Sedation Flashcards
Definitions
Tranquiliser: calm without sleepiness–> phenothiazines, butyrophenones
Neuroleptic: tranquilizer used in treatment of pyschoses–>phenothiazines
Sedative: sedation w/ drowsiness–> alpha 2 adrenoceptor agonists
Hypnotic: chiefly taking about anaesthetic induction/maintenance–>induces sleep- e.g. benzodiazepines (thiopentone, propofol etc)
Phenothiazines
tranquilizer
acepromazine/acetylpromazine (ACP)- commonest pre-anaesthetic used in UK
CNS physiology
Central synaptic transmission similar to peripheral but with complex interneuronal connections
AA neurotransmitters: glutamate (excitatory); GABA and glycine (inhibitory)
Noradrenaline: alertfullness/wakefullness
5-HT: feelings of well-being
Dopamine: important in control of movement/consciousness
ACh: arousal, learning
nb: role in ANS–>indirect effects on neural function–> side fx out in periphery too
Phenothiazine mechanism of action
Non-selective dopamine antagonist (activity in basal ganglia, limbic system)
Most phenothiazines affect other receptors too e.g alpha 1, serotonin, histamine receptors, muscarinic receptors
-wide range of peripheral and central effects
Pharmacodynamics of Phenothiazines
CNS- tranquilizer
CVS, resp, GIT/anti-emetic, antihistamine, hypothermia, others
CV effects of Phenothiazines
arterial hypotension (10-20% decrease in arterial blood pressure)–d/t alpha 1 receptors on VSM
peripheral vasodilation (alpha adrenergic blockage)
direct action on VSM
central actions, medulla (decrease sympathetic outflow by decreasing amount of noradrenaline–> can contribute to fall in BP)
Minimal myocardial depression–> however at excessively high doses–>bradycardia
Contraindications: shock, hypovolemia, compromised CV
Mild reflex tachycardia–>response to hypotension–>antimuscarinic effect d/t widespread effect of drug, decreased vagal inhibition of the heart
Anti-arrhythmic action: raise threshold to adrenaline-induced arrhythmias
Respiratory and GI effects of Phenothiazines
Respiratory: generally minimal, however sedation may worsen degree of respiratory distress in dyspnoeic patients
Anti-emetic effects: effective anti-emetics; centrally active dopamine antagonists at CTZ
GIT effects: decreased GI smooth muscle activity (antimuscarinic); delayed gastric emptying; decreased gastro-oesophageal tone; anti-sialagogue (decreased production of saliva)
Antihistamine and hypothermic effects of Phenothiazines
Antihistamine: all drugs have some effects; promethazine is the most potent
Hypothermic effects: due to peripheral vasodilation, lose more heat from body
also get direct hypothalamic effect–> sedated patients generate less heat
Other effects of phenothiazines
effect on seizure threshold: evidence refutes claims that it reduces seizure threshold– totally safe for use in epilepsy
penile prolapse: due to anti-adrenergic effects, vasodilation. correlates with onset and duration of sedation–> priapism in stallions, reported in geldings
Decrease PCV: uptake of RBCs into the spleen
Potentiate effects of other drugs: opioids, LAs, neuromuscular blocking drugs. Reduce induction and maintenance anaesthetic requirements.
Butyrophenones
chemically unrelated to phenothiazines
Mechanism of action: dopamine antagonist
CNS effects: sedative, antiemetic properties; hallucinations and agitation in people
CVS effects: some vasodilation and hypotension (alpha 1 antagonism)
Clinical use of phenothiazines (ACP)
1) premedication prior to GA; seldom used by themselves
often combine with opioids (neuroleptanalgesia)- synergistic effects so animal is more sedate
2) sedation for minor procedures
3) control of motion sickness- potent anti-emetics
4) calming (fireworks,etc)
Acepromazine (ACP)
used extensively; licensed in dog, cat, horse
high therapeutic index
poor dose-response relationship–little correlation between plasma levels and clinical effects–> it essentially either works or doesn’t–> giving more doesn’t help with sedation, but rather prolongs side effects.
