Analgesics / NSAIDs / sedatives Flashcards
How is remifentanil metabolized
By non-specific esterases in blood and tissues (does not involve liver and kidneys)
What is the mechanism of action of local anesthetics when administered locally vs systemically (or via epidural)
- Peripheral -> bind to voltage-gated Na+ channel (on intracellular side) + cause membrane expansion leading to closure of the channel -> prevent Na influx -> no depolarization - > noconduction of signal (sensory / motor)
- Central -> at the level of the spinal cord also inhibit Ca and K-channels, inhibit substance P binding, inhibit glutamate-mediated transmission
What drug can increase the duration of action of lidocaine when used peripherally / as a nerve block
Epinephrine (causes vasoconstriction -> less systemic absorption)
What is the concentration (mg/mL) of bupivacaine 0.5%
5 mg/mL
What are the max doses of lidocaine and bupivacaine in dogs and cats
Lidocaine:
- Dogs 6-10 mg/kg
- Cats 3-5 mg/kg
Bupivacaine:
- Dogs 2 mg/kg
- Cats 1-1.5 mg/kg
Mechanism of actions of opioids
- Binding to G-protein coupled receptors -> inhibit adenyl cyclase -> decreased cAMP -> inhibit iCa influx -> no depolarization
- Also decrease pre-synaptic release of neurotransmitters
- act on modulation of pain, not transduction / conduction
What is the effect of opioids on respiration (with mechanism)
Mainly respiratory depression:
- Direct depression of medullary and pontine respiratory centers
- Decreased and delayed response of chemoreceptors to CO2
Can also cause tachypnea / panting due to excitation and alteration of thermoregulation center
What opioids can cause histamine release
Morphine, meperidine, methadone
->contra-indicated in case of mast cell tumor
What is the opioid most / least susceptible to cause hyperthermia in cats
- Most: hydromorphone
- Least: supposed to be buprenorphine
What is the effect of opioid overdose on their duration of action
Greatly prolonged duration of action due to saturation of hepatic metabolism (conjugation)
What is the oral transmucosal bioavailability of buprenorphine
50% in both dogs and cats
What is the main difference between the effects of pure mu-agonists and partial mu-agonists
The effects of pure mu-agonists are dose dependent, the effects of partial mu-agonists have a ceiling effect after a certain dose and can never reach a maximum (thought to be more true for respiratory depression than analgesia)
Mechanism of action of benzodiazepines
- Bind to GABA-A receptors and facilitate inhibitory function of GABA (enhances affinity of receptor for GABA)
- Serotonin antagonists
- Decrease release of ACh in CNS
Why should cats not receive diazepam CRIs
Diazepam is formulated in propylene glycol which can cause MetHb / Heinz body anemia especially in cats
What is the recommended dose for flumazenil
0.01-0.02 mg/kg IV
Where are alpha2-adrenoreceptors found
- Pre-synaptic on noradrenergic neurons to give negative feedback –> inhibition of norepinephrine release
- Post-synaptic on smooth muscle, liver, pancreas, platelets, kidney, adipose tissue, eye
Mechanism of action of alpha2-agonists
Bind to alpha2-adrenoreceptor (= Gi receptor) -> inhibition of adenyl cyclase ->decreased cAMP -> inhibition of Ca influx, enhancement of K efflux and Na/H exchange -> no depolarization -> no signal
Sedation due to effect in brainstem (corpus ceruleus) and analgesia due to effect in dorsal horn of spinal cord and brainstem
Explain the cardiovascular effects of alpha2-agonists
- Phase I: stimulation of alpha2 receptors on vascular smooth muscle -> vasoconstriction -> hypertension -> reflex bradycardia (baroreflex)
- Phase II: inhibition of sympathetic tone by pre-synaptic alpha2 receptors (decrease release of norepinephrine) -> bradycardia, possible arrhythmias, hypotension (once vascular resistance back to normal)
What is a metabolic adverse effect of alpha2-agonists
Inhibition of insulin and stimulation of GH -> hyperglycemia
What other receptors (non-adrenergic) do alpha2-agonists bind
Imidazoline receptors (I1 and I2) responsible for some cardiovascular, renal and metabolic effects
What alpha2-antagonist is supposed to only reverse peripheral (eg. cardiovascular) effects of alpha2-agonists
Vatinoxan (does not cross blood-brain barrier)
Describe the arachidonic acid cascade and indicate the mechanism of action of NSAIDs, corticosteroids, and grapiprant
See picture
- Corticosteroids = phospholipase inhibitors
- NSAIDs = COX inhibitors
- Grapiprant = EP4 receptor inhibitor (nociception from PGH2)
What are the different cyclo-oxygenase (COX) enzymes and their roles
- COX-1 = constitutive -> housekeeping prostaglandins
