Opiod Analgesics and Antagonists Flashcards
Opioids - MoA
Activation of opioid receptors leads to inhibition of adenylyl cyclase, and a decrease in the concentration of cyclic adenosine monophosphate, an increase in K+ conductance and a decrease in Ca2+ conductance.
The activated Gai subunit of the G protein directly inhibits the adenylate cyclase enzyme, and the Gbetagamma subunits are thought to mediate the changes at the Ca and K channels. These actions cause both presynaptic inhibition of neurotransmitter release from the central terminations of small diameter primary afferent fibers and postsynaptic inhibition of membrane depolarization of dorsal horn nociceptive neurons.
Opioid agonists - Effects
CNS: Analgesia, sedation, euphoria or dysphoria, miosis, respiratory depression and inhibition of coughing reflex, nausea and vomiting
Analgesia: produced by activation of opioid receptor in the spinal cord and at several supraspinal levels.
Sedation and euphoria due to effects on midbrain dopaminergic, serotonergic and noradrenergic nuclei.
Miosis (constricted pupils): produced by the direct stimulation of the Edinger Westphal nucleus of the oculomotor nerve –> parasymp stimulation of iris sphincter muscle.
Cardiovascular: Vasodilation (caused by histamine release from mast cells in peripheral tissues), Orthostatic hypotension (decreased peripheral resistance and reduction in baroreceptor reflex activity). Pt w CAD the decreased peripheral resistance –> reduction of cardiac work and myocardial oxygen demand.
GI, Biliary and Genitourinary system: Constipation (increased intestinal smooth muscle tone), increased biliary sphincter tone and pressure –> exacerbation of pain in patients with biliary dysfunction or gallbladder attack.
Genitourinary: increased bladder sphincter tone, prolongation of labor, urinary retention
Neuroendocrine: inh of LH release. Stimulation of release of ADH and prolactin.
Immune system: Suppress the activity of some lymphocytes, incl natural killer cells –> high rate of infectious diseases in heroin addicts.
Dermal: flushing, pruritus, urticaria
Opioids - Adverse effects
Respiratory depression
Decreased Hypercapnic drive (stimulation of resp centers by increased CO2 levels) + little effect of hypoxic drive
Decreased Respiratory tidal volume and rate –> rate falls to 3-4 pr min after overdose
Increased intracranial pressure due to increased cerebral blood flow
Nausea and vomiting by stimulating the chemoreceptor trigger zone in medulla
Itching/pruritus, flushing reaction (histamine release by mast cells)
Allergic reactions
Tolerance: decrease in initial pharm effect observes after chronic or long-term adm. Results from down-regulation of opioid receptors. Not developed to miosis and constipation. Considerable tolerance to resp depp. Accompanied by physical dependence
Cross tolerance
Opioids - Contraindication and antidote
Closed-head injury
Naloxone
Strong opioid agonists
Morphine Fentanyl Sufentanil Alfentanil Remifentanil Meperidine Methadone Oxycodone
Which strong opioid agonists have some effect on Kabba receptor?
Morphine and Sufentanil
Morphine - Clinical use
Severe pain associated with trauma, MI and cancer.
MI: relieves pain and anxiety + dilating coronary arteries and decrease myocardial oxygen demand.
Which drugs is the diacetic acid ester of morphine?
Heroin
Metabolites of Morphine
Principle metabolite: 3-glucuronide (inactive)
6-glucuronide is more active than morphine + longer half-life. It contributes to analgesic effectiveness of morphine.
Most potent opioid agonists
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Sufentanil - MoA
Strong mu receptor agonist. Some effect on kabba and delta receptors.
Fentanyl - Clinical use
Long-acting transdermal skin patch: Continuous pain relief for pt with severe or chronic pain
Mucosal, buccal and nasal spray: Breakthrough pain
Parenteral: preop and postop + adjunct to general anesthesia
Fentanyl - Adverse effects
Produces less nausea and vomiting.
Truncal rigidity when used as an adjunct to parenteral anesthesia.
Alfentanil - Clinical use
Part of anesthesia procedures
Remifentanil - Clinical use
Short term procedures and outpatient surgery
Meperidine - Clinical use
DOC for pain ass w labor and pt w biliary dysfunction or gallbladder attack because it has less pronounced action of smooth muscle.
Analgesia for obstetric or postsurgical analgesic.
Oral: moderate to severe pain in outpatient setting
Short-term: acute pain syndromes.
Meperidine - Adverse effects
Less constipation (Less pronounced effect on GI, biliary and uterine smooth muscle --> less likely to cause constipation or increased biliary pressure) High doses --> converted to toxic metabolite normeperide -->CNS excitation, convulsions and tremors.
Methadone - Clinical use
Ambulatory patients to treat opioid dependence (methadone maintenance program) or chronic pain.
Opioid-dependent pt: prevent craving for heroin or other opioids
Oxycodone - MoA
Strong mu receptor agonist
Oxycodone - Clinical use
Moderate or severe pain
Oxycodone - Adverse effects
Incidence of death (Only crushproof tablet available)
Moderate opioid agonist
Codeine
Hydrocodone
Propoxyphene
Moderate opioid agonists - MoA
Are less potent than the strong opioid agonists. Because they do not produce maximal analgesia at doses that are well tolerated by patient, they are used in submaximal doses, and almost always combined with an NSAID analgesic.
Codeine - MoA
Converted to morphine by CYT P450 isozyme CYP2D6
3-O-methyl derivative of morphine
Codeine, Hydrocone and Propoxyphene - Clinical use
Mild to moderate pain
Antitussive effect
Propoxyphene have half the analgesic effect of codeine –> more antitussive effect
Codeine - Contraindication
pregnant and nursing mothers who are ultrarapid metabolizers of codeine have a risk of lethal morphine exposure to the fetus or nursing infant.
Persons with deficient variations of CYP2D6 obtain little pain relief.
Codeine - Adverse effects
Constipation
Propoxyphene - MoA and Adverse effects
Chemical analogue of methadone
Cardiac abnormalities
Other opioid agonists
Tramadol Tapentadol Dextrometorphan Diphenoxylate Loperamide Eluxadoline
Tramadol - MoA
Agonist at mu-opioid receptors and inhibited the neuronal reuptake of serotonin and norepinephrine. Reuptake inh may potentiate the inhibitory effects of serotonin and norepinephrine on pain transmission in the spinal cord.
Tramadol - Clinical use
Moderate pain
Chronic pain syndrome
Tramadol - Adverse effects
Produce minimal cardiovascular and respiratory depression.
The drug lowers seizure threshold and the risk of seizures is increased when used with antidepressants.
Increased risk of suicidal thought and behavior
Tapentadol - MoA and Clinical use
Agonist at mu-opioid receptors and reuptake transporters, but inhibits only norepinephrine reuptake
Moderate pain
Dextrometorphan - MoA
Nonselective serotonin reuptake inhibitor
Sigma-1 receptor agonist
NMDA antagonist
Dextrometorphan - Clinical use
Cough Pseudobulbar affect (emotional lability) in comb w quinidine
Diphenoxylate
Loperamide - MoA and Clinical use
Activate opioid receptors in gastrointestinal smooth muscle
Diarrhea
Eluxadoline - MoA and Clinical use
Agonist at mu and kappa opioid receptors and antagonist at delta opioid receptors.
Activation of mu receptors leads to decreased intestinal motility and relief of diarrhea, whereas actions of eluxadoline on other opioid receptors reduces the incidence of constipation caused by mu opioid agonists.
IBS with diarrhea
Mixed opioid agonist-antagonist and partial agonists
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
Mixed opioid agonist-antagonist and partial agonists - MoA
Partial agonist or antagonist at mu-opioid receptors and show agonist or antagonist at kappa-receptors.
Mixed opioid agonist-antagonist and partial agonists - Clinical use
Parentally: preoperative and postoperative analgesia, obstetric analgesia during labor and delivery.
Orally/nasally: moderate to severe pain
Mixed opioid agonist-antagonist and partial agonists - Adverse effects
Less respiratory depression as the doses are increased
Lower liability for drug dependence and abuse.
Can cause anxiety, nightmare, psychotomimetic effect; hallucinations (result of activation of kappa-receptors), precipitate withdrawal in a person physically dependent on full opioid agonist.
Less constipation
Buprenorphine - MoA
Partial agonist at mu-opioid receptor and has slow dissociation from the receptor after binding –> therefor somewhat longer acting then other opioids.
Buprenorphine - Clinical use
Outpatient treatment of opioid dependence.
Butorphanol
Nalbuphine - MoA
kappa-receptor agonist, have partial agonist or antagonist activity at mu-opioid receptors.
Butorphanol
Nalbuphine - Clinical use
Relieve pain during child birth
Pentazocine - MoA
kappa-receptor agonist with additional activity at (sigma) receptors, a class of receptors mediating the psychotomimetic effect of PCP and Ketamine.
Pentazocine - Clinical use
Parenteral: preanesthetic medication and supplement to surgical anesthesia.
Oral: moderate to severe pain
Pentazocine - Adverse effect
Parenteral use of an oral formulation: Severe cardiovascular effect, especially in patients with existing cardiovascular disease.
Causes hallucinations.
Opioid antagonists
Naloxone
Natrexone
Naloxegol
Methylnaltrexone bromide
Naloxone and Naltrexone - MoA
Competitive opioid receptor antagonist and can rapidly reverse the effects of morphine and other opioid agonists. They are chemical analogues of morphine, with bulky chemical groups attached to the morphine molecule. This modification allows the molecule to bind to the opioid receptor but prevents the confirmation change in the receptor required for agonist activity.
Naloxone - Clinical use
Opioid overdose- given IV
Alcohol and opioid dependence
Decrease opioid-induced constipation
Comb with opioid agonist in oral formulation to prevent crushing of the pill and IV abuse.
Opioid maintenance therapy comb w buprenorphine
Naloxone - Adverse effects
If given IV: block opioid effects and withdrawal effect
Naltrexone - Clinical use
Alcohol and opioid dependence
Naloxegol - MoA
PEGylated naloxone. Pegylation increases drug solubility and improves pharmacokinetic profile.
Opioid analgesics inh GI motility, Naloxegol binds to GI opioid receptors and block the opioid-induced constipation.
Naloxegol
Methylnaltrexone bromide - Clinical use
Relief of opioid-induced constipation
Methylnaltrexone bromide - MoA
Its ability to block opioid binding in peripheral tissues decreases opioid-constipation effects.