Oral bioavailability: 20-55% due to variable GI uptake
IM route preferred (can also give IV or SC)
Duration: 4-6 hours, dose-dependent–>not appropriate for short procedures
Liver metabolism–> avoid with hepatic disease–> glucuronide metabolites
Excretion in urine–> doesn’t cause a lot of problems with renal disease
ACP: Cautions
Contraindicated in breeding stallions and bulls–> ACP relaxes retractor penis muscle in large animals (also vasodilation). Can cause priapism=sustained erection–>can damage penis
Hypovolemic animals: hypotension can be precipitous. Maintain BP by vasconstriction and ACP causes vasodilation.
Boxers- may faint- use in low doses
Giant dog breeds have increased sensitivity
Clinical use of Butyrophenones- Azaperone
Azaperone (stresnil)- used in farm practice to sedate/modify behavior in pigs
Pharmacokinetic aspects: deep IM injection preferred (pigs have large fat layer); leave undisturbed for 30 minutes; lasts for 2-3 hours
Pharmacological effects: dose-related sedation, slight fall in BP (well tolerated in healthy pigs)
Side fx: similar to ACP: milde hypotension, hypothermia, priapism, minimal respiratory effects
Other butyrophenones
Fluanisone: not used alone, but in combo with fentanyl=Hypnorm–>pre-med/sedative in small furries
Droperidol: antiemetic in humans
Sedatives: Alpha 2 Agonists
Widespread distribution of alpha 2 adrenoceptors
alpha 2 inhibit adenylate cyclase (AC) and decrease cAMP. Inhibit voltage gated Ca2+ channels and activate Ca2+-dependent K+ channels.
Pre-synaptically: alpha 2s inhibit NT release via inhibiting cAMP production
Post-synaptically: vasoconstriction
In CNS, mediate sedation and analgesia
Effects of alpha 2 agonists in CNS
Sedative, analgesic, muscle relaxant–> central alpha 2 receptors
Decrease presynaptic NA release–> depression of neurons in locus ceruleus (area of brain involved in altertness)
Effect on sympathetic drive: decreased symp drive, vagal tone predominates
Effects of alpha 2 agonists in blood vessels
Normally, cAMP inhibits contraction, however, alpha 2 agonists decrease cAMP, therefore get contraction of vascular smooth muscle
Specificity of alpha 2 agonists
Ratio of alpha 2: alpha 1 specificity
medetomidine- 1620:1
detomidine- 260:1
xylazine- 160:1
Important of receptor subtype: alpha 2a- presynaptic– this is where we get sedative/analgesic effects; alpha 2b=postynaptic
Effects of alpha 2 agonists on Blood Pressure
vascular tone: peripheral postsynaptic alpha 1 or alpha 2 (vasoconstriction)
peripheral and central pre-synaptic (vasodilation)
Initially, BRR detects increase in BP d/t vasoconstriction, but then central decrease in sympathetic drive allows predominance of vagal tone.
Balance of effects leads to changes in BP
Initially vasoconstriction results in hypertension, but then followed by sustained fall (normalization?) of BP as central effects dominate.
Is there anything we can do to offset bradycardia? Logical to think that we can use an anticholinergic to tx, but tachycardia and increased hypertensive phase further decreases CO i.e atropine would just exacerbate the situation.
Simplest solution: use alpha 2 antagonist to reverse bradycardia nb: sedation and analgesia will also be reversed.
Sedative effects of alpha 2 agonists
dose-dependent (not at higher serum concentration- see more side effects rather than increased sedation)
mild to deep sedation
licensed in dog, cat, horse, cattle
Analgesic effects of alpha 2 agonists
potent analgesic–>central action, spinal and supraspinal
Spinal: receptors located densely in laminae I and II of dorsal horn of spinal cord
Supraspinal: receptors located in PAG, locus ceruleus and nucleus raphe magnus–>associated with pain info processing.
CV and respiratory effects of alpha 2’s
CV: initial hypertension–>reverts to hypotension/normotension; marked bradycardia that persists for duration of action
Respiratory: mild-moderate depression in cat, dog and horse
ruminants: arterial hypoxemia d/t mistmach of pulmonary ventilation and perfusion; can be very severe in sheep
GIT, endocrine, urogenital and miscellaneous effects of alpha 2 agonists
GIT: vomiting in some spcies; generally GIT motility is depressed d/t decreased NT release
Endocrine: inhibition of ADH promotes diuresis; inhibition of insulin release causes hyperglycemia
Urogenital: uterine contraction–> low doses decrease contraction, high doses increase contractions
Miscellaneous: act synergistically with anaesthetics–>marked sparing effect.
