Benzodiazepines, flumazenil, naloxone, doxapram Flashcards
what are the pharmacologic effects of benzodiazepines?
- sedation
- anxiolysis
- anticonvulsants
- skeletal muscle relaxation
- antegrade amnesia (only remembers from that time forward) *good for kids in holding with separation anxiety
describe the MOA of benzodiazepines.
BZD receptors are part of the GABA receptor, when activated, causes increased binding of GABA to its receptor opening Cl- channel, hyperpolarizing the neuron inhibition of the neuron to excitation
-also have an attraction to the glycine receptors in the brainstem and the spinal
what results from the action of benzos on the GABA receptors?
- sedation from GABA receptors at the cortex
- anticonvulsant from GABA receptors at motor circuits in brain
what results from the action of benzos on the glycine receptors?
- muscle relaxation from glycine receptors at spinal cord motor neurons
- antianxiety from inhibition of afferent conduction at glycine receptors at brainstem
describe the GABA receptor
has separate binding sites for benzodiazepines, barbiturates, and ETOH
*if receptor is activated at more than one site (benzo with propofol or with alcoholic) effect is synergistic
describe midazolam (Versed)
- most commonly admin as premedication or IV sedation
- water-soluble at pH 3.5
- imidazole ring makes it water soluble except when pH > 4 (body pH), it is lipid soluble (no pain on injection)
- compatible with opioids and LR (acidic solutions)
- routes: po, IM, sublingual, intranasal (uncooperative patients, very rapid onset), IV
what are some uses of midazolam?
- premedication
- sedation
- induction of anesthesia
- maintenance of anesthesia (not best choice, infusion has longer duration)
what are some CV effects of midazolam?
- decrease in BP r/t SVR decrease
- increase in HR (more than diazepam)
- no change in CO
- hemodynamic effects exaggerated in hypovolemic patients (no big change with normovolemc)
- synergistic effects with opioids
what are some respiratory effects of midazolam?
- dose-dependent decreases in ventilation (similar to diazepam)
- *exaggerated in COPD, esp elderly with COPD
- apnea with rapid injection of dose > 0.15 mg/kg IV and with opioids (don’t give both in holding!)
what are the CNS effects of midazolam?
- decreases CMRO2 (metabolic rate, O2 consumption in brain)
- decreases cerebral blood flow similar to barbiturates
- *cannot cause EEG to become isoelectric like with pentothal (ceiling effect)
- treat seizures from local anesthetic toxicity
- excitement occurs in < 1% (peds) (treat with flumazenil)
what is the onset of midazolam?
0.9-5.6 minutes
how much of the oral dose of midazolam reaches circulation after hepatic first pass?
50%
what is the elimination 1/2 time of midazolam?
1-4 hrs
- short duration of action d/t redistribution
- may be doubled in elderly (give smaller dose)
how is midazolam metabolized and excreted?
- hydroxylation by hepatic microsomal oxidative mech (C-P450)
- hepatic clearance rate is 5x faster than lorazepam and 10x faster than diazepam
describe emergence from midazolam
- slower awakening than pentothal
- no N/V
- no emergence excitement
- one hour later after awake, no difference in alertness
- *not good for outpatients since slower emergence
describe diazepam (Valium)
- insoluble in water, dissolved in propylene glycol
- *pain on injection, not good IM
- rapidly absorbed orally
- *peak concentration in 1 hr
what are CV effect of diazepam?
- minimal BP, CO, or SVR decrease
- less effects than barbiturates and midazolam
- synergistic decreases with fentanyl
- decreases exaggerated with hypovolemic patients
what are respiratory effects of diazepam?
- depresses the response to CO2
- minimal depressant effects until 0.2 mg/kg IV
- *decrease in TV
- apnea rarely occurs with dosages < 10 mg IV
what are CNS effects of diazepam?
- decreases in CMRO2, CBF, ICP (less than barbiturates)
- relaxant effects on skeletal muscle tone
- decreases MAC up to 30%
- decreases induction dose of thiopental
- anticonvulsant prophylaxis (effects last longer than elimination 1/2 life, metabolites have same effect)
- anxiolysis, amnestic (less than midazolam)
how is diazepam absorbed?
- lipid soluble
- quickly absorbed for GI tract and crosses placenta
how is diazepam metabolized?
hepatic microsomal enzymes to:
- desmethyldiazepam
- oxazepam
- both active metabolites
describe desmethyldiazepam
- only slightly less potent than diazepam
- drowsiness returns 6-8 hrs after admin (redistribution)
- causes prolonged effects of diazepam
- elimination 1/2 life 48-96 hrs
what is the elimination 1/2 life of diazepam?
