Pharmacology - Opioid Analgesics, Agonist-Antagonists, & Antitussives

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Receptor Types

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- 3 major classes: miu, delta, and kappa
- they are G-protein linked receptors, coupled to inhibition of adenylyl cyclase, activation of receptor-operated potassium channels, and suppression of voltage-operated Ca channels
- analgesia, euphoria, resp depression, and physiological dependance result from activation of miu receptors

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Cellular Actions of Opioids

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2 actions

1. close voltage-gated Ca channels on PRESYNAPTIC nerve terminals --> reduce NT release

2. open K channels --> hyperpolarization --> inhibition of POSTSYNAPTIC neurons

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Analgesic Effects of Opioids

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arise from their ability to directly inhibit the ascending transmission of nociceptive info from the spinal cord dorsal horn and to indirectly activate pain-inhibitory circuits

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Spinal Analgesia

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- all three types of receptors present in dorsal horn of spinal cord (pain tranmission neurons) and presynaptically on the primary afferents relaying the pain
- Actions: inhibit release of excitatory NT (substance P and glutamate) from primary afferents; directly inhibit dorsal horn pain transmission
- thus spinal analgesics provide regional analgesic effects while min the unwanted resp depression, nausea/vomit, and sedation that occur from supraspinal axns

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Supraspinal Analgesia

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- pain-inhibitory descending neurons send processes to spinal cord and inhibit pain transmission neurons
- activated by opioids resulting from the inhibition of inhibitory neurons

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Peripheral Analgesia

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- there are opioid miu receptors on peripheral terminals of sensory neurons
- stimulation of peripheral miu receptors decreases sensory neuron activity and NT release

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CNS Effects of Opioids

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- Analgesia
- Euphoria
- Sedation and drowsiness (ameliorated w/ amphetamine, methylphenidate, or modafil)
- Resp depression
- Cough suppression
- Miosis
- Truncal rigidity (axn at supraspinal levels)
- Nausea and vomiting (CTZ)

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Peripheral Effects of Opioids

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- Hypotension (inhibition of vasomotor centre in brainstem causing vasodilation, inhibit baroreceptor reflex, increase histamine)
- GIT - constipation
- Biliary tract - contract biliary SM
- Gentourinary tract - dec renal plasma flow --> depressed renal fxn
- Uterus - prolong labor
- Neuroendocrine - stimulate release of ADH, PRL, and somatotropin, and inhibit LH)
- Pruritis

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Metabolism of Opioids

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- opioids converted to polar metabolites (mostly glucuronides) that are excreted by the kidneys
- morphine --> M3G (neuroexcitatory) + M6G (active metabolite w/ analgesic potency 4-6x that of parent compound) [both cant cross BBB so not sig in CNS effects]
- Heroin --> morphine --> glucuronic acid
- Acc of meperidine and normeperidine may occur in pts w/ dec renal fxn; in high doses normeperidine --> seizures
- Fentanyl met by CYP3A4
- Codeine, oxycodone, and hydrocodone met by CYP2D6 --> prod of metabolites of greater potency (ex: codeins --> morphine)

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Genetic polymorphisms of CYP2D6

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- linked to variation in analgesic response seen among pts
- codeine --> morphine important b/c codeine has low affinity for opioid receptors

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Clinical Uses of Opioid Analgesics

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- Analgesia (mod-severe pain)
- Acute pulmonary edema - IV morphine (dyspnea from pulmonary edema assoc w/ LVF)
- Cough - dextrometorphan, codeine, levopropoxyphine, noscapine
- Diarrhea - loperamide, diphenoxylate; if diarrhea b/c of infection, chemotherapy indicated
- Shivering - meperidine (axn on alpha-2 adrenoceptors)
- Anesthesia - premedicant drug (sedative, anxiolytic, analgesic); intraoperative; regional analgesic (admin into epidural/subarachnoid)

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Adverse Effects of Opioid Analgesics

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- Resp depression
- Nausea
- Constipation
- Urinary retention
- Hypotension
- Sedation
- Drowsiness
- Miosis

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Tolerance, Dependence, Addiction

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- frequent admin --> loss of effectiveness (tolerance)
- physio. dependance --> occurrence of w/drawal or abstinence syndrome
- addiction - euphoria, indiff to stimuli, and sedation esp when given IV promote compulsive use

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Contraindications/Cautions in Therapy

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- Combining full agonist with partial agonist opioids should be avoided
- Pts w/ head injuries (CO2 retention --> cerebral vasodilation)
- Pregnancy (fetal w/drawal sx)
- Pts w/ impaired pulmonary fxn
- Pts w/ impaired hepatic fxn
- Pts w/ impaired renal fxn (half-life of opioids can be prolonged)
- Pts w/ endocrine disease (adrenal insufficiency or hypothyroidism --> prolonged/exaggerated response)

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Drug Interactions

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- Sedative-hypnotics = increased CND depression (esp resp)
- Antipsychotics = increased sedation and accentuated CV effects
- MAO inhibitors - meperedine + MAOI = life-threatening rxn (excitement, muscle rigidity, hyperthermia, unconsciousness) [similar rxns seen w/ tramadol + MAOI]

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Strong Agonists

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Morphine
Hydromorphine and Oxymorphone
Heroin
Meperidine
Fentanyl
Methadone
Levorphanol (closley parallel morphine)

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Morphine

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- High affinity for miu receptors and low affinity for delta and kappa receptors
- standard tx

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Hydromorphone and Oxymorphone

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- strong agonists useful in treating severe pain

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Heroin

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- rapidly hydrolyzed --> 6-MAM --> morphine
- both heroin and 6-MAM are more liposoluble than morphine and enter the brain more readily
- morphine and 6-MAM are responsible for pharmacological actions of heroin