Uses of alpha 2 agonists
sedation/pre-medication
to offset mucle hypertonicity with ketamine (don’t use ketamine on it’s own)
analgesia: horses with colic (sedation and analgesia)–>alpha 2s very good for visceral pain (cf. somatic); often infused during anaesthesia
Used IM, IV, SC or epidural
Oral route: high 1st pass metabolism; well absorbed buccally
Xylazine (Rompun)
licensed in dogs, cats, horses, cattle
Pharmacokinetic aspects: admin IV or IM
Duration: species, route and dose-dependent
Metabolized to multiple products that are excreted in urine
Low selectivity for alpha 2 receptors–>side effects
Ruminants are VERY sensitive (recumbent sedation even with low dose); pigs are relatively insensitive (likely d/t decreased number of alpha 2 receptors in brain)
CVS side fx: arrhythmogenic
urogenital: contraction of uterine SM; increase in urine output d/t inhibited ADH
Detomidine (Domosedan)
only licensed in large animals
Imidazole derivative; used in horse and cattle
Admin IV or IM
Longer duration of action (1-2 hours in horse); xylazine relatively short acting
Standing sedation in both species–> equipotent
Typical alpha 2 agonist
NB: do NOT administer with trimethyprin sulfominide (ABX)–> some horses develop severe arrythmias
Romifidine (Sedivet)
used in horses
longer duration, up to 3 hours; typical alpha 2 agonist
CNS: causes less ataxia in horses- useful for x-rays?
Medetomidine (Domitor)
used mainly in dogs, cats and small furries
admin IM, IV or SC
Rapid onset, duration of effect up to 3 hours
V. potent and v. selective for alpha 2- 10x more specific than xylazine
Sedation may be profound-dose dependent
Some effects on CV and sedation can last up to 3 hours
CVS: may be anti-arrhythmic- may protect heart against catecholamines
vomiting in some patients (less than xylazine)
L vs. D medetomidine
Medetomidine is a racemic mixture of L and D. Dexdemedtomidine is the active isomer, and L-medetomidine is “inactive”.
Levomedetomidine may reduce activity of dexmed.; may delay metabolism of other hepatically metabolized drugs (e.g. ketamine) because L-medetomidine needs to be hepatically metabolized too.
Despite “inactivity”, may be responsible for some of the undesirable CV effects of medetomidine. Limits the number of receptors for dexmed to bind to–> blunts actions that we want from the active isomer
Dexmedetomidine (dexdomitor)
active isomer of medetomidine; despite all theoretical advantages, doesn’t appear to be significantly clinically different from medetomidine.
Alpha 2 ANTAGONISTS
Atipamazole (Antisedan)- licensed in dog and cat by IM route
alpha 2 agonist gets antagonized– analgesia is also reversed
Works, but not licensed, in horses and cattle
Hypnotics- Benzodiazepines
used in humans as anxiolytics–>chronic tx
used in humans as premeds and hypnotics–>acute tx
in vet med: useful sedative in the v. old, v. young or in patients with complicating factors
V. good safety profile
Also, used as anticovulsant
Role of GABA in CNS
main inhibitory NT in CNS
2 receptors: GABAA and GABAB
GABAA: ligand gated Cl- channel; mediate fast inhibitory synaptic responses–>influx of Cl- –>hyperpolarization–> decrease in excitability–>inhibition
Mechanism of action of Benzodiazepines (BZPs)
BZPs potentiate GABA–> not actually agonists
With GABA present, BZPs facilitate opening of GABA activated Cl- channels.
BZP binding site is distinct from GABAA site
BZP increases affinity of GABA for its receptor–>enhanced agonist effect
We’re not sure what endogenous molecule is meant for the BZP binding site
General Pharmacological effects of BZPs
CNS: primarily anxiolytic action
muscle relaxation: useful in combo with other drugs i.e. ketamine
anticonvulsant properties
CVS/resp: minimal depression
Pharmacokinetics of BZPs
well-absorbed orally; highly plasma protein bound; lipid soