Opioid Pharmacology Flashcards
Opiate
a naturally-occurring plant-derived alkaloid
compound
Opioid
any compound that works at an opioid receptor - includes naturally-occurring and synthetic agents
3 Families of Opioid Receptors
mu, delta and kappa
Mu is most heavily distributed in CNS regions related to pain, reward
Presynaptic - decrease release of
neurotransmitters
- Inhibition of AC, cAMP and PKA - prevents vesicle docking
2. Inhibition of voltage-gated Ca2+ channels - prevents vesicles from releasing contents into synapse
Postsynaptic - decrease action potentials
- Stimulating K+ efflux keeps
neurons more polarized, less likely
to fire an action potential
Tolerance development MOA
Acute desensitization (caused by G subunit phosphorylation after activation) occurs within minutes to hours
occurs over a period of days to weeks, and is thought to involve:
- up regulation of cAMP system
- beta-arrestin mediated receptor endocytosis and down regulation
Opioids are used for…
nociceptive (sensory) and emotional (affective) pain, NOT neuropathic pain
OPIOID ANALGESIA MOA
- Pain signal transduction - inhibiting activity of nociceptor neurons, which sense noxious stimuli and send pain signals to spinal nerves
- Transmission - reducing activity of spinal neurons that transmit pain signals up to brain
- Perception - acting in brain processing centers to limit cognitive awareness of & emotional response to pain
- Modulation - up or down regulation of pain signals throughout the spinal cord and the brain
Fentanyl, and Su, Al, and Remi fentanil
CLINICAL USES - ANALGESIA
More potent opioids are reserved for treatment of higher levels of pain
Opioids are often used for premedication before anesthesia
and surgery
DOA: shorter-acting opioids are generally preferred for use during anesthesia
Codeine
CLINICAL USES - COUGH
Antitussive - medication that suppresses coughing
Opioids directly inhibit the cough center in the medulla
Suppression of cough occurs at much lower doses than used for analgesia
Codeine is sometimes used as antitussive, although less common currently, since other safer options exist
loperamide (Imodium ®; PO)
CLINICAL USES - DIARRHEA
Diarrhea from any cause can be treated with opioids
Opioids reduce GI motility and inhibit GI secretions by acting at neurons in the gut
Opioids receptors are widely distributed in the GI tract; they decrease activity of enteric nervous system neurons
Loperamide is a strong substrate Mice with no P-gp at the BBB for the blood-brain barrier efflux transporter, P-glycoprotein (so it acts in the body but does not enter brain)
Naltrexone
CLINICAL USES - SUBSTANCE USE DISORDERS
Alcohol use disorders - preventing relapse - naltrexone (long acting) indicated in treating and preventing relapse of alcohol use disorders and may similarly prevent relapse of opiate dependence
Opioid detoxification - full detoxification involves transition to opioid antagonist (naltrexone)
Methadone, Buprenorphine, Clonidine
CLINICAL USES - SUBSTANCE USE DISORDERS
*Opioid withdrawal treatment - treating opioid withdrawal symptoms (craving, anxiety, GI distress, diaphoresis, tachycardia)
Buprenorphine advantages include relatively long duration of action and greater safety in overdose than full agonists like methadone
As a partial agonist, buprenorphine activates OP receptors, but to a
lesser extent than a full agonist → occupation of receptors prevents
full agonists from reaching maximum efficacy
Naloxone (Narcan ®; IV/IM/IN)
OPIOID OVERDOSE REVERS
Naloxone is an opioid receptor pure antagonist (no agonist effects)
Competitive antagonist - no effects alone; only in the presence of opioids
Short duration of action (t ½ = 30-80 min), often necessary to give additional
doses until agonist is cleared
Respiratory depression
Adverse Effects of Opioids
Respiratory depression - opioids act directly on OPRs in brainstem respiratory
centers to depress respiratory function (reduce rate, depth of breathing)
-major cause of fatality in opioid clinical use and overdose (respiratory collapse and hypoxic brain death)
Pruiritis / urticaria - some opioids can stimulate mast cell-mediated histamine release, causing itching and hives
Constipation
Adverse Effects of Opioids
Constipation - all opioids slow GI motility (see section on anti-diarrheal uses); common
Potential cause of mortality, particularly in elderly or cancer patients
Requires treatment, since tolerance does not develop for opioid constipating effects
Naloxegol (Movantik ® PO)
REVERSAL OF PERIPHERAL OPIOID EFFECTS
Naloxegol is a pegylated derivative of naloxone, for treatment of opioid-induced constipation
Pegylation limits ability of the drug to cross the blood-brain barrier → only peripheral
effects
Nausea
Adverse Effects of Opioids
Nausea - with or without vomiting, nausea can affect overall outcome, medication compliance, enteral absorption, quality of life
Can be treated with anti-emetics, although tolerance to nausea usually develops within days to weeks
Sedation (effects on sleep)
Adverse Effects of Opioids
Sedation (effects on sleep) - drowsiness and sleep, with disrupted sleep
patterns → potential for interaction with CNS depressants
Addiction
Adverse Effects of Opioids
Addiction - pathologic pursuit of reward and relief through substance use
Dysfunction in reward, motivation memory circuitry
Rewarding effects of opioids are mediated by opioid receptor on dopamine reward pathways and other mechanisms
Drug Interactions with Opioids
- Sedative-hypnotics*: increased CNS depression, especially respiratory depression
- Antipsychotics agent*: increased sedation, variable effects on respiratory depression. Accentuation of cardiovascular effects (anti-muscarinic and alpha-blockng actions)
- Monoamine oxidase inhibitors*: contradiction to all opioid analgesics due to high incidence of hyperpyrexic come, also HTN
GENETIC POLYMORPHISMS
Opioids are generally converted to polar metabolites and excreted in urine
Some opioids are transformed by P450 enzymes to active metabolites of greater potency (e.g., codeine is metabolized to morphine)
Polymorphisms in CYP 2D6 can result in responses to opioids that are greater or less than expected
OPIOID OVERDOSE DEATHS
Most recently, overdose death increase is associated with fentanyl and synthetic opioids
OPIOID PRESCRIBING
Overprescription can contribute to diversion and misuse
Balance caution in prescribing opioids with risk of leaving pain untreated or under-treated
