECTS• OPIOD WITHDRAWAL SYNDROME

INTRODUCTION/TERMINOLOGY

• Opioids: It includes all the natural and semisynthetic alkaloid

derivatives from opium as well as their synthetic surrogates with the action that mimic those of morphine.

It includes:1. Opiates 2. Synthetic opioids( agonist, mixed agonist-

antagonist and antagonist)3. Endogenous opioids

• Opiates opiates are taken to those opiod drugs that are derived from alkaloids

of the opium poppy( papaver somniferum)Opium is a Greek word meaning “juice,” or the exudate from the

poppy

Opium is obtained from the opium poppy by incision of the seed pod after the petals of flower have dropped. The white latex that oozes out on incision turns brown and hardens on standing. This sticky brown gum opium. It contains 20 alkaloids. The principle alkaloid in opium is morphine(10%), codeine is present in <0.5%

Poppy Plant - images

Poppy to Opioids

Endogenous opiods

• Enkephalins (act through delta receptor)• Endorphins( act through mu receptor)• Dynorphins( act through kappa receptor)Enkephalins and endorphins mediate supraspinal

control of pain while dynorphins mediate pain control at spinal level.

enkephalins are responsible for producing acupuncture mediated analgesia

Opioid - History

• Friedrich Wilhelm Serturner – A German Pharmacist– Isolated Morphine in 1803 and named it after the Greek god

of Dreams “MORPHEUS”• Used for thousands of years to produce:– Euphoria– Analgesia– Sedation– Relief from diarrhea– Cough suppression

Opioid- history

• Used medicinally and recreationally from early Greek and Roman times

• Opium and laudanum (opium combined with alcohol) were used to treat almost all known diseases

• Invention of the hypodermic needle in 1856 produced drug abusers who self administered opioids by injection

• Controlling the widespread use of opioids has been unsuccessful because of the euphoria, tolerance and physiological dependence that opioids produce

Classification of Opioids

Low efficacy for mild and moderate pain High efficacy for severe painCodeineDihydrocodeinePentazocine

MorphinePethidineMethadonephenazocine

NATURALLY OCCURING SEMI-SYNTHETIC SYNTHETIC

• Morphine• Codeine• Thebaine

• Heroin• Dihydromorphone• Oxymorphone• Pentamorphone

• Butorphanol• Levorphanol• Pethidine• Fentanyl, alfentanil,sufentanil• Tramadol• Buprenorphine

CLASSIFICATION ON BASIS OF RECEPTOR INTERACTION

PURE AGONIST AGONIST ANTAGONIST PURE ANTAGONIST

•Morphine•Fentanyl•Alfentanil•Sulfentanil•Pethidine

•Pentazocine•Butorphanol•Nalorphine•Buprenorphine•Dezocine

•Naloxone•Naltrexone•Nalmefene•Diprenorphine•Methylnaltrexone

1. Pure agonist: are agonist to all opioid receptors with highest propensity for mu receptors

2. Agonist-antagonist: All agonist and antagonist (except buprenorphine and dezocine) are agonist at kappa and sigma receptor and antagonist at mu receptor.. Buprenorphine and dezocine are classified as partial agonist antagonist as at low dose they are agonist at mu receptor whereas at high dose become antagonist. Produces ceiling effect.

3. Pure antagonist: antagonist to all receptor

OPIOID RECEPTORS

• Mainly 3 (three) types of receptors – μ (mu), κ (kappa) and δ (delta)

• Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2 • Location: Peripheral Nerve endings, SG in spinal chord,

Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala

• Sigma receptors are not considered as opioid receptors as they are not activated by morphine and not blocked by naloxone. Actions mediated by it are : dysphoria, hallucination,tachycardia and htn

• Nociceptin(orphanin FQ) has been identified as new opiod receptor through which endogenous opiod act.

Distribution of opiod receptors

• Dorsal horn of spinal cord• Subcortical regions of brainThalamusMidbrain periaqueductal grayRostral ventral medulla sites(nucleus raphe magnus)• Locus ceruleus of brainstem• Hypothalamic nuclei

Receptors and its effects

μ (mu) receptors• μ 1: mediates analgesia (supraspinal),sedation, miosis,

urinary retention, muscle rigidity, prolactin release• μ 2: mediates respiratory depressionK (KAPPA) receptor:• K1: mediates spinal analgesia• K3: mediates supraspinal analgesiaδ (delta) receptor: mediates analgesia at spinal level,

respiratory depression and dependence.

MECHANISM OF ACTION OF OPIOIDS

SUPRASPINAL: opioids binds with receptors in rostroventral region of medulla and cause stimulation of off cells present there, thereby blocking nociceptive stimuli transmission

SPINAL LEVEL: act in substantia gelatinosa of dorsal horn cells and inhibit the release of excitatory transmitters

Cellular level: opioids bind with the receptors and stimulate G protein synthesis and increases cAMP which causes:

Increase K+: hyperpolarization of membraneDecreases calcium: decreases excitability

Mechanism

All are G protein coupled receptors• inhibit adenylyl cyclase• Associated with ion channels, 1. ↑ postsynaptic K+ efflux

(hyperpolarization) 2. ↓ presynaptic Ca+2 influx leading

to inhibition of excitatory neurotransmitter release

Uses in anesthesia

Mainly used for analgesia, for both intraoperative and postoperative Blunting cardiovascular reponse to intubation. Fentanyl is most

commonly used but sulfentanil is the agent of choice Painless labour (fentanyl+bupivacaine by epidural route) Sedation in ICU Pulmonary edema ( morphine is the agent of choice) Intraoperative myocardial ischemia( morphine is used) To abolish shivering( pethidine ad tramadol) For day care surgery( propofol+remifentanil is the combination of

choice)

Systemic effects

CARDIOVASCULAR SYSTEMHYPOTENSION: due to decreased central sympathetic tone.(minimum with fentanyl) . Pethidine and pentazocine causes hypertension

BRADYCARDIA,( except pentazocine and pethidine causes tachycardia)

Shifting of blood from pulmonary to systemic circulation( Rx of left ventricular failure)

Vasolidation, Decrease peripheral vascular resistance, Decrease pulmonary vascular resisitance

RESPIRATORY SYSTEM

•Respiratory depression• Medulla: mu2 receptor• Decreases both the rate and volume• Usual cause of death in opioid poisoning

•Bronchospasm• Morphine, pethidine: histamine release• Directly acting on bronchial muscle opiods

are bronchodilator but can cause bronchoconstriction by release of histamine

•Inhibits airway and tracheal reflex(so used in intubation and laryngoscopy and used in cough syrups(codeine))

Central nervous system

•Analgesia, visceral pain more relieved than somatic pain•Sedation: sedation at lower dose which progress to deep coma in high dose•Decrease cerebral metabolic rate(cmr), cbf(cerebral blood flow) and icp in resting brain but increses in head injury and icsol•EEG: produces high voltage slow waves( delta) but cannot cause flattening due to ceiling effect•Nausea and vomiting due to stimulation of CTZ•Mood changes and mental clouding•Hypothermia•Convulsions

Systemic effects

• Muscular system:can cause muscle rigidity which can sometime severe in thoracic muscle that hypoxia occurs.( wooden chest syndrome or stiff chest syndrome)

• GIT: Decrease peristalsis• Ileus• Constipation

• Constriction of sphincter of oddi and Increase of biliary duct pressure• Urinary system: urinary retention due to relaxation of urinary bladder• Eye: causes miosis, decreases IOP

Systemic effects

• Endocrine: stress hormones decresed like ACTH,FSH,LH and cortisol. Whereas ADH, GH and prolactin synthesis increased

• Decrease effect of shivering: pethidine• Tolerance, physical dependence and

addiction

Pharmacodynamics(effects of opioid)

Systemic effects

Opioid agonist

MORPHINE• Clearance mainly by hepatic biotransformation

• M-3-glucuronide (inactive) • M-6-glucuronide,highly active metabolite

• Metabolites cleared by kidney• Plasma half life:2 hr duration of analgesia: 4-6hrs• Dose: 0.1-0.2mg/kg • Route: iv, im, subcutaneous, oral, epidural, intrathecal• Respiratory depression in renal failure• Death from morphine poisoning : respiratory arrest

