Pharmacology of opiod analgesics.txt

• 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

• 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

• 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

• 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

• 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

promotes renal excretion of drugs

• analgesia
• euphoria
• miosis
• respiratory depression
• cough suppression
• nausea/vomiting
• mood altering / rewarding 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)

• 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

due to excitation of the parasympathetic nerve innervating the pupil

• 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

• 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

• 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

• 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

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

• 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

• Morphine decreases propulsive peristalsis through GI tract: leads to constipation
• Morphine suppresses awareness of bowel stimuli

• 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

• Morphine causes urinary hesitancy and urinary urgency: increased tone of bladder smooth muscle; increased tone of sphincter muscle
• Morphine suppresses awareness of bladder stimuli!!: ***

• 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

• Tolerance: tolerance develops to - analgesia; respiratory depression
• Tolerance does not develop to: constipation; pupillary mitosis
• Depencence: too

• Triad of 3 signs strongly suggests opioid poisoning:
• Coma
• Pinpoint pupils
• Depressed respiration

• Maintain patent airway and ventilate the patient
• Treat with antagonists to reverse CNS effects - Naloxone is drug of choice

• 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

Morphine binds to opiate receptors concentrated within the reward pathway and the pain pathway

• Spinal and supra-spinal analgesia
• Miosis
• Respiratory depression
• Euphoria
• Physical dependence
• decreased GI motility

• Spinal analgesia
• Miosis- less intense than Mu
• Respiratory depression - less intense than Mu
• Sedation
• Durphoria

• Opioid drugs produce analgesia by activating the same receptors that are acted on by the endogenous pain suppressing system:
• enkephalins
• endorphins
• dynorphins

have similar structures and produce the same psychic effects

• 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

• 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