Chp. 22: Sedatives and Tranquilizers Flashcards
What is the difference between a sedative and tranquilizer?
A tranquilizer induces a feeling of calm (anxiolysis). Sedatives reduce anxiety but also reduce the overall response to external stimuli.
What sedative is associated with extrapyramidal effects (tremor, coma/catalepsy, rigidity)?
Acepromazine
What receptors primarily mediate the sedative effects of acepromazine? What additional receptors may be involved?
- Dopamine receptor blockade, specifically D2 receptors
- A1, muscarinic, and histaminic receptor blockade may also contribute
What receptors mediate the hypotensive effects of acepromazine? What additional effects does blockade of this receptor type cause?
- A1 receptor antagonism
- May play role in sedation and decrease in thermoregulatory control
Neuroleptanalgesia
A state characterized by both sedation and analgesia
What is the onset of effect of acepromazine? The elimination half life (dogs and horses)?
- Onset in 10-20 minutes after IV administration, 30-40 minutes after IM
- Elimination half-life of 3-5 hr in horses, 7 hr in dogs
What are the CV effect of acepromazine?
Peripheral vasodilation, decreased SV, CO, and ABP
HR changes are variable, but mild reflex tachycardia secondary to decreased SVP and ABP have been reported
What is the effect of acepromazine on the respiratory system?
Minimal
What is the effect of acepromazine on MAC?
Significant, dose-dependent reduction
Does acepromazine impact seizure frequency?
No
What are the non-primary effects of acepromazine?
- Hematocrit reduction by 20-30% (splenic engorgement and A1 blockade)
- Well-recognized antiemetic properties ***
- LES tone and gastric emptying reduced
- Priapism in stallions
- Antihistaminic effects preclude use for intradermal skin testing
What is the mechanism behind the anti-emetic effects of acepromazine?
Antagonism of dopamine receptors in the CRTZ
What is the relationship between acepromazine and the MDR1 mutation?
Anecdotal reports that homozygous dogs may show increased sensitivity to various sedative or analgesic drugs, including ace
Can acepromazine be used in Boxers?
Anecdotal reports of collapse and sudden death in Boxers. Undefined, but could represent enhanced vasovagal response, indicating use of a much-reduced dose or pre-treatment with an anticholinergic
What is the effect of acepromazine on equine anesthetic morbidity and mortality?
DECREASED RISK
Dose 0.01-0.05mg/kg IV
What is the relationship between acepromazine and malignant hyperthermia in pigs?
High doses (1.1 and 1.65mg/kg IV) reduce the incidence of halothane-induced malignant hyperthermia. Lower doses (0.55mg/kg) only delay onset.
Azaperone
- Butyrophenone derivative
- Clinical applications in swine, zoo, and wildlife
- Antagonism of central dopaminergic receptors (primarily D2)
- Potentially less hypotension than ace due to decreased affinity for vascular A1-receptors
What class of controlled substances are benzodiazepines?
Schedule IV
What is the mechanism of action of the benzos?
Augment GABA-mediated inhibitory transmission at all levels of the CNS through positive allosteric modulation of the GABA(A) receptor, resulting in increased chloride conductance and hyper polarization of postsynaptic cell membranes.
ENHANCE endogenous GABA binding but lack direct agonist activity = wide safety margin
What drugs show synergistic effects with benzos?
Barbiturates, ethanol, etomidate, and propofol
In what patient populations are paradoxical behavioral effects less often seen with benzodiazepine administration?
Neonatal, geriatric, and systemically ill patients
What route of administration is not recommended for diazepam?
IM (erratic and unpredictable)
What is the risk of repeated dosing of diazepam in cats and why?
Diazepam-induced liver injury due to limited capacity to form glucuronide conjugates of diazepam and its metabolites
Why is midazolam amenable to IM administration?
Diazepine ring closes at injection at physiologic pH, rendering it lipid-soluble and able to cross the BBB to produce central effects.
What is the elimination half-life, time to peak concentration, and bioavailability of IV midazolam?