Morphine

Indications: As analgesic in visceral pain, following operation, terminal illness(cancer), burn Myocardial infarction Travelers diarrhea To suppress cough Acute LVF and pulmonary edema

Contrainication Respiratory depression Nausea. Vomiting Constipation, biliary and ureteric spasm Hypotension Bronchospasm

Pethidine(meperidine)

• It is a synthetic morphine• 1/10th potent than morphine• Short duration of action(2-3hr).• Large dose shows anticholinergic effect: mydriasis, antispasmodic action,

atropine like side effects • Histamine release is less than morphine• Metabolic producxt of pethidine noepethidine can cause convulsion and

delirium.• Pethidine abolishes shivering so drug of choice in shivering.• Contraindicated in mao inhibitor therapy and in patient with myocardial

ischemia(as it depresses myocardium)• Dose is 0.1-1mg/kg

Fentanyl

• 100 times more potent than morphine• Due to high lipid solubility it has rapid onset( 2-5 minute) and rapid

recovery(1-2hrs)• Can be given im, iv, tranmucosal(fentanyl lollipop), transdermal(fentanyl

patch), intrathecal and epidural route• Cardiac stability• With bupivacaine used epidurally for painless labour• Fentanyl can produce significant muscle rigidity• Dose: 2-5mcg/kg• Sulfentanil analogue of fentanyl is 500 times more potent than morphine,

agent of choice for inhibiting stress response to laryngoscopy and intubation

Tramadol

• Synthetic derivative of codeine • Produces analgesia by dual mechanism: first by acting on

opioid receptor and secondly by increasing serotonin levels• 2nd drug of choice in shivering

Other opioid agonistCodeine: used for suppressing coughHeroin: highest addiction potentialMethadone: used in prevention of opiod withdrawal symptoms

Agonist -antagonist

Produces ceiling to respiratory depression.PENTAZOCINE( FORTWIN) Agonist at kappa and delta receptor and antagonist at mu receptor Mainly acts on kappa receptors at spinal level Causes tachycardia and hypertension Depress respiration but has ceiling effect on respiratory depression Less nausea/vomiting Less addiction potential than morphine Dose: 1mg/kg can be given iv, im, routes Pentazocine is used for sequential analgesic anesthesia. Th this technique

pentazocine is administered after fentanyl is given in moderate doses

Buprenorphine

• mu agonist at low dose but become antagonist at high dose(after 1.2mg in adults), so respiratoey depression which may be seen intially is reversed and there is increased ventilation.

• 25 times more potent than morphine• Dose: 0.3mg

Opioid antagonist

Naloxone

Acts on all receptors with maximum propensity for mu receptors Reverses the action of all opioIds with partial reversal of buprenorphine Onset of action is 1-2 minutes and duration of action is 30-60 minutes Metabolized in liver Systemic effects: cvs- causes sympathetic stimulation and produces

severe hypertension and tachycardia and in cns causes incresed metabolic rate, oxygen consumption and blood flow(increse icp)

Naloxone

Contraindication Myocardial ischemia Intracranial lesion Pheochromocytoma

Uses of naloxone:• Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min, maximum 10 mg.• Reverse the effect of diazepam, barbiturates(though GABA receptor), nitrous oxide,

endogenous opioids, alcohol, ketamine• Diagnosis of opioid dependence• Treating neonatal asphyxia if opioid are used during labour• Treatment of septicemia, hypovolemic and spinal shock• In treating alzheimer’s disease. schizophrenia.

Opiate withdrawal syndrome

Opiate withdrawal syndrome

Treatment: withdrawal of morphine and substitution with oral methadone, followed by gradual withdrawal of methadone

Drug interactions

• The depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs.

• Analgesia enhanced by: Low doses of amphetamine & hydroxyzine.

THANK YOU FOR YOUR ATTENTION