- gastroprotection (secretion of mucus and HCO3- + increased blood flow to gastric mucosa): PGE2, prostacyclin (PGI2)
- renal perfusion (vasodilation of afferent +/- efferent arteriole, inhibition of Na reabsorption): PGE2, prostacyclin (PGI2)
- hemostasis (increased platelet aggregation): thromboxane - COX-2 = inducible -> most involved in inflammation, increased after tissue injury
- Cytokines, endotoxins, growth factors ->sensitization of nociceptors
- responsible for gastric mucosa healing mechanisms
- anticoagulant (inhibition of platelet aggregation): prostacyclin (PGI2) - COX-3 = subform of COX-1 in cerebral cortex
(some functions of COX-2 are constitutive and some functions of COX-1 also contribute to inflammation)
Where is COX-1 preferentially found in the body
Stomach, kidneys, endothelium, platelets
What is a risk with co-administration of NSAIDs and PPIs
PPIs leading to dysbiosis and predisposing to lower GI effects of NSAIDs (although protects against gastric ulcers)
By what mechanism are NSAIDs metabolized
Glucuronidation (phenolic compounds: acetaminophen, cartrofen) or oxidation (oxicam group) by cytochrome P450 in liver
What are the generations of NSAIDs
- First generation = non-selective COX inhibitors
Aspirin (irreversible COX inhibition), phenylbutazone - Second generation = non-selective COX inhibitors
Meloxicam, Carprofen - Third generation (coxibs) = selective COX-2 inhibitors
Firocoxib, Robenacoxib, Deracoxib
What is the difference between aspirin and other NSAIDs
Irreversible binding to COX complex -> irreversible inhibition of COX -> since platelets cannot synthesize new COX (no nucleus) they are inactivated for 9-11 days (lifespan)
Also cause direct injury to the gastric mucosa
What prostaglandin is the most associated with inflammation and nociception
Prostaglandin E2
Name 2 COX-3 antagonists
Acetaminophen
Metamizole
How is gabapentin eliminated
Renal excretion
What is the metabolite of tramadol responsible for its opioid activity? What is the enzyme responsible for its formation
O-desmethyltramadol (M1)
-> found in cats but not in dogs
Enzyme CYP2D15 (a type of cytochrome P450 enzyme)
Name some drugs known to be cytochrome P inhibitors
- Azole antifungals (ketoconazole)
- Macrolides
- Phenothiazines
- Chloramphenicol
- Cannabidiol (CBD)
Mechanism of action of trazodone
- Inhibitor of serotonin transporter and serotonin type 2 receptor -> inhibition of reuptake of serotonin and changes in pre-synaptic 5-HT receptor -> 5-HT2A and 5-HT2C antagonist + increases cerebral serotonin
- Blocks histamine H1 receptor, alpha-1 adrenergic receptor, and T-type calcium channels
What are clinical signs of serotonin syndrome? What drugs can contribute to its development? What drug can be used to treat it?
- Vomiting, diarrhea, seizures, hyperthermia, hyperesthesia, mydrasis, vocalization, hypersalivation, dyspnea, ataxia, (coma, death)
- Metoclopramide, trazodone, tramadol, selective serotonin reuptake inhibitors (Fluoxetine), tricyclic antidepressants (amitriptyline), mirtazapine
- Can use cyproheptadine
What is the relative potency (compared to morphine) of methadone, hydromorphone, butorphanol, buprenorphine, fentanyl, remifentanil
See picture
What is the mechanism of opioid tolerance
Internalization and inactivation of mu-receptors replaced by delta-receptors + NMDA up-regulation
What protein is deficient in the MDR1 (ABCB1) mutation
P-glycoprotein (protein regulating transport of several drugs including opioids and acepromazine across the blood brain barrier)
Mechanism of action of propofol
GABA-A agonist (potentiation of GABA induced chloride current) + NMDA inhibitor
Mechanism of action of ketamine
- Non-competitive NMDA antagonist: binds to phencyclidine‐binding and prevents glutamate binding –> dissociation of limbic and thalamocortical systems
- Muscarinic antagonist
+ interaction with opioid receptors and monoaminergic receptors (adrenergic, serotoninergic, etc) but unclear significance
Name 3 possible contra-indications to the use of ketamine
- Cardiac disease
- Tachycardia / hypertension / arrhythmias
- Glaucoma
- Patients with high ICP
What are the 3 categories of active chemical constituents in cannabis
- Phytocannabinoids
- Terpenes and terpenoids
- Flavonoids
List 5 characteristics (good and bad) of propofol anesthesia
- Rapid kinetics allowing titration of anesthetic depth
- Prolonged recoveries due to increased half-time as duration of administration increases
- Dose dependent hypoventilation and apnea
- Vasodilation and myocardial depression
- Risk of Heinz body anemia in cats
What is the pathophysiology behind propofol induced Heinz body anemia?