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Meperidine

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- predom miu receptor agonist
- has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem
- negative inotropic action on heart
- large doses = tremors, muscle twitches, dilated pupils, hyperactive reflexes, convulsions (b/c of acc of normeperidine which has a half-life of 15-20 hrs compared to 3 hrs for meperidine)
- decreased renal or hepatic fxn increases likelihood of toxicity

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Meperidine - Drug Interactions

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Serotonin syndrome - delirium, hyperthermia, headache, rigidity, convulsions, coma, death
- rxn may be due to ability of meperidine to block neuronal reuptake of serotonin and resulting serotonergic overactivity
- so meperidine should NOT be used in pts taking other serotonergic agents such as MAOI

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Fentanyl

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- primarily a miu agonist
- rapid onset; short duration of action
- also includes sufentanil, alfentanil, remifentanil
- fentanyl = 100x more potent than morphine; sufentanil = 1000x
- fentanyl and sufentanil --> anesthetic adjuvants, chronic pain tx
- transdermal patch available, oral transmucosal formation (pain in cancer pts), effervescent buccal tablet

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Methadone

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- synthetic, orally effective, equal in potency to morphine, BUT LESS EUPHORIA and LONGER duration of action
- miu receptor agonist, NMDA receptor antagonist, and a serotonin and NE reuptake inhibitor
- effective analgesic activity, efficacy by oral route, extended duration of action in suppressing w/drawal sx of pts w/ physical dependence, tendency to show persistent effects w/ repeated admin
- useful drug for detox and maint. of chronic relapsing heroin addict
- no active metabolites so useful in pts w/ renal insufficiency

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Methadone - Adverse effects, Uses and Related Compounds

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- AE: dose-related QT prolong; torsades de pointes, death
- Uses: relief of chronic pain, tx of opioid abstinence syndromes, tx of heroin users
- Related compound: levomethadyl acetate (even longer half-life than methadone)

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Mild to Moderate Agonists

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Codeine, Oxycodone, & Hydrocodone
Propoxyphene
Tramadol

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Codeine, Oxycodone, & Hydrocodone

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- less efficacious than morphine
- rarely used alone; combined w/ aspirin, acetaminophen, and others
- analgesic effect of codeine bc of its conversion to morphine by CYP2D6
- codeine's antitussive axns may involve distinct receptors binding codeine itself

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Propoxyphene

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- primarily miu receptors
- dextro isomer = analgesic for mild to mod pain
- levo isomer = antitussive
- weaker than codeine (need twice the dose for same effect)
- AE: increased risk of seizures and cardiac conduction abnormalities so should be avoided in elderly
- metabolized --> norpropoxyphene (longer half-life, acc = toxicity)
- controlled substance

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Tramadol

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- weak miu agonist, NE/serotonin reuptake inhibitor
- useful in neuropathic pain
- inc risk of seizures in pts w/ seizure disorder and those taking medications that lower seizure threshold
- tramadol + serotonergic drug (eg serotonin reuptake inhibitor, TCA, MAOI) should be avoided b/c --> serotonin syndrome

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Antimotility Agents

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Diphenoxylate and Loperamide
-tx of diarrhea
- miu or delta receptors on enteric nerves, epithelial cells, and muscle

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Diphenoxylate

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- not used for analgesia
- tx of diarrhea
- schedule V (minimal control b/c abuse is remote)

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Loperamide

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- potential for abuse is very low b/c of its limited access to brain
- control diarrhea
- available over-the-counter

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Mixed Agonist-Antagonist

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Pentazocine, Butorphanol, Nalbuphine, Buprenoprhine
- potent analgesics in opioid-naive pts but precipitate w/drawal in pts who are physically dependent on opioids
- poor choice for pts w/ severe pain or as a routine analgesic b/c dosing is limited by a ceiling effect

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Pentazocine, Butorphanol, Nalbuphine

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Pentazocine: kappa agonist and a miu antagonist/partial agonist

Butorphanol: kappa agonist and a miu antagonist/partial agonist

Nalbuphine: kappa agonist and a miu antagonist

All 3: psychotomimetic effects

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Buprenorphine

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- partial miu agonist and kappa antagonist
- management of opioid addiction
- tx initiated w/ buprenorphine alone and then with adding naloxone to minimize abuse potential
- pychotomimetic effects uncommon

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Caution for Mixed Agonist-Antagonist

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- care should be taken not to administer any partial agonist or drug w/ mixed opioid receptor actions to pts receiving pure agonist drugs b/c of the unpredictability of both drugs' effects: reduction of analgesia or precipitation of an explosive abstinence syndrome can result

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Opioid Antagonists

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Naloxone, Naltrexone, and Nalmefene

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Naloxone, Naltrexone, and Nalmefene

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- high affinity for miu receptors
- lower afffinity for kappa and delta but can reverse the action of agonists at kappa and delta receptors
- Naloxone = tx of acute opioid overdose
- Naltrexone = long duration of action so is proposed as maint drug for addicts in tx programs
- Naltrexone decreases craving for alcohol in chronic alcoholics

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Antitussives

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- opioid analgesic --> suppression of cough
- different receptors than those assoc with other actions of opioids
- Dextrometorphan, codeine, levopropoxyphene, noscapine
- should be used w/ caution in pts taking MAOIs

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Dextrometorphan

Codeine

Levopropoxyphene

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Dextrometorphan - dextro isomer of a derivative of levorphanol

Codeine - useful antitussive at doses lower than those required for analgesia

Levopropoxyphene - isomer of weak opioid agonist dextropropoxyphene