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Pharmacology of opiod analgesics
- Nociceptive pain: results from injury to tissues - somatic and visceral pain
- Neuropathic pain: results from injury to peripheral nerves
- both types respond differently to analgesic drugs
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Nociceptive pain
- Somatic: from injury to tissues - bones, joints, muscles; localized and sharp in quality
- Visceral: Results from injury to visceral organs - e.g. small intestine; vaguely localized with a diffuse aching quality
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Opium alkaloids
- Morphine: chiefly responsible for pharmacological actions of opium
- Codeine: methylmorphine, has similar but weaker actions
- Thebaine: practically devoid of analgesic activity; no medicinal use, but it provides a synthetic route for hydroxylated opioids
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Structural relationships among some opiates
- heroin is converted to morphine - on its own has no activity
- Codeine - has increased bioavailability but decreased action
- Naloxone: perfect antagonist blocks pharmacological action of heroin
- Oxycodone: have methyl group at 3 position increases bioavailability but decreased action
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Opiods: absorption, distribution, metabolism, excretion
- absorption: absorbed well IM, SC, and oral and nasal mucosa
- rapidly distributed: from blood into highly perfused tissues (lung, liver, kidney, spleen) - brain < other tissues, due to BBB
- First pass metabolism: in the liver inactivates many opiods (e.g. morphine)
- Polar metabolites are excreted: in urine
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Glucoronidation of opioids
promotes renal excretion of drugs
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Pharmacological Actions of Morphine: CNS
- analgesia
- euphoria
- miosis
- respiratory depression
- cough suppression
- nausea/vomiting
- mood altering / rewarding properties
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Analgesic properties
- Relief of moderate to severe acute pain
- renal colic
- biliary colic
- acute MI
- dyspnea associated with LVF and pulmonary edema
- extensive surgical procedures and post-operative pain
- severe burns*
- serious wounding*
- severe chronic pain (e.g., associated with malignancy)
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Continuous dull pain***
- is relieved more effectively than sharp intermittent pain: Adelta fibers; sharp pain is more memorable, and dull pain tends to be forgotten
- In patients suffering from pain, morphine induces a feeling of well being and tranquility (euphoria)
- In pain-free individuals, the response to morphine is not always present!!: general malaise; sensations of anxiety or fear (dysphoria); also nausea and vomiting
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Miosis
due to excitation of the parasympathetic nerve innervating the pupil
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Respiration
- Morphine depresses respiration, even at normal therapeutic doses: due to decreased sensitivity of brain stem to increases in Pco2 and H+
- The main stimulus to breathing at this point: becomes hypoxia
- This effect is increased by the concurrent use of other CNS active drugs: alcohol, barbiturates, benzodiazepines
- Caution: pregnancy (neonate)**** b/c fetal respiratory drive will also be affected
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Respiration effects
- Suppression of respiratory drive contributes to usefulness of morphine in relieving difficult or labored breathing in certain conditions such as
- Left ventricular failure - very difficult to breathe, decreased respiration, lower "depth" of respiration
- Pulmonary edema
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Morphine increases intracranial pressure
- Mechanism: indirect
- Decreased respiration, increased pCO2 -> causes arteriolar dilatation -> CSF pressure
- But, if respiration is maintained at a normal rate, ICP will remain normal: especially if ask the patient to breathe consciously more
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Antitussive action
- Morphine suppresses the cough reflex that originates in the medulla oblongata: unrelated to its analgesic action, unrelated to its respiratory depressant action
- Can modify the morphine molecule to select this single property: dextromethorphan
- Dextromethorphan: cough suppressant - binds possibly at glutamate receptors, not morphine receptors
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Emesis
Morphine stimulates the CTZ in the medulla to cause nausea and vomiting: a vestibular component? possibly because people laying down have less than those with an orthostatic change
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Cardiovascular system
- Blunts the baroreceptor reflex
- Causes peripheral arteriolar and venous dilatation: results, in part, from morphine-induced release of histamine
- Orthostatic hypotension and fainting: in recumbent individuals, effect is mild; in standing individuals, the effect is profound
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GI Tract
- Morphine decreases propulsive peristalsis through GI tract: leads to constipation
- Morphine suppresses awareness of bowel stimuli
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Propulsive peristalsis through GI tract is decreased
- Passage of GI contents is delude
- This leads to enhanced absorption of water: dehydration of feces
- Tone of anal sphincter is increased: the constipation action of morphine
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Urinary retention
- Morphine causes urinary hesitancy and urinary urgency: increased tone of bladder smooth muscle; increased tone of sphincter muscle
- Morphine suppresses awareness of bladder stimuli!!: ***
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Biliary colic
- Morphine can cause spasm of the lower end of the common bile duct (the sphincter of oddi)
- increases pressure within the biliary tract
- in patients with pre-existing biliary colic, morphine can intensify the pain
- so DON'T GIVE MORPHINE TO A PT UNLESS YOU KNOW WHAT THE CAUSE OF THE PAIN IS
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Chronic Actions of Morphine
- Tolerance: tolerance develops to - analgesia; respiratory depression
- Tolerance does not develop to: constipation; pupillary mitosis
- Depencence: too
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Opioid poisoning
- Triad of 3 signs strongly suggests opioid poisoning:
- Coma
- Pinpoint pupils
- Depressed respiration
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Treatment of opioid poisoning
- Maintain patent airway and ventilate the patient
- Treat with antagonists to reverse CNS effects - Naloxone is drug of choice
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Mechanism of action - the morphine receptor
- Morphine binds to a specific receptor:
- binding is stereospecific: only the L-isomer is active; implies that binding involves at least three binding sites
- Regional distribution: the regions of highest binding are associated with the limbic system
- Three principal receptors: mu, kappa, delta
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Opiate binding sites
Morphine binds to opiate receptors concentrated within the reward pathway and the pain pathway
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Mu Morphine receptor
- Spinal and supra-spinal analgesia
- Miosis
- Respiratory depression
- Euphoria
- Physical dependence
- decreased GI motility
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Kappa Morphine Receptor
- Spinal analgesia
- Miosis- less intense than Mu
- Respiratory depression - less intense than Mu
- Sedation
- Durphoria
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Endogenous opioids
- Opioid drugs produce analgesia by activating the same receptors that are acted on by the endogenous pain suppressing system:
- enkephalins
- endorphins
- dynorphins
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Enkephalins:
have similar structures and produce the same psychic effects
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Mechanisms of Action
- Opioid receptors respond to opioids and to endogenous peptides (suppress painful simuli)
- Opioids work both presynaptically and post-synaptically:
- In general, opioid receptors are G-protein-coupled receptors
- Activation reduces Ca++ influx during the action potential, leading to less neurotransmitter release
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Spinal sites of opioid action
- Mu, Kappa, delta agonists reduce transmitter release from presynaptic terminals of nociceptive primary afferents
- Mu agonists also hyperpolarize second-order neurons: by increasing K+ conductance -> imps
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