7- NARCOTIC (opioid) ANALGESICS.ppt

Narcotic Analgesics 1 Learning Objectives • Describe Opium and Poppy and their – Active Principle - Morphine • Classify Opioid drugs (agonists and antagonists) and explain their: – – – – – – Pharmacological actions Pharmacokinetics Adverse Effects Precautions and Contraindications Interactions...

Narcotic Analgesics 1 Learning Objectives • Describe Opium and Poppy and their – Active Principle - Morphine • Classify Opioid drugs (agonists and antagonists) and explain their: – – – – – – Pharmacological actions Pharmacokinetics Adverse Effects Precautions and Contraindications Interactions Clinical uses 2 What is opium? Poppy? Opium: Poppy (Papaver somniferum) unriped seed capsules Two types of alkaloids • Phenanthrene derivatives – Morphine: 10% – Codeine: 0.5% – Thebaine • Benzoisoquinoline derivatives – Papaverine: 1% – Noscapine: 6% – Narcine 3 Chemistry Generic name Templa R1 te R2 R3 R4 Morphine A -OH -OH -CH3 -H Codeine A -OCH3 -OH -CH3 -H Heroin A -OCOCH3 -CH3 OCOCH3 -H Naloxone B -OH -O -CH2CH=CH2 -OH Levorpha nol C -OH -H -CH3 -H FOR REFERENCE ONLY Activation of nociceptive neurons Modulating mechanism in pain pathway Classification of opioids Opioid Receptors • Endogenous opioid peptides: – 3 families: Endorphins, Enkaphalins, and Dynorphins • Three classical opioid receptors: – , , and , have been studied extensively – recently discovered: N/OFQ • Analgesia – Supraspinal : 1, 3, and  – Spinal : 2, 1, and  9 FOR REFERENCE ONLY Opioids: Mechanism of Analgesia Activation of opioid receptors Inhibition of Adenylate cyclase ↓ in c-AMP: ↓ entry of Ca+ also it causes K+ efflux Hyperpolarization ↓ release of substance P, dopamine, serotonin and nociceptive peptides Block of nociceptive transmission 11 Morphine: Pharmacological actions • CNS depressant actions: – Analgesia and Sedation – Mood and subjective effects: prominent – Calming effect – Respiratory centre, Cough centre, Temp regulating centre and Vasomotor centre are depressed. • CNS Stimulatory Actions: – CTZ: Nausea and vomiting – Edinger Westphal nucleus: Miosis – Vagal centre: bradycardia occurs – Cortical and hippocampal areas: Excitation is seen 12 Morphine: Pharmacological actions_2 • Neuro-endocrine: – FSH, LH, ACTH levels: ↓ed – Prolactin and GH levels: ↑ed – Sex hormone and corticosteroid: • lowered on short term • CVS vasodilatation due to: – 1. decreasing tone of blood vessels – 2. histamine release – 3. depression of vasomotor centre Morphine: Pharmacological actions_3 • GIT: – Constipation: a prominent feature – Biliaty tract: spasm of sphincter of Oddi→pressure is increased → may cause biliary colic • Urinary bladder: – Urinary urgency and difficulty in micturition • Uterus: – slightly prolongs labour • Bronchi: – Bronchoconstriction- Morphine releases histamine Pharmacokinetics • Oral bioavailability: very less • Distribution wide; Concentrates in liver, spleen and kidney • Freely crosses placenta • Metabolized in liver by glucuronide conjugation – Morphine-6-glucuronide: an active metabolite • Undergoes Enterohepatic circulation 15 Adverse Effects • Sedation, mental clouding, lethargy and dysphoria • Vomiting is occasional • Constipation is common • Respiratory depression • Blurring of vision • Urinary retention • BP may fall (hypovolemic patients) • Apnoea: more newborn • Idiosyncrasy/allergy: Urticaria, itch, swelling of lips 16 • • • • • • • Precautions and Contraindications Infants and the elderly Respiratory insufficiency Bronchial asthma Head injury Hypotensive states and hypovolemia Undiagnosed acute abdominal pain Unstable personalities: – Liable to continue with its use and become addicted 17 Interactions • Potentiation: morphine and other opioids – Phenothiazines – Tricyclic antidepressants – MAO inhibitors – Amphetamine and – Neostigmine • Morphine delays gastric emptying: – retards absorption 18 Uses of Morphine and its congeners • As analgesic: Transdermal fentanyl – chronic cancer and terminal illness pain • Preanaesthetic medication: Morphine and pethidine • Dry and irritating Cough: Codeine or its substitutes • Balanced anaesthesia and surgical analgesia: – Fentanyl, morphine, pethidine, alfentanil or sufentanil • Relief of anxiety and apprehension myocardial infarction, internal bleeding (hematemesis, threatened abortion etc.) • Acute left ventricular failure (cardiac asthma): – Morphine IV affords dramatic relief • Diarrhea: – The constipating action of codeine 19 Tolerance and dependence • High degree of tolerance – Mainly pharmacodynamic (cellular tolerance) – Pharmacokinetic (enhanced rate of metabolism) • Tolerance: – exhibited to most actions – but not to constipating and miotic actions • Dependence: – Pronounced psychological and physical dependence – So its abuse liability is very high Tolerance and dependence_2 • Withdrawal of morphine: marked drug seeking behavior. Physical manifestations: – Lacrimation, sweating, dehydration – Anxiety, fear, restlessness – Mydriasis, tremor, rise in BP, palpitation • Opioid antagonists: Naloxone, Nalorphine – precipitate acute withdrawal syndrome in the dependent subject • Treatment: – Methadone : long acting and orally effective, followed by gradual withdrawal of methadone Codeine- COUGH • Occurs naturally in opium, and is partly converted in the body to morphine. • It is less potent than morphine (1/10th as analgesic), also less efficacious; is a partial agonist at μ opioid receptor • The degree of analgesia is comparable to aspirin (60 mg codeine ~ 600 mg aspirin); can relieve mild to moderate pain only. • codeine is more selective cough suppressant (1/3rd as potent as morphine); subanalgesic doses (10–30 mg) suppress cough • Constipation is a prominent side effect when it is used as analgesic. • Codeine has been used to control diarrhoea • Pholcodeine, Ethylmorphine- codeine like properties and have been used mainly as antitussive claimed to be less constipating Heroin (Diamorphine,Diacetylmorphine) • • • • • • It is about 3 times more potent than morphine; more lipid soluble, therefore enters the brain more rapidly, but duration of action is similar. It is considered to be more euphorient (especially on i.v. injection) and highly addicting. Because of its high potency, it has been favored in illicit drug trafficking. The sedative, emetic and hypotensive actions are said to be less prominent. However, it has no outstanding therapeutic advantage over morphine and has been banned in most countries except U.K. Pethidine • Chemically unrelated to morphine but it interacts with μ opioid receptors and • Its actions are blocked by naloxone. Important differences in comparison to morphine are: • Dose to dose 1/10th in analgesic potency • It does not effectively suppress cough. • Spasmodic action on smooth muscles is less marked—miosis, constipation and urinary retention are less prominent • It is equally sedative and euphoriant, has similar abuse potential. • The degree of respiratory depression seen at equianalgesic doses is equivalent to that with morphine • It causes less histamine release and is safer in asthmatics • Pethidine injected in patients receiving a SSRI may produce the ‘serotonin syndrome’ by enhancing 5-HT release • Tolerance and physical dependence develop slowly Fentanyl • • • • • • • • • A pethidine congener 80–100 times more potent than morphine In analgesic doses it produces few cardiovascular effects. It has less propensity to release histamine. high lipid solubility, it enters brain rapidly and produces peak analgesia in 5 min after i.v. injection. The duration of action is short: starts wearing off after 30–40 min due to redistribution, while elimination t½ is ~4 hr. In the injectable form it is almost exclusively used in anaesthesia Transdermal fentanyl has become available for use in cancer/ terminal illness or other types of chronic pain for patients requiring opioid analgesia. Buccal use is possible, but not oral Tramadol • This centrally acting analgesic is an atypical opioid which relieves pain by opioid as well as additional mechanisms. • Its affinity for µ opioid receptor is low, while that for κ and δ is very low. • Unlike other opioids, it inhibits reuptake of NA and 5-HT, increases 5HT release, and thus activates monoaminergic spinal inhibition of pain. • Its analgesic action is only partially reversed by the opioid antagonist naloxone. Injected i.v. 100 mg tramadol is equianalgesic to 10 mg i.m. morphine . • Tramadol should not be given to patients taking SSRI therapy because of risk of ‘serotonin syndrome • Tramadol is indicated for mild-to-moderate short-lasting pain due to diagnostic procedures, injury, surgery, etc, as well as for chronic pain including cancer pain, but is not effective in severe pain. COMPLEX ACTION OPIOIDS & OPIOID ANTAGONISTS 1. Agonist-antagonists (κ analgesics) •Nalorphine, Pentazocine, Butorphanol 2. Partial/weak µ agonist + κ antagonist •Buprenorphine 3. Pure antagonists •Naloxone, Naltrexone, Nalmefene Clinically, the agonist-antagonist (agonist at one opioid receptor, antagonist at another) and partial/weak agonist (low intrinsic activity) opioids are analgesics of limited efficacy equivalent to low doses of morphine. Naloxone • Competitive antagonist on all types of opioid receptors. • It blocks µ receptors at much lower doses than those needed to block κ or δ receptors. • It is devoid of any kind of agonistic activity even at high doses (20 times µ blocking dose). • No physical/psychological dependence or abstinence syndrome has been observed • Injected intravenously (0.4–0.8 mg) it promptly antagonizes all actions of morphine: analgesia is gone, respiration is not only normalized but stimulated—probably due to sudden sensitization of respiratory centre to the retained CO2. • Naloxone is the drug of choice for morphine poisoning (0.4– 0.8 mg i.v. every 2– 3 min: max 10 mg) and for reversing neonatal asphyxia due to opioid use during labour (10 μg/kg in the cord). Endogenous Opioid Peptides • Endorphins: β-endorphin (β-END) having 31 amino acids is the most important of the endorphins. It is derived from Proopiomelanocortin (POMC) which also gives rise to γ-MSH, ACTH and two lipotropins. β-END is primarily µ agonist, but also has δ action. • Enkephalins: Methionine-encephalin and leucine-encephalin are the most important. Both are pentapeptides. The two ENKs have a slightly different spectrum of activity; while met-ENK has equal affinity for µ and δ sites, leu-ENK prefers δ receptors. • Dynorphins: Dynorphin A and B (DYNA, DYN-B) are 8–17 amino acid peptides derived from prodynorphin. DYNs are more potent on κ receptors, but also activate µ and δ receptors • The opioid peptides constitute an endogenous opioid system which normally modulates pain perception, mood, hedonic (pertaining to pleasure) and motor behaviour, emesis, pituitary hormone release and g.i.t. motility, etc Notes