Learning outcome 2 Flashcards
Peripheral nervous system neurotransmitters
Acetylcholine, norepi, epi only. 21 known in CNS
Monoamines (CNS Neurotransmitters)
Dopamine, Epinephrine, Noreip, Serotonin
Amino acids (CNS Neurotransmitters)
Aspartate, GABA, Glutamate, Glycine
Purines (CNS Neurotransmitters)
Adenosine
Adenosine monophosphate and triphosphates
Opioid Peptides (CNS Neurotransmitters)
Dynorphins, Endorphins, Enkephalins
Nonopioid Peptides (CNS Neurotransmitters)
Neurotensin Oxytocin Somatostatin Substance P Vasopressin
Others (CNS Neurotransmitters)
Acetylcholine
Histamine
Increased therapeutic effects in CNS
Antipsychotics, antidepressants need to be taken for several weeks to develop full effects. Beneficial responses may be delayed as they result from adaptive changes, not direct effects.
Decreased side effects in CNS
Possible for therapeutic effects to remain the same as side effects decrease.
Phenobarb produces sedation but that declines while it still prevents seizures. Thought to be a cause of adaptive changes
Tolerance
Decreased response occurring in the course of prolonged drug use
Physical dependence
State in which abrupt discontinuation will precipitate withdrawal syndrome
Serendipitous
Occurred or happened by chance in a beneficial way
Difficulties finding new psych drugs
Can’t test on animals for obvious reasons, can’t test on healthy people because they have different effects
Opioid vs opiate
Opioid any drug (natural or synthetic) that has actions similar to morphine, where opiate applies only to compounds present in opium (morphine, codeine)
Three endogenous opioid peptides
Enkephalins, endorphins, dynorphins which serve as neurotransmitters, neurohormones, and neuromodulators
Three classes of opioid receptors
Mu, kappa, delta.
Opioid analgesics act primarily by activating mu and lesser extent kappa. Opioids generally don’t interact with delta but endogenous opioids act on all three.
Mu receptors
Responses include analgesia, respiratory depression, euphoria and sedation. Also related to physical dependence.
Analgesic defintion
Drugs that relieve pain without causing loss of consciousness
Psychotomimetic effects
relating to or denoting drugs that are capable of producing an effect on the mind similar to a psychotic state.
Kappa receptors
Produce analgesia, sedation and may underlie psychotomimetic effects
Partial agonist
Low to moderate receptor activation alone but blocks actions of full agonist if two are given together
Pure opioid agonists
Agonize Mu and Kappa, cause sedation, analgesia, euphoria, sedation, resp depression, dependence, cough suppression, and constipation
Morphine (prototype of strong opioid agonist)
Codeine (prototype of moderate to strong opioid agonist)
and other morphine like drugs
Agonist-antagonist opioids
Pentazocine (talwin, which is the prototype) , nalbuphine, butorphanol all antagonize mu and agonize kappa
Buprenorphine partial mu agonist, antagonist to kappa
Pure opioid antagonists
Antagonize mu and kappa, naloxone, naltrexone and others.
Methylnaltrexone to treat opioid induce constipation
Other effects of morphine
Resp depression, constipation, urinary retention, orthostatic hypotension, emesis, miosis, cough suppression, biliary colic.
Produce analgesia by mimicking actions of endogenous opioid peptides
Resp depression
At equinanalgesic doses, all cause resp depression to same extent by activation of mostly mu and lesser kappa
Resp depression kicks in 7 minutes after IV, 30 after IM, 90 after sub q and may persist 4-5 hours.
Morphine by spinal ejection might delay resp depression by hours
Constipation in opioids
Activating gut mu receptors suppresses propulsive intestinal contractions, intensifies nonpropulsive contractions, increase tone of anal sphincter, inhibit secretion of fluids into intestinal lumen.
Goal is to produce soft formed stool every 1-2 days.
Opioid constipation tx
Physical activity, increased fibre and fluids, enemas, senna to counter reduced bowel motility, docusate as stool softener, polyethylene glycol as osmotic laxative.
Rescue therapy is strong osmotic laxative like lactulose or sodium phosphate.
Methylnaltrexone blocks mu in intestines and is last resort (can’t cross BBB)
Orthostatic hypotension from opioids
Morphine like drugs block baroreceptor reflex and dilate peripheral arterioles and veins.
Peripheral vasodilation mostly from histamine
Morphine like drugs urinary retention
Increased tone of bladder sphincter, increase tone of detrusor muscle (elevating pressure within bladder, causing sense of urgency) and may suppress by diminishing awareness of fullness.
TCAs and antihistamines (antichols) worsen it, as well as underlying BPH
Also decreases renal blood flow which lowers urine production, and promotes releases of antidiuretic hormone
Morphine like drugs cough suppresion
May lead to accumulation. Act on medulla to suppress. Pts may need to be instructed to forcefully cough
Biliary colic morphine like drugs
Can induce spasm of bile duct, causing increased pressure in biliary tract causing epigastric distress to biliary colic.
In pts with biliary colic, opiods may intensify rather than relieve.
Morphine is worse than others for this
Emesis in morphine like drugs
Direct stimulation of chemoreceptor trigger zone of medulla. Greatest with initial dose. Occur in 15-40% of walking pts (uncommon in recumbent pts)
Stillness and antiemetics help this
Elevation of ICP in morphine like drugs
Indirect, as it suppresses resps which increase CO2 which dilates cerebral vasculature. ICP will remain normal if resps are kept normal
Dysphoria in morphine like drugs
Anxiety and unease. Uncommon if in pain, can happen if there is no pain
Sedation in morphine like drugs
Minimized with smaller more frequent dosing, short half lives, and small doses of CNS stimulants given with
Miosis in morphine like drugs
Can cause poor night vision
Birth defects in morphine like drugs
2-3x higher incidence. Worse during conception/early on.
Can cause congenital heart defects (av septal defects, hypoplastic left heart, conoventricular septal defects) and spina bifida and gastroschisis
Gastroschisis
Protrusion of intestine through abdo wall near umbilicus
Neurotoxicity in morphine like drugs
Delirium, agitation, myoclonus, hyperalgsia.
Risk factors are renal impairment, preexisting cognitive impairment, prolonged high dose use.
Manage with reduced dose and hydration and if long term use is indicated, occasionally switching
Long term use in morphine like drugs
Hormonal changes, altered immune function, decline in cortisol, increase in prolactin, decrease in LH and FSH
Pharmacokinetics of morphine
IM, IV, SUB q lasts 4-5 hours
Epidural, intracathecal up to 24 hours
Oral IR is 4-5 hours, ER up to 24.
Tolerance in morphine like drugs
Tolerance doesn’t develop to miosis and constipation
Cross-tolerance exists with other opiods but not other CNS depressants
Physical dependence in morphine like drugs
Short half lives give intense short withdrawal. Longer is longer
Withdrawal symptoms
Yawning, rhinorrhea, sweating (approx 10 hours after final dose) then anorexia, irritability, tremor, gooseflesh (term cold turkey) and peak with violent sneezing, weakness, nausea, vomiting, diarrhea, abdo cramps, bone and muscle pain, muscle spasm, kicking movements (kicking the habit)
Lasts 7-10 days in morphine
Rarely dangerous
Labor and delivery in morphine like drugs
Suppresses uterine contractions, resp depression in neonates
Head injury in morphine like drugs
Can increase ICP, and make tough to diagnose
Other precautions in morphine like drugs
Inflammatory bowel disease pts can get toxic megacolon or paralytic ileus.
Liver impaired pts may hae intensified effects
BPH, hypotension, reduced blood flow pts
CNS depressants in morphine like drugs
All CNS depressants can intensify sedation and resp depression
Anticholingerics in morphine like drugs
Can exacerbate morphine induced constipation and urinary retention
Hypotensive drugs in morphine like drugs
Can exacerbate the hypotension obvi
Monoamine oxidase inhibitors in morphine like drugs
Can produce a syndrome of excitation, delirium, hyperpyrexia, convulsions and severe resp depression. Hasn’t been reported with morphine (just meperidine)
Ampehtamines, clnidine, dextromethorphan in morphine like drugs
Can enhance opioid induce analgesia and can offset sedation
Embeda
Moprhine/naltrexone combo. Morphine in ER capsules and inner core of naltrexone. If swallowed only morphine is absorbed, if crushed to be injected naltrexone gets released
ETOH accelerates released of morphine from embeda
Morphine general dosing guidelines
Sharp stabbing pain needs higher doses than dull.
Older and younger need less, neonates need very low as BBB not developed
Routes and dosage morphine
Oral is 10-30, don’t chew capsules, don’t drink ETOH,
Children IM SUBQ is 0.1-0.2mg/kg
IV over 4-5 minutes
Fentanyl
100X POTENCY of morphine
Metabolized by CYP3a4
Patches come in 12.5,25,50,85,100mcg/hr don’t expose patches to heat, no strenuous exercise
Sufentanil
Potency 1000X morphine, alfentanil 10x morphine
Remifentanil
Rapidly metabolized by plasma and tissue esterases, not hepatic metabolism or renal excretion. About 100X potency of morphine. Effects in minutes, terminate in 5-1minutes. Given as infusion during surgery at 0.05 to 2mcg/kg/min and post operative at 0.025 to 0.2 mcg/kg/min
Muscle rigidity like fentanyl
Meperidine
Used to be bigger, not so much because of short half life, adverse interactions, and toxic metabolites. Excessive activation of serotonin reuptake inhibition.
Methadone
Prolonged QT, torsades in 65-400mg a day. Metabolized by CYP3A4
Equianalgesic dosing mg codeine
PO 200
IM subq 130
Equianalgesic dosing mg fentanyl
0.1 IM/IV
Equianalgesic dosing mg hydrocdone
30 PO
Equianalgesic dosing mg hydromorphone
PO 7.5
Injection 1.5
Equianalgesic dosing mg levorphanol
PO 4
Injection 2
Equianalgesic dosing mg Meperidine
PO 300
Injection 75
Methadone Equianalgesic dosing mg
PO 20
IM IV 10
Equianalgesic dosing mg Morphine
PO 30
Injection 10
Equianalgesic dosing mg oxycodone
20 PO
Equianalgesic dosing mg oxymorphone
PO 10
Injection 1
Rectal 10
Tapentadol Equianalgesic dosing mg
PO 100
Moderate to strong opioid agonists vs moprhine
Less analgesia, resp depression and have a somewhat lower potential for abuse
Can be reversed with naloxone
Codeine
30mg = 325mg of acetaminophen for pain relief
10% undergoes metabolism to morphine in the liver by CYP2D6
As the dose is higher for therapeutic doses, analgesia is more difficult to attain SAFELY
Codeine metabolism
Some people lack effective CYP2D6 gene and can’t convert codeine to morphine so no relief is felt
Hyper metabolism in 7% of whites, 3% of blacks, and 1% of hispanic and asians is possible, and will also prevent analgesia
Codeine in da boob
Rare, but possibly for severe toxicity, usually from ultrarapid metabolism
Nursing mothers should look for excessive sleepiness, breathing difficulty, lethargy, poor feeding
Antitussive codeine
10mg
Oxycodone
Equivalent to codeine. Metabolized by CYP 3a4
Controlled release is oxycontin
Used to be stamped OC, now OP and are tough to crush and form a gel with liquids
Oxycontin OP burns if snorted. It is immediate release. Also gel in water or alcohol
Hydrocodone
5mg
Only available in combination with ibuprofen or acetaminophen.
If used as cough suppressant combined with antihistamines and nasal decongestants.
Vicodin, vidoprofen, lortab
Tapentadol
Similar pain relief to oxycodone
Differs in it activates mu receptors, also blocks reuptake of norepi (like tramadol) and causes less constipation
Other names meperidine
Demerol
Other names methadone
Diskets, dolophine, methadose
Other names Hydromorphone
Dilaudid, exalgo, jurnista
Other names oxymorphone
Opana
Other names oxycodone
Oxycontin, roxicodone, oxecta, oxyIR
Other names hydrocodone
Vicodin, vicoprofen, lortab
Drug interactions tapentadol
ETOH, opoids, barbs, benzos will cause extra depression and sedation like anything
MAOI because it blocks reuptake of norepi can cause hypertensive crisis
Don’t mix with SSRIs or TCAs or seratonin agonsists (SSRI has no problems in clinical trials)
4 agonist-antagonist opoids
Nalbuphine, butorphanol, pentazocine, buprenorphine
First three antagonize mu and agonize kappa
Pentazocine actions and uses
AKA talwin.
Prototype for ag/antag
Kappa only, antags mu, therefore limited resp depression, and high doses cause anxiety, strange thoughts, nightmares, hallucinations (thought to be from kappa activation)
Also less effective for pain control
*Increases MVO2
Will trigger withdrawal in addicts as it blocks Mu AKA don’t give it to addicts
Can cause dependence but mild (cramps, fever, anxiety, restlesness)
Nalbuphine
Like pentazocine
Analgesic similar to morphine at low doses, but has a ceiling and a ceiling to resp depression like penta
Less withdrawal than morph, more than penta
In labor, causes fetal bradycardia and apnea, cyanosis, hypotonia
Butorphanol
Similar to pentazocine Less analgesia than morph Resp depress ceiling Psychotomimetic reactions possible but rare Increases MVO2
Buprenorphine (the other antag/ag opioid)
Partial ag at mu, antagonist at kappa.
