Opioid Analgesics and Antagonists PDF

Opioid Analgesics and Antagonists Dr. Anuroop Singhai Oral Surgery Division Opioid Analgesics and Antagonists Introduction Opium The dark brown, resinous material obtained from poppy (Papaver somniferum) capsule is called ‘Opium’. It contains two types of alkaloids. o Phenanthrene derivatives § Morp...

Opioid Analgesics and Antagonists Dr. Anuroop Singhai Oral Surgery Division Opioid Analgesics and Antagonists Introduction Opium The dark brown, resinous material obtained from poppy (Papaver somniferum) capsule is called ‘Opium’. It contains two types of alkaloids. o Phenanthrene derivatives § Morphine (10% in opium) § Codeine (0.5% in opium) o Benzoisoquinoline derivatives § Papaverine (1%) Nonanalgesic § Noscapine (6%) CLASSIFICATION OF OPIOIDS OPIODS Synthetic Natural opium alkaloids Semisynthetic Pethidine (Meperidine) Morphine Diacetylmorphine (Heroin) Codeine Pholcodeine Fentanyl, Alfentanil, Sufentanil, Remifentanil Methadone Dextropropoxyphene Tramadol MORPHINE Morphine is the principal alkaloid in opium and is described as prototype of this class of drugs. Pharmacological actions Central Nervous System Morphine has site specific depressant and stimulant actions in the CNS produced primarily through interaction with μ opioid receptor as a full agonist. MORPHINE – Pharmacological actions (CNS - depression) The depressant effects are: 1. Analgesia: Morphine is a strong analgesic. Though dull, poorly localized visceral pain is relieved better than sharply defined somatic pain; higher doses can mitigate even severe pain—degree of analgesia increasing with dose. Perception of pain and its emotional or suffering component are both altered so that pain is no longer as unpleasant or distressing, i.e. the patient tolerates pain better. MORPHINE – Pharmacological actions (CNS - depression) 2. Sedation: The character of sedation caused by morphine is different from that produced by hypnotics. Drowsiness, indifference to surroundings and to own body occurs without motor incoordination and ataxia or apparent excitement (contrast alcohol). Higher doses progressively produce sleep and coma. It has no anticonvulsant action, rather, fits may be precipitated. MORPHINE – Pharmacological actions (CNS - depression) 3. Mood and subjective effects: These effects are prominent. Morphine has a calming effect; there is loss of apprehension, feeling of detachment, lack of initiative, limbs feel heavy and body warm, mental clouding and inability to concentrate occurs. In the absence of pain or apprehension, these effects are generally appreciated as unpleasant by normal people. However, patients in pain or anxiety and especially addicts, perceive it as pleasurable: refer it as ‘high’. Thus, one has to learn to perceive the euphoric effect of morphine. MORPHINE – Pharmacological actions (CNS - depression) 4. Respiratory centre: Morphine depresses respiratory centre in a dose-dependent manner; rate and tidal volume are both decreased. However, analgesic dose in an otherwise healthy individual produces no cognizable respiratory depression. But the same may be marked in sedated patients or those with pulmonary/cardiac/hepatic/ renal disease. The cause of death in morphine poisoning is respiratory failure. MORPHINE – Pharmacological actions (CNS - depression) 5. Cough centre: It is depressed; more sensitive to morphine than respiratory centre. 6. Temperature regulating centre: It is depressed; hypothermia occurs in cold surroundings. 7. Vasomotor centre: It is depressed at higher doses and contributes to the fall in BP. MORPHINE – Pharmacological actions (CNS - stimulation) Morphine stimulates: 1. CTZ: Nausea and vomiting occur as side effects, especially if stomach is full and the patient stands or moves about. Thus, morphine appears to sensitize the CTZ to vestibular and other impulses. Larger doses depress vomiting centre directly: emetics should not be tried in morphine poisoning. 2. Edinger Westphal nucleus of III nerve: Is stimulated producing miosis. No miosis occurs on topical application of morphine to the eye because it is a central action exerted in the brain. MORPHINE – Pharmacological actions (CNS - stimulation) 3. Vagal centre: It is stimulated; morphine can cause bradycardia. 4. Certain cortical areas and hippocampal cells: These are stimulated. Muscular rigidity and immobility is consistently manifested at high doses. Convulsions may occur in morphine poisoning. The proconvulsant action has been ascribed to inhibition of GABA release by hippocampal interneurones. MORPHINE – Pharmacological actions (Neuro-endocrine) Neuro-endocrine 1. Morphine weakens hypothalamic influence on pituitary. 2. ACTH, FSH and LH levels – fall. 3. GH and prolactin release - increase. 4. Effect on sex hormone levels are clinically insignificant, except in heavy abusers, who may suffer from impotence, menstrual irregularities, and infertility. 5. Morphine enhances ADH release and can reduce urine volume. 6. It also causes central sympathetic stimulation resulting in mild hyperglycaemia. MORPHINE – Pharmacological actions (CVS) CVS Morphine causes vasodilatation due to: a) Histamine release. b) Depression of vasomotor centre. c) Direct action decreasing tone of blood vessels. There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter. Therapeutic doses cause little change in BP of recumbent normovolaemic patient. Postural hypotension and fainting can occur due to vasodilatation and impairment of vascular reflexes. Morphine has little direct effect on heart. Cardiac work is consistently reduced due to decrease in peripheral resistance imparting antiischaemic property. Intracranial tension tends to rise as a consequence of CO2 retention leading to cerebral vasodilatation. MORPHINE – Pharmacological actions (GIT) GIT: Constipation is a prominent feature of morphine action. Several factors contribute: 1. Action directly on intestines and in CNS increases tone and segmentation but decreases propulsive movements. 2. Tone of duodenum and colon may be increased to the level of spasm. 3. Spasm of pyloric, ileocaecal and anal sphincters. 4. Decrease in all gastrointestinal secretions. 5. Central action causing inattention to defecation reflex. No tolerance develops to this action: addicts remain chronically constipated. MORPHINE – Pharmacological actions (Other smooth muscles) Other smooth muscles: a) Biliary tract Morphine causes spasm of sphincter of Oddi → intrabiliary pressure is increased → may cause biliary colic. b) Urinary bladder Tone of both detrusor and sphincter is increased → urinary urgency and difficulty in micturition. c) Bronchi Morphine releases histamine which can cause bronchoconstriction. This is of no consequence in normal individuals, but can be dangerous in asthmatics. MORPHINE – Pharmacological actions summary MORPHINE – Pharmacokinetics Pharmacokinetics The oral absorption of morphine is unreliable because of high and variable first pass metabolism; oral bioavailability is 1/6 to 1/4th of parenterally administered drug. About 30% is bound to plasma proteins. Only a small fraction enters brain rather slowly. Morphine freely crosses placenta and can affect the foetus more than the mother. It is primarily metabolized in liver by glucuronide conjugation. Plasma t1⁄2 life of morphine averages 2–3 hours. Effect of a parenteral dose lasts 4–6 hours. Elimination is almost complete in 24 hours and morphine is noncumulative. Small amounts may persist due to enterohepatic circulation.