Pharm Quiz 2 Flashcards
What are 3 Phenylpiperidine derivaties of synthetic opioids?
- fentanyl
- Sufentanil
- remifentanil
What receptors sites do opioid antagonist/agonist interact with?
Mu
Kappa
Delta
Phenylpiperdines vary greatly in _____ & _____ between _____ & _____ _____ _____.
potency & equilibration
plasma & site of action
(ex. demerol to carfentanil)
What types of receptors and where are they located that opioids primarily act upon?
sterospecific receptors at pre and post synaptic sites in the CNS(brainstem & spinal cord)
Opioid receptors are designed to be activated by endogenous opioids. What are these endogenous opioids?
- Endorphins
- Enkephalins
- Dynorphins
- Endomorphins
- Nociceptin
Only ____ & ____ forms of opioids bind to receptors. Opioid receptor activation decreases neurotransmission via _____ _____ _____.
nonionized & levorotary
presynaptic neurotransmitter inhibition
What was the first drug shown to bind to mu receptors?
Morphine
What was the first drug found to bind to kappa receptors?
Ketocyclazocine-no longer in use.
What are two drugs used today that interact with kappa receptors?
nubain and staidol
4 characteristics of kappa receptors?
- activated by endogenous opioid dynorphin
- there is a ceiling affect, usually not potent enough to stop surgical pain
- mixed agonist/antagonist sites
- mediates analgesia less than mu receptors(mediate dysphoria, sedation)
What endogenous opioid receptor do Delta interact with and what do they facilitate?
enkephalin and facilitates mu activities
What endogenous opioid receptor do Nociceptin receptors interact with and how does is affect mu agonist?
Endogenous opioid nociceptioin
develops tolerance to mu agonist
instinctive and emotional behaviors
What is the opioid receptor function?
endogenous pain suppression system
What are the 5 receptor location for opioids?
periaqueductal gray matter in:
- brainstem
- amygdala
- corpus striatum
- hypothalamus
- substantia gelatinosa of the spinal cord
Opioid receptors are involved in(3)?
- pain perception
- integration of pain impulses
- pain response
What are neuroaxial opioids?
opioids that are delivered into the epidural or subarachnoid tracts
How do neuroaxial opioids provide analgesia?
effect due to mu receptors in SUBSTANTIA GELATINOSA OF THE SPINAL CORD
How much more is the epidural opioid dose more then the subarachnoid dose?
5-10 times more
Epidural opioid placement works via (2)?
- mu spinal cord receptors
2. systemic action
Epidural fentanyl/sufentanil works in part via SYSTEMIC absorbition….what is it dependent upon?
how lipid soluble it is
The absorbtion of epidural does of opioids is dependent upon what 3 things?
- epidural fat
- systemic absorption-epidural space venous plexus
- CSF
Cephalad movement of opioids is dependent upon what two thing?
- greater with less lipid soluble opioids like morphine
2. follows CSF currents into cisterna magna > fourth and lateral ventricles
What are 2 reasons for adverse effects of neuroaxial opioids?
- greater CSF concentrations
2. greater systemic concentrations
List 8 adverse effects of neuroaxial opioids.
- pruitis
- N&V
- urinary retention
- respiratory depression(lethal adverse effect)
- sedation
- constipation
- poikothermia
- water retention(ADH secretion)
What are the 4 main side effects of neuroaxial opioids.
- pruritis
- urinary retention
- ventilatory depression
- sedation
Side effects are dose dependent
What is the number 1 side effect of neuroaxial opioids?
PRURITIS-especially face, neck and upper thorax
What causes the side effect of pruitis with neuroaxial opioids?
Not from histamine but cephalad migration in CSF to trigeminal nucleus
What is the treatment for neuroaxial opioid puritis?
naloxone(#1), antihistamines
What are some characteristics of the Neuroaxial opioid side effect of urinary retention?
- most common in young males
- Neruoaxial urinary retention more common than IM/IV
- Due to opioid receptor activation in sacral spinal cord
- inhibits sacral parasympathetic outflow causing: detrusor muscle relaxation & greater bladder capacity
- may be reversed by naloxone
What is the most serious adverse effect of neuroaxial opioids? What is the mechanism of action.