Propofol leads to inhibition of erythrocyte glutathione reductase (GSH), increasing susceptibility to oxidative damage –> Heinz bodies –> increases fragility of RBCs and decreases their flexibility –> intravascular hemolysis and hemoglobinemia
What is the mechanism of action of alfaxalone?
Binds GABA receptor in CNS
Explain why cats may have slower recoveries from ketamine and in which patient population should it be avoided (for this reason in particular)?
In dogs, ketamine is metabolized to inactive metabolites in the liver and really excreted.
In cats, it is metabolized to norketamine (active metabolite) before being excreted in urine –> can lead to significant accumulation especially in cats with renal disease
Why is ketamine contra-indicated in animals with increased ICP?
Sympathomimetic effects –> increased cerebral blood flow ICP
True or false: Etomidate is a reasonable drug choice for maintenance anesthesia in mechanically ventilated patients.
False! Not recommended due adrenocortical suppression (even with a single bolus)
Which opioid may be associated with the development of hyperalgesia?
Remifentanyl
A patient receiving multimodal anesthesia (CRIs) on the MV develops lactic acidosis, hyperosmolality, hemolysis and cardiac arrhythmias. What drug could cause this and why?
Diazepam - propylene glycol toxicoses –> not seen with midazolam
What is the mechanism of action of acepromazine?
Phenothiazine
- Blockade of D2 dopamine receptor
- Alpha-1 blockade –> hypotension
What type of medication is gabapentin?
Calcium channel antagonist
Inhibition of alpha-2-delta-1 subunit of voltage gated calcium channels (presynaptic membrane)
What is the mechanism of action of methadone?
mu-agonist + noncompetitive inhibitor of NMDA
Reduce reuptake of norepinephrine and serotonin
Complete the sentence:
Butorphanol is a _ agonist
kappa
partial mu antagonist & antagonsist
For the following drugs, list the time of onset and duration of action
- Propofol IV
- Alfaxalone IV
- 30 seconds, 5-10 minutes
- 60 seconds, 14-50 minutes
List 3 cardiovascular effects of ketamine
Centrally mediated sympathetic response + endogenous catecholamine release:
1. Increased HR
2. Increased BP
3. Increased CO
- Direct myocardial depression
List 3 effects of lidocaine
- Analgesia
- Antiarrhythmic
- Free radical scavenger
List 3 drugs that should be avoided in animals with splenic disease and why
- Propofol
- Acepromazine
- Thiopental
–> these drugs can result in splenomegaly –> could lead to tumor rupture or hemorrhage
Why do some mu-agonists cause hypotension when given IV too quickly?
They release histamine
What is an adverse effect of bupivacaine?
Arrhythmias and reduced CO
List at least 5 physiologic effects of opioids (other than analgesia) and why they occur
- Excitatory response –> activation of dopaminergic receptors in the hypothalamus
- Respiratory depression –> depression of pontine and medullary respiratory centres + delayed and decreased response to arterial CO2
- Tachypnea –> excitation and/or alteration of thermoregulatory centre
- Hypo/hyperthermia –> alteration of thermoregulatory centre
- Bradycardia –> Vaguely mediated (or pain relief)
- Hypotension –> histamine release (only morphine, methadone meperidine)
Why are morphine & methadone contra-indicated in patients with mast-cell tumours?
Can cause release of histamine
Why do anesthesiologists get mad at us if a patient has received buprenorphine prior to GA :)
Buprenorphine binds with great affinity to the receptors and is difficult to reverse.
Dissociates slowly from mu receptors
3 regions of the CNS where benzodiazepines act
Limbic
Thalamic
Hypothalamic
What route of diazepam administration has been associated with idiosyncratic hepatic failure in cats?
PO
List 3 differences between midazolam and diazepam
- Diazepam is not water soluble
- Diazepam is formulated with propylene glycol
- Midazolam is poorly available when given rectally
- Midazolam is shorter acting (short half-life)
List 3 drug interactions with alpha2-gonists that may improve analgesia
- Potentiation of opioid induced analgesia
- Decreased development of opioid tolerance
- Synergistic analgesic effect with NSAIDs and acetaminophen
What can happen if atipamezole is given IV?
Transient but sometimes severe dysphoria
Why are cats more sensitive to acetaminophen?
They have deficient glucuronidation (essential for NSAID metabolism via P-450)
True or false: acetaminophen cannot be given with NSAIDs
False
Explain NSAID induced lower GI toxicity
Enterohepatic recycling –> prolonged and repeated exposure of the intestinal mucosa to the drug and its compounds
Independent of acid secretion