21-37 hrs
- increases with age
- increases up to 5x with cirrhosis of the liver
- prolonged with Tagamet, which has inhibitory effect on hepatic enzymes
what is the peak effect of diazepam?
55 minutes
describe lorazepam
- insoluble in water, dissolved in polyethylene glycol or propylene glycol
- less painful than diazepam
- absorbed orally and IM
- *slow onset and prolonged duration of action (not useful for outpatient))
- *most potent
- *antegrade amnesia lasts up to 6 hrs
how is lorazepam metabolize?
into inactive metabolites
why is lorazepam’s clinical effect longer?
slower release from the GABA receptors
what is the elimination 1/2 life of lorazepam?
10-20 hrs (not as slow as diazepam d/t inactive metabolites)
*good for cardiac cases of younger patients (<50)
what is the peak concentration time of lorazepam?
2-4 hrs (slower onset)
describe flumazenil
-benzodiazepine antagonist
what is the MOA of flumazenil?
competes with benzodiazepines for the BZD receptor sites on GABA receptors
*reverses respiratory depression effect of benzos
what reversal effects can be seen with flumazenil?
DO NOT SEE: acute anxiety, stress response, HTN, tachycardia
- could see withdrawal seizures for those on seizure tx
- reversal of benzo effects buffered by weak agonist effect
what is the onset of flumazenil?
2 minutes
what is the duration of flumazenil?
30-60 minutes
*may need to redose or start infusion since benzo effects are longer and may become sedated or respiratory depressed again with lorazepam or diazepam
describe naloxone (Narcan)
- opioid antagonist
- antagonizes mu receptors more than kappa
what is the MOA of naloxone?
attraction of naloxone for the receptor displaces the opioid from the receptor; the antagonist binds and inactivates the receptor
what are clinical indications for naloxone use?
- opioid overdose
- post op ventilatory depression d/t opioids
- neonatal ventilatory depression d/t maternal opioids
- adverse effects of spinal and epidural opioids
what is the onset of naloxone?
1-3 minutes
what is the duration of naloxone?
30-45 minutes d/t redistribution
*may need to redose for opioids with longer effects
how is naloxone metabolized?
primarily in the liver
what are the respiratory effects of naloxone?
- primary goal is to reverse respiratory depression
- if titrated properly, can reverse depression without weakening analgesic effect
- acute pulmonary edema can be caused by an increase in pressure and increased permeability of pulmonary capillaries (give small, incremented doses
what are the cardiovascular effects of naloxone?
- sympathetic stimulation **PAIN
- tachycardia, ventricular irritability (V fib)
- HTN
- r/t speed and extent of reversal
- titrate in small doses or even better just avoid reversal if possible
what are CNS effects of naloxone?
- N/V (r/t speed and dose)
- return of airway reflexes (possible laryngospasm)
how does naloxone affect the neonate?
crosses the placenta and may cause life threatening withdrawal symptoms if opioid abusing mother
how does naloxone affect opioid dependency?
if patient normally on opioids, may precipitate abstinence syndrome
*too much narcan can cause life threatening withdrawals
when should you avoid naloxone?
- critically ill
- CAD
- preexisting drug disease
- CHF
- cardiac surgery
- opioid dependence
describe doxapram
-CNS stimulant
what is the MOA of doxapram?
- stimulates hypoxic drive via the activation of the chemoreceptors in the carotid bodies
- 1 mg/kg = PaO2 of 38 mmHg
- produces an increase in TV and small increase in RR
what are clinical indications for doxapram?
- COPD patients who breathe based on hypoxic drive, but need supplemental O2
- ventilatory depression and CNS depression d/t drugs (helps blow off volatile agent)
- may see with propofol infusion but surgeon wants spontaneous breathing
what is the onset and duration of doxapram?
onset: 1 minute
duration: 5-10 minutes
how is doxapram metabolized?
mostly liver
what are the CNS effects of doxapram?
- stimulates hypoxic drive d/t activation of chemoreceptors in the carotid
- mental status changes like confusion, dizziness, seizures (20-40x dose)
- increased sympathetic outflow
- vomiting
- increased body temperature
what are respiratory effects of doxapram?
- increased minute ventilation by increasing tidal volume and slightly increasing RR
- increases O2 consumption
- wheezing (not good for COPD)
- tachypnea (not good for COPD)
what are CV effects of doxapram?
- increased sympathetic stimulation
- HTN
- tachycardia
- cardiac dysrhythmias
when should doxapram not be used?
- seizure disorder
- cerebrovascular disease
- acute head injury
- CAD
- HTN
- asthma
- halothane (sensitized to catecholamines)