VENTILATORY DEPRESSION
1% incident
depression within 2 hours due to systemic absorption(not cephalad migration)
depression after 2 hours due to cephalad migration of opioids in CSF—> interaction with ventral medulla
occurs most often with morphine
What are the characteristics of Neuroaxial opioid sedation.
- dose related
- most common with sufentanil because it is the most lipid phillic has the most systemic absorbtion.
- sedation accompanies ventilatory depression!
Morphine induced CNS excitation is caused by?
cephalad migration, interaction with non-opioid receptors
What are 6 other effects neuroaxial opioids can have on the body?
- delayed gastric emptying
- lower body temp(inhibition of shivering)
- water retention due to vasopressin release
- spinal cord damage(if opioids with perservatives~duromorph~ is used
- reactivation of herpes 2-5 days post opioids
- newborns with ventilatory depression
Morphine is the prototype _____ opioid _____.
mu, agonist
Morphine is effective for _____ & _____ muscle pain
visceral and skeletal
When analgesia best achieved with morphine?
before pain
Why is PO morphine unreliable?
first pass clearance
What are the characteristics of IM morphine?
- well absorbed
- onset 15-30 minutes
- peak 45-90 minutes
- duration 4 hours
What are 3 characteristic of the peak effects of morphine?
- peak effect delayed compared to fentanyl(slower BBB penetration)-due to being less lipophiliac
- CSF {} peaks 15-30 minutes after administration
- analgesic and ventilatory effects seen after plasma {} peaks
Why does morphine have poor CNS penetration(4)?
- high amount of ionization of 7.4 pH
- poor lipid solubility
- protein binding-longer duration of action if Renal impared
- rapid conjugation via glucuronic acid
What amount of morphine reaches CSF?
only small amounts (0.1%)
What is the result of morphine having a high accumulation in kidneys, liver and skeletal muscle?
large volume of distribution
What is the main metabolic pathway of Morphine?
mainly glucuronic acid conjugation in liver & kidney
- 75-85% changed to morphine-3-glucuronide, pharmacologically INACTIVE
- 5-10% changed to morphine-6-flucuronide(black tar heroin)-greater analgesia than morphine
How is morphine eliminated?
via urine
- cumulative effects in ESRD patients
- Glucuronide metabolism impaired with MAO patients(results in exaggerated effects)
Neonates are more sensitive to ventilatory depressant effects of morphine
What are the CV side effects of morphine(5)?
- reduced venous return(decreased CO, lower BP)
- decreased SNS tone to capacitance vessels(vessels that holds the bodies blood volume
- bradycardia-greater vagus nerve activity from stimulation of vagal nuclei in medulla
- histamine release-may lower BP
- treatment with H1&H2 blockers minimizes hypotentioin
How might the hypotensive effects of morphine be marginalized?
- give no faster than 5mg/min
- supine position
- give fluids to “fill the tank”
What is the #1 treatment for morphine induced puritis?
narcan
Morphine with nitrous will _____ the _____?
depress, myocardium
Greater drops in BP seen with _____ administration with _____.
cocomitant, benzodiazepines
By what action does morphine cause ventilatory depression?
via agonist effect on the brainstem ventilation centers
How does morphine effect the respiratory center?(5)
- Morphine decreases sensitivity of ventilatory centers to CO2
- Morphine interferes with pontine and medullary ventilatory centers that regulate breathing rhythm
- decreased RR, greater VT-changes in pattern of breathing(net result-increased PaCO2)
- Morphine depresses airway ciliary activity
- Morphine increases airway resistance(bronchial smooth muscle actions & release of histamine)
What counteracts the ventilatory depressive effects of morphine?
pain
Why is morphine bad for neuro patients specifically?
- decreased wakefulness bad for neuro exams(sometimes they use remifentanil cause its short acting you can wake the patient up for a neuro exam)
- ventilatory depression which raises ICP via increased cerebral blood flow from higher PaCO2
By what mechanism does thoracic and abdominal rigidity(lead chest) occur with morphine administration?
with rapid administration due to actions on dopaminergic and GABA neurons
By what mechanism does miosis occur with morphine?
excitation of Edinger-Westphal nucleus of the oculomotor nerve
What are some side effects of morphine seen on the biliary/GI systems?