Similar pain analgesia to morph, but don’t get significant tolerance
Depressed resp but not severe
Up to 2 weeks for withdrawal to start
Naloxone can’t reverse, but pretx can prevent toxicity (binds to tight for naloxone to displace)
Treats opioid addiction
Buprenoprhine physically
Prolongs QT.
Adverse effects increased with underlying psychosis, ETOH abuse, adrenocortical insufficiency, severe liver or renal impairment
Can cause spasms of sphincter of Oddi
Sphincter of Oddi
Where bile duct and pancreatic duct enter duodenum. Buprenorphine induces these, and creates risk of pancreatitis or biliary disease in the predisposed
Withdrawal
Clinically significant dependence occurs within 20 days from high doses
Tape over 3 days, up to 7-10 if dependence is high
Physical dependence definition
Abstinence syndrome will occur if drug is abruptly withdrawn. NOT the same as addicition
Abuse definition
A drug used inconsistent with medical or social norms
Addiction definition
Disease process characterized by continued use of a psychoactive substance despite physical, psychologic, or social harm. Completely separate from physical dependence, physical dependence doesn’t need to exist, does up chances of addiction tho yo
Addiction concerns
Boston Collaborative Drug Study says of 12,000 hospitalized pts taking opioids, 4 became drug abusers.
Addiction is not a reason to withhold
Drug abuse screening tool
NIDA-modified ASSIST
PCA
Patient controlled analgesia
Obstetric Analgesia
Morphine and meperidine may cause depressed fetal resps and uterine contractions given parenterally, still given though.
Fentanyl, sufentanil, alfentanil,, remifentanil shorter duration of action and don’t produce significant neonatal depression.
Also mixed like nalbuphine, butorphanol, pentazocine, buprenorphine offer increase pain relief without causing further resp depression
MI Pain control
Pentazocine and butorphanol both increase MVO2 so avoid.
Morphine good for decreasing MVO2
Opioids head injury
Can cause ICP, and miosis, mental clouding and vomiting can make diagnostics more difficult
4 pure antagonists
Narcan, methylnaltrexone (relistor), alvimopan (entereg) and naltrexone (revia, vivitrol)
Pharmacokinetics naloxone
IV immediate
IM 2-5 minutes
Half life approx 2 hours
Methylnaltrexone actions and use
Selective mu antagonist for opioid induced constipation for those who have not responded to standard laxative therapy.
Methyl group prevents it from crossing BBB, so it also does not decrease ANALgesia
Alvimopan
Selective peripherally acting mu opioid antagonist like methylnaltrexone
Only for short term use (methylnaltrexone can be used long term) because it increases MI risk
Naltrexone (ReVia, Vivitrol)
Pure opioid antagonist used for opioid and ETOH abuse.
It prevents euphoria
It can cause withdrawal if pts still addicted. It doesn’t stop cravings like methadone
Can cause hepatocellular injury in high doses
Nonopioid centrally acting analgesics
Tramadol, clonidine, zionotide, dexmedetomidine
Relieve pain by mechanisms largerly or completely unrelated to opioid receptors so little or no resp depression, dependence, or abuse
Tramadol
Moderately strong analgesic with low potential for abuse, resp depression
Works through combo of opioid and nonopioid mechanisms
MOA tramadol
Analog of codeine that works with weak agonist activity at mu receptors, ut mostly by blocking norepi and serotonin reuptake and thereby activating monoaminergic spinal inhibition of pain.
Naloxone only partially blocks effect
Therapeutic use tramadol
Not as good as morphine, same as codeine plus asa or tylenol
Analgesia at 1 hour after oral dosing, max at 2 hours and continues for 6
Sides of tramadol
Serious adverse effects are rare, resp depression is minimal at recommended doses Sedation, dizziness, headache, dry mouth, constipation Rarely seizures (probably only an issue in epileptics)
Drug interactions tramadol
Sedation with other CNS depressants
HTN crisis if given with MAOI
Serotonin syndrome with SSRI TCA MAOI triptans etc
Clonidine (catapres, duraclon)
TX HTN and relief of severe pain
