Pharmacology of Sedative Drugs Flashcards
Premedication
1+ agents given in preparation for an operation, other procedure or txt
Tranquilisation
the act to sedate through administration of drugs as the purpose of relieving anxiety & stress
Sedation
Act of administration of a sedative agent to produce a state of calm or sleep (deeper state)
Hypnosis
Refers to a sleep-like state induced by the administration of certain drugs. A patient may be roused from the effects of hypnotic drugs by stimulation
Narcosis
A state of stupor, drowsiness, or unconsciousness produced by certain drugs from which it is NOT easy to rouse the P
What drugs are in the phenothiazine class?
Acepromazine, Chlorpromazine, Methotrimeprazine (levopromazine), Prometazine
Outline the pharmacokinetics of Acepromazine
- Admin/absorption: oral & liquid unreliable, iv/im 5-20 mins/30-45 mins
- Distribution: highly protein bound, crosses BBB
- Metabolism: extensive liver metabolism
- Excretion: conjugated & unconjugated metabolites lost in urine
What are the actions of Acepromazine?
Antagonises:
* Dopamine receptors for sedative effects
* Histamine receptors for antihistaminic effects
* Cholinergic muscarinic receptors for spasmolytic effects on GIT
* Alpha-1 adrenergic receptors on vessels for vasodilation
What are the CNS pharmacodynamics of Acepromazine?
- Sedation
- Anti-emesis
- Extrapyramidal effects at high doses
- Lowered seizure threshold
What are the GIT pharmacodynamics of Acepromazine?
- Antispasmodic
- reduced LOS tone
- increased risk of regurgitation
What are the CVS pharmacodynamics of Acepromazine?
- Hypotension due to vasodilation
- Anti-arrhythmic
- Reduction in PCV due to RBC sequestration in spleen causing splenomegaly
- reduces platelet aggregation
What is a contraindication due to the anti-histaminergic effects of Acepromazine?
- Interference w/ intradermal skin tests
What are the pharmacodynamics of Acepromazine in the reproductive tract?
- Paralysis of retractor-penis muscle
CAUTION IN STALLIONS
When is Acepromazine contraindicated?
- very sick/moribund patients
- AV block (Boxers, MDR1 dogs)
- Vasodilation/syncope
What are some key points of overdose with Acepromazine?
- No reversal agent
- treat symptomatically w/ alpha-1 agonist & BP maintenance
- Do NOT use adrenaline if BP very low
What drugs are in the alpha-2 agonist class?
- (Dex)medetomidine & detomidine
- Xylazine
- Romifidine
Rate the Alpha-2 agonists from least selective for alpha-2 receptors to the most selective.
- Xylazine (least)
- Detomidine
- Romifidine
- Medetomidine
- Dexmedetomidine
What is the mechanism of action of alpha-2 agonists?
- noradrenaline is a natural ligand released & binds to pre & post-synaptic receptors then causing neg FB to stop noradrenaline
- very stressed/ agitated/ anxious animals may have high circulating noradrenaline in blood, so if given a low dose, it won’t work, but the animal can become overdosed if you keep giving more
Alpha-2 receptors are everywhere in the body so…
Caution when using these drugs
What are the centrally mediated effects of alpha-2 agonists?
- sedation
- analgesia (central/spinal)
- peripheral vasodilation
- late bradycardia due to vagal tone
- emesis in SA
- reduction of ADH release –> diureis
What are the peripherally mediated effects of alpha-2 agonists?
- vasoconstriction when bound on the receptors –> hypertension, initial bradycardia in response
- Inhibition of insulin release –> increase in plasma glucose concentration
- reduction of intestinal mobility –> colic (Eq)
What occurs when you give a bolus of alpha-2 agonists?
leads to Vasoconstriction –> BP increases –> increase afterload of the heart and decreases HR –> reduction of CO –> reduction of O2 delivery
What animals can you give Xylazine & in what concentrations?
- Farm Animals 2%
- Equines 10%
What is the duration of action of Xylazine?
- 30 mins to 1 hour
What are some things to remember about Xylazine in farm animals?
- ruminants are very sensitive to it (lower conc)
- hypoxaemia & pulmonary oedema in sheep/goats which can be fatal so if you have to give, give IV very slowly
- can induce labour
What are some key points about Xylazine in equines?
- spasmolytic, analgesic (good for colic)
- myometrial activity in mares possible
Why is Xylazine NOT used in small animals?
- causes vomiting
- associated w/ increased anaesthetic mortality
What is the specificity of Xylazine for alpha-2 receptors?
160 a-2 receptors : 1 a-1 receptor
What is the specificity of Detomidine for alpha-2 receptors?
260 a-2 : 1 a-1
What is the primary way of giving Detomidine?
IV
What is the bioavailability of Detomidine if given IM?
66-85%
Oral preparations of Detomidine are used in…
horses
Detomidine can be used for…
- infusion intra-op
- standing sedation
Detomidine is not ecbolic. What does this mean & what species is it good for?
- Does not increase contractility of the uterus
- suitable for use in pregnant cattle, especially if in last trimester
Detomidine should not be used w/ what type of drug in horses? Why?
- Potentiated sulphonamides
- Can cause cardiac arrhythmias
- Can cause ataxia in horses
Detomidine is not suitable in what species?
Small animals
Romifidine is for what species only?
Equines
What is the specificity of Romifidine for a-2 receptors?
340 a-2 : 1 a-1
Out of the alpha-2 agonists, which has the longest duration of action?
Romifidine
Romifidine causes the least amount of this side effect in horses.
Ataxia
Romifidine can be used as a CRI intra-op in what species?
Horses
What is the specificity of (Dex)medetomidine for a-2 receptors?
1620 a-2 : 1 a-1
What are the names of the racemic mixtures of medetomidine?
- Levomedetomidine
- Dexmedetomidine
What are some side effects of (Dex)medetomidine?
- Profound CVS effects
- V (uncommon)
- Nausea if given IM
When does (Dex)medetomidine have analgesic properties?
- at high doses
- acts at shorter duration than sedative effects
- Esp if given with opioids
When should you use alpha-2 agonists?
- When strong sedation or analgesia is required
- in stable patients only (avoid in heart dz)
- dysphoric animals, esp coming out of anaesthesia
- aggressive patients
When should you avoid alpha-2 agonists?
- Puppies/kittens
- Do not combine w/ anticholinergics to correct HR –> can exacerbate BP
What are the main alpha-2 ANTagonists?
- Yohimbine
- Atipamezole
- Tolazoline
- Vatinoxan
What is important to remember about giving Atipamezole when other drugs aside from an alpha-2 agonist are on board?
It will NOT reduce the other medications on board (such as opiates)
Atipamezole will reverse what effects of an alpha-2 agonist?
- CV depression
- Sedation/analgesia
Atipamezole should be administered by what route?
IM! (IV will wake the animal up too suddenly)
What species is Vatinoxan used in for sedation purposes?
Dogs only
What species can Vatinoxan be a peripheral antagonist?
Horses
What are the properties of Vatinoxan?
- selective & peripheral A-2 antagonist (does not cross BBB)
- prevents/minimises early vasoconstriction w/o compromising sedation & analgesia
- Reduction in duration of time b/c of the effects on the vascular system –> metabolised faster
- hastens IM absorption of A-2 agonist
What are the main benzodiazepines used?
- Midazolam
- Diazepam
- Alprazolam
What is the mechanism of action of Benzodiazepines?
- enhances affinity of Gaba-alpha receptor for GABA, increasing Cl- conductance to the cell
- increased Cl- conductance –> hyperpolarisation of post-synaptic membrane –> decreased neuronal transmission
GABA = NT w/i CNS
What are the main pharmacodynamic effects of benzodiazepines on the CNS?
- unreliable sedation in animals
- healthy adults may have agitation
- synergistic effect w/ other CNS depressants
- central muscle relaxant
- anticonvulsant, decrease in ICP
- amnesia
- appetite stimulation in cats
What are the main pharmacodynamic effects of benzodiazepines in CVS?
- Midazolam: reduced inotropy, mild vasodilation at high doses
- very safe w/i normal ranges
- may potentiate resp depression of other drugs, but doesn’t cause on its own
What are the main pharmacodynamic effects of benzodiazepines on the respiratory system?
- minimal depression
- might potentiate respiratory depression of other agents
What are some things to note about benzodiazepines?
- use in very young or old or sick patients, NOT in healthy patients
- no analgesia!
What are the pharmacokinetics of benzodiazepines?
- 95-99% protein bound, dose reduction in hypoproteinaemic patients
- metabolised in liver (caution in liver P’s)
Diazepam is solubilised in… which can make it very … in texture
- propylene glycol
- oily
Diazepam should only be given by what route of administration? Why?
- IV
- IM has erratic absorption and can cause pain
How fast is the onset of action of Diazepam when given IV?
Rapid
Diazepam is highly…
lipid soluble & protein bound
Diazepam is metabolised in the…
liver in CYP450 isoforms (CYP2DP, CYP3A4)
What is the active metabolite of Diazepam? What are its properties?
Nordiazepam
Has long T1/2 & can cross the placenta
Metabolism of diazepam is inhibited by…
microsomal enzyme inhibitors (Cimetidine, erythromycin, omeprazole)
Midazolam use in vet med is considered…
Off-label
Midazolam is water soluble if the pH is…
< 4
Midazolam is lipid soluble at… causing it to have a … onset
body pH
fast onset
What routes can midazolam be given?
IV/IM/SQ/intranasal
What is the duration of action of midazolam?
1-2 hours
Midazolam has how many active metabolites?
2
Midazolam should be used with caution in what patients? Why?
- liver issues
- inhibits CYP450 which reduces hepatic clearance and can increase the duration of action
Which is more suitable for CRI: diazepam or midazolam?
Midazolam
Acute overdose/toxicity of benzodiazepines can cause…
long-lasting sedation, CNS depression, coma
What is the antagonist for benzodiazepines?
Flumazenil
What is the main drug of importance in the butyrophenones? What animal is it used in?
Azaperone
Pigs only
What are some things to note about Azaperone use in pigs?
- onset: up to 30 min after IM inj
- DO NOT DISTURB AFTER INJ
- lasts 2-4 hrs
- distribution: large
- metabolism: liver
- Excretion: faeces, urine
- NO REVERSAL AGENT!
What are the main cardiovascular effects of butyrophenones?
- A-1 receptor blockade may cause hypotenion
- Antiarrhythmic
- May protect against catecholamine induced arrhythmias
What are the main CNS effects of butyrophenones?
Anti-emetic via action at CTZ
Dopamine antagonist –> sedation
What other non-specific signs can appear with butyrophenones?
- transient salivation, piling, panting, shivering in pigs
- NO analgesia
- paradoxical excitement in horses <– don’t give to a horse dumbass