- spasms of biliary smooth muscle(increased intrabiliary pressures which causes angina like pain-relived by NARCAN, glucagon or NTG)
- may constrict smooth muscle of the pancreatic duct raising amylase and lipase levels
- constipation-weaker peristalsis, increased sphincter tone, slower passage causes greater water absorption
What are some characteristics of morphine administration and N&V?
- result of direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle(dopaminergic agonist at CTZ dopamine receptors)
- less common when given IV(IM morphine depresses medullary vomiting center simultaneously with CTZ)
- less common also in supine patients(vestibular component)
What are some GU side effects seen with morphine?
GU-greater ureteral tone and peristalsis, may be reversed by anticholinergics
Urinary urgency-via augmentation of detrusor muscle tone yet vesicle sphincter muscle tone is increased, making voiding difficult
How does morphine affect the cutaneous tissue?
- vasodilation due to histamine release which leads to:
1. urticaria, erythema
2. flushing of face, neck, and upper chest–>may make nose itch(flushing where folks normally “blush”)
What is the addiction potential of morphine?
- tolerance and physical dependence occurs with repeated use
- tolerance/addiction are major limitations to use
- tolerance occurs in less then 2-3 weeks, complete physical dependence in 25 days, some physical dependence in 48 hours
What are the S/S of Morphine withdrawal?
yawning, diaphoresis, insomnia, restlessness, abdominal cramps, N&V, diarrhea
withdrawals begins in 15-20 hours from last dose, peaks in 2-3 days, last 10-14 days
Meperidine(demorol) was the first synthetic opioid derivative and interacts with what 2 pain modulators?
- Mu
2. Kappa
Meperidine is a product of using _____ _____ with dichloroethyl methyl amine.
benzyl CYANIDE
How does Meperidine compare to morphine?
- 10% the potency of morphine.
- structurally related to fentanyl
- shorter duration of action…..2-4 hours.
- equal to morphine in sedation, euphoria, N&V and ventilatory depression
demorol is fentanyl grandfather
What is the principle metabolic of Meperidine?
nor-meperidine(1/2 meperidine’s analgesic potency)
Is Meperidine well absorbed from the GI system and how much is lost via first pass clearance?
Yes it is well absorbed
half lost in first pass clearance
When patients say they are allergic to Meperidine they are usually referring to wha 3 side affects produced by its principle metabolite nor-meperidine?
- CNS stimulation
- myoclonus
- seizures
What is Nor-meperidines 1/2 life?
elimination half life 15 hours(longer than demerol)
(T/F)Nor-meperidine has been implicated in confusion and hallucinations, especially in long term and PCA meperidine use.
True
How much of Meperidine is plasma protein bound, which results in greater effects in(3)?
60%;
- elderly
- malnourished
- liver failure
Meperidine has the _____ therapeutic index of any clinical opioid.
Narrowest
(Plasma {} changes as small at 0.05 mcg/ml can represent pain to complete analgesia and ventilatory depression
What is the principle use of Meperidine?
- analgesia for labor and delivery
- post-op pain relief
- shivering in PACU(Kappa-mediated: change in shivering threshold)
If an epidural opioid agonist is less lipophilic, such as morphine, will it exert less of an effect and require a higher dose or more of an effect and a smaller dose?
Less of an effect and require a higher dose
If you use a more lipophilic epidural opioid agonist such as fentanyl or sufentanil, systemic absorption will play a greater role in exerting pharmacologic effects(T/F)?
true
What portion of morphine will actually reach the brain?
-0.1%
-poor CNS penetration due to :
high amount of ionization at 7.4 pH
poor lipid solubility
significant protein binding
rapid conjugation via glucuronic acid
-high accumulation in kidney, liver and skeletal muscle
What are 2 major reasons to not give demerol to a cardiac patient?
- increase in HR(structurally similar to atropine)
2. myocardial depressant
Describe Fentanyl
- Phenylpiperidine derivative r/t meperidine
- 75-125 x stronger than morphine
- more rapid onset, shorter duration of action, greater lipid solubility
- rapid distribution to inactive tissues(fat/skeletal muscle)
- Lungs: large inactive storage site…takes up to 75% of initial dose
- much greater volume of distribution than morphine(greater lipid solubility)
What is fentanyl metabolized to?
- Nor-fentanyl, which undergoes renal excretion
- minimal analgesic potency
- much greater volume of distribution than morphine(greater lipid solubility)
Once inactive tissue sites become saturated with repeated doses of fentanyl, it changes from short acting to long acting drug(t/f).
true; fentanyl plasma {} sustain content high rate
What is the fentanyl dose for analgesia?
1-2 mcg/kg
What is the fentanyl dose as adjuvant to inhaled anesthesia?
2-20 mcg/kg; will blunt circulatory response to laryngoscopy and sudden increases in surgical stimulation
When used as sole surgical anesthetic, what is the fentanyl dose and what is its effect?
- 50-150 mcg/kg
- not reliable amnesia
- post-op ventilatory depression
- sympathetic breath through
- absorbed by CPB circuits
- NOT a myocardial depressant
- NO histamine release
- suppression of stress response
- IV and transdermal, lollipop
How much fentanyl is delivered via a lollipop?
5-20 mcg/kg
-increased incidence of PONV and hypoxemia
How much fentanyl is delivered with a transdermal patch?
75-100 mcg/hr
-peak effects in 18 hours
Fentanyl analgesic effects go hand in hand with ventilatory depressant effects(T/F)?
true
What are the adverse effects of fentanyl?
- persistent/recurrent ventilatory depression
- 2nd plasma peak {} occurs when sequestered fentanyl from gastric fluid/lung washout re-enters systemic circulation
What are the CV effects associated with fentanyl?
- minimal dilation of capacitance vessels….by itself(no histamine release)
- carotid sinus baroreceptor reflex heart control is DEPRESSED
- bradycardia more prominent than with MS
- bradycardia dangerous with neonates as stroke volume is fixed(SV+HR=CO)
Are there any allergic reactions associated with fentanyl?
rare to never
What is seizure activity with fentanyl associated with?
- depression of inhibitory neurons
- dose not interfere with monitoring of evoked potentials
Fentanyl causes moment increases in ICP even with maintaining baseline ETCO2(T/F)?
- true
- ICP increases joined by decreased cerebral perfusion pressure pressure and lower MAP
Describe Sufentanil:
- analogue of fentanyl(sufentanil comes from fentanyl)
- 5-10 x greater potency
- less risk of seizures than fentanyl
- elimination 1/2 time intermediate between fentanyl and alfentanil
- prolonged elimination in elderly, obese
- rapid penetration of BBB unlike MS
- rapidly redestruibution to inactive tissue in small doses
- cumulative effect in large doses like fentanyl
- 60% 1st pass pulmonary uptake
- 92% plasma protein binding = small Vd
- Alpha-1 acid glycoprotein(#1 plasma protein it binds to)
- enhanced neonate effect from lower plasma protein levels
How is sufentanil metabolized?
- dealkylation into inactive metabolites and
- Demethylation to desmethyl sufentanil
Desmethyl sufentanil is 10% as potent as sufentanil(T/F)?
true
Sufentanil undergoes extensive hepatic extraction…sufentanil clearance sensitive to hepatic blood flow, not to changes in hepatic drug metabolizing capacity(T/F)?
true
If sufentanil is excreted in urine and stool, what will the effects be for ESRD patients?
prolonged ventilatory depression
Cessation of sufentanil’s effect is due to _____ and _____?
metabolism & redistribution to inactive tissues
Single doses of sufentanil produce greater analgesia and less ventilatory depression than fentanyl(T/F)?
true; quicker on and quicker off then fentanyl
What is the induction dose of sufentanil? Are there any hemodynamic changes?
- 10-30 mcg/kg
- MINIMAL HEMODYNAMIC CHANGES….VERY STABLE
Sufentanil bradycardia may be slow enough to decrease CO?
true
Sufentanil is THE BEST phenylpiperidine derivative for blunting BP and catecholamine responses to surgical pain.