- Elimination half-life of 63-77 minutes (dogs)
- Elimination half-life of 216-408 minutes in horses depending on dose
- Time to peak plasma concentration after IM administration of 7.8-15 minutes
- 50% bioavailability of 50-90% after IM administration
What benzo can be administered rectally?
Diazepam
CV and respiratory effects of midazolam
Minimal. Respiratory depression may be evident at high doses, when combined with other CNS depressants, or when given to patients with significant pulmonary disease
Do benzos improve cardiopulmonary stability when co-administered with propofol or alfaxalone?
No
What is the ceiling MAC reduction produced by midazolam?
30%
What is the effect of benzos on cerebral perfusion?
Generally favorable, reducing cerebral oxygen consumption to a greater extent than cerebral blood flow
What species sedate reasonably well with benzos?
Small ruminants, ferrets, rabbits, and birds
Flumazenil
- Competitive antagonist with high affinity for benzodiazepine recognition site on the GABA(A) receptor.
- Does not antagonize CNS effects of other GABA-interacting anesthetic agents
- Devoid of direct CV, respiratory, or MSK effects
- Dogs 0.01-0.04mg/kg IV, horses 0.01-0.02mg/kg IV
What is the molecular MOA of the alpha-2 agonists?
Allosteric inhibition through Gi/o > inhibition of AC > decreased cAMP > inhibition of Ca2+ entry and activation of K+ channels > membrane hyperpolarization > suppression of neuronal firing
What A2 receptor subtypes predominate in the CNS? What effects are these responsible for?
A2A and A2C
Responsible for sedative, analgesic, and sympatholytic effects
What is the effect of alpha2s on NE?
Inhibition of NE release and reduced activity in ascending noradrenergic pathways, resulting in hypnosis and sedation. Activation of this negative feedback loop may also produce reductions in HR and BP and attenuation of sympathetic stress response
What mechanism is thought to be responsible for the analgesia associated with alpha2s?
Agonist binding to pre- and postsynaptic A2 receptors in the substantia gelatinosa of the SC dorsal horn and locus coeruleus of the brainstem. Afferent input is modulated and dampened by decreases in NE and substance P (presynaptic). Neuronal hyperpolarization and inhibition of nociceptive neurons (postsynaptic).
Analgesic effects shorter-lived than sedative effects
What is the A2:A1 receptor selectivity for each A2 agonist and antagonist agent?
Xylazine 160:1
Detomidine 260:1
Romifidine 340:1
Medetomidine 1620:1
Dexmedetomidine 1620:1
Tolazoline 4:1
Yohimbine 40:1
Atipamezole 8526:1
Vatinoxan 105:1
*activation of A1 results in vasoconstriction and increased SVR
What is the role of the imidazoline receptors in alpha2 agonist effects?
All agonists, except xylazine, may also activate the imidazoline receptors.
I1 receptor plays a role in CV regulation and has been implicated in modulation of sodium excretion and urine output, inhibition of catecholamine-induced arrhythmias, and neuroprotective effects
I2 involved in central noradrenergic and HPA axis activity and opioid-induced antinociception.
I3 may play a role in insulin secretion and contribute to A2-induced hyperglycemia**
What is the onset of action of alpha2s?
Rapid (within minutes) with peak effects shortly thereafter
What is the role of the alpha2s in neuraxial and peripheral nerve anesthesia?
Highly lipophilic, resulting in systemic absorption after neuraxial anesthesia and effects comparable to systemic administration. Perineural administration associated with fewer systemic side effects.
The pharmacologic actions of medetomidine are due to what?
The dextrorotary isomer, which is isolated in dexmedetomidine
How is dexmedetomidine metabolized?
Hepatic metabolism to inactive metabolites by hydroxylation, oxidation, or conjugation
What are the biphasic effects of the alpha2s?
Initially, activation of postsynaptic A1 and A2B receptors results in peripheral vasoconstriction, increased SVR, and increased ABP. Effects induced a baroreceptor-mediated reflex bradycardia, resulting in significant reductions in CO.
Activation of central presynaptic A2A and A2C receptors results in reduced NE release and sympathetic outflow, perpetuating bradycardia and reduction in CO. These secondary changes cause bradycardia and hypotension.
What are the effects of alpha2s on the heart?
Reduction in CO due to increased SVR and bradycardia, not direct myocardial contractility alteration. Do not adversely impact myocardial perfusion and may beneficially modulate coronary blood flow during myocardial ischemia.
What are the effects of alpha2s on the respiratory system?
Centrally mediated reductions in RR and minute ventilation (PaCO2 increases and PaO2 decreases not clinically significant)
Low-dose CRIs (1mcg/kg/hr) improved oxygenation and respiratory system compliance and reduced intrapulmonary shunt fraction and airway resistance in isoflurane anesthetized dogs
What are the effects of alpha2s in sheep?
Hypoxemia due to activation of pulmonary intravascular macrophages, which damage capillary endothelium and alveolar type I cells, leading to intra-alveolar hemorrhage and interstitial and pulmonary edema
How do alpha2s achieve sedation?
Activation of A2 receptors in the locus coeruleus of the pons and the rostroventral lateral medulla > reduces NE release > discharge frequency of tracts into cortex slows > diminishes arousal
What are the MAC-sparing effects?
Significant, up to 90% reported
What are the effects of alpha2s on cerebral hemodynamics?
Dexmedetomidine reduced cerebral blood flow with no alteration in cerebral metabolic rate of oxygen
How are the diuretic effects of alpha2s mediated?
Reduced production or release of ADH from the pituitary, inhibition of ADH on renal collecting tubules, and enhanced sodium excretion
What is responsible for A2 agonist mediated hyperglycemia?
Imidazoline receptor activity (I3) AND activation of A2A receptors in pancreatic beta cells suppressing insulin release. May also stimulate glucagon by alpha cells to promote gluconeogenesis. Doesn’t usually exceed renal threshold (180mg/dL).
Rank the species from most to least sensitive to alpha2s.
Goats > sheep, cattle > camelids > horses, dogs, cats > pigs > small laboratory animals
What alpha2s are approved by the FDA for use in cattle?
None, but xylazine is used frequently off-label
What cattle breeds are more sensitive to the alpha2s?
Herefords, Brahmans
What is the MOA of alpha2 antagonists?
Act as competitive antagonists at A2-adrenergic receptors and have no subtype specificity.
What alpha2 antagonist impacts peripheral receptors only?
Vatinoxan
What is the MOA of vatinoxan?
Poor lipid solubility results in exclusion from the CNS after systemic administration. Selectively antagonises peripheral postsynaptic A2 receptors in vascular endothelium with minimal effects on supraspinal and spinal A2 receptors.
No clinically relevant effect at A1 receptors.
What are the CV effects of A2 antagonists?
Minimal dose-dependent changes including increased HR and increased SVR. Even with high A2 specificity, antagonists do not completely reverse the CV effects of A2 agonists.
Does vatinoxan prevent A2 agonist hemodynamic effects?
It attenuates but does not prevent them, including reductions in HR and CI and increases in SVR and ABP.
Seems to better prevent pulmonary effects with pretreatment (bronchoconstriction, pulmonary edema, arterial hypoxemia).
Are the MAC reducing effects of A2 agonists reversed by antagonists?
Yes.
Do the A2 antagonists reverse the non-CV effects of the agonists?
Yes, including the effects on GI function, urine output, and glucose regulation.
What are the negative effects of IV tolazoline?
Adverse CNS effects (hyperesthesia and opisthotonos). Very high doses associated with CNS, CV, respiratory, and GI side effects.
Zenalpha
Vatinoxan combined with medetomidine. Purported to maintain centrally mediated sedative and analgesic effects while counteracting CV depressant effects. Label dose is 40mcg/kg medetomidine and 800mcg/kg vatinoxan in a 20kg dog.
NOT labeled for administration with any other drugs, doing so would constitute extra-label use.