True
How is Remifentanil different from fentanyl?
- has an ester linkage
- makes it RELATED to fentanyl family
Remifentanil is the only IV form of opioid agonist that you can adjust like a vaporizer
True
What does the unique metabolism of remifentanil provide?
- short action
- precise titration
- no cumulative effect
- rapid recovery
How is remifentanil metabolized?
- rapidly metabolized by hydrolysis of propanoic acid-methyl ester linkage by non-specific tissue and blood esterase’s
- No liver/kidney involvement
- Patients with atypical plasma cholinesterase metabolize remifentanil normally
Remifentanil has a small Vd and rapid clearance. Infusion steady state reached in 10 minutes.
true
Remifentanil metabolites are pharmacologically inactive.
true
Name 2 surgeries were remifentanil would be great in?
- Neuro: for rapid wake-up
2. Retrobulbar block
What is the dose for remifentanil?
- 1mcg/kg bolus
- 0.05-2 mcg/kg/min
Describe remifentanil>
- Mu receptor agonist
- comes in a white lyophilized powder…for IV administration after reconstitution and DILUTION!
- Mu receptor agonist with rapid onset and peak effects, short duration of action
- No histamine release
- Synergistic with hypnotics, inhaled anesthetics and benzos
- effects increase with increasing age of patient
- does not alter ICP with controlled ventilation maintain ETCO2 less than 30 mmHg
For remifentanil blood {} decrease 50% in 3-6 minutes following a 1 min infusion?
true
-recovery is rapid; 5-10 min independent of duration of infusion
If you adjust your remi gatt, how long will it take to get to steady state {}?
5-10 minutes
List ways to decrease hypotensive effects of remifentanil.
- lowering infusion rates
- decrease volatile agents
- use fluids/vasopressors
The duration of remifentanil depression does not increase with the length of infusion, due to a lack of drug accumulation?
True
What increases risk of “lead” chest?
- single doses(high dose)
- > 1mcg/kg administered over 30-60 sec
- infusion rates > 0.1 mcg/kg/min
hypnotics and neuromuscular blockers will block chest wall rigidity effects
Codeine is an effective antitussive @ 15 mg PO doses, minimal 1st pass clearance, maximal analgesia @ 60 mg PO
True
Why is codeine not given IV?
histamine release
Hydromorphone is a semi-synthetic 8 x more potent than morphine, slightly shorter duration, uses and side effects like morphine.
true
Methadone is a synthetic opioid effective by oral route, prolonged duration of action useful in chronic pain and suppression of withdrawal and cravings for heroin addicts.
- true
- come from thebane
Describe opioid agonist/antagonists
- bind to opioid receptors BUT exert partial effects
- act on Mu, Kappa and Delta receptors
- less ventilatory depression
- limited analgesia(ceiling effect)
- lower abuse potential
- may block effects of pure mu agonists
- Examples: Pentazocine, nubain, stadol
What are the adverse effects of opioid agonist/antagonists?
- sedation
- diaphoresis
- dizziness
- dysphoria(minimal with stadol/butorphanol)
- increased HR
- increased BP
- increased LVEDP(not for ASCVD patients)
Describe Pentazocine
- opioid agonist/antagonist
- Benzomorphan derivative
- delta and kappa receptor action
- can precipitate opioid withdrawal
- most often given for pain control in ESRD patients
- PO, IM, IV routes with extensive 1st pass clearance
- dose: 10-30 mg IV or 50 mg PO
Describe Naloxone
- Alkyl derivative of oxymorphone
- pure antagonist…no agonist activity
- displaces opioid agonist from the mu receptor sites and binds to the site without eliciting any response
- used for opioid induced ventilatory depression, OD, anesthetic misadventures
- short duration of action may require additional doses for antagonism of prolonged ventilatory depression
- reverses analgesia
- increased sympathetic activity after administration > tachycardia, HTN, pulm edema, dysrhythmias
- administration to opioid dependent moms can trigger withdrawal in neonates as naloxone crosses BBB
What is the dose of narcan?
1-10 mcg/kg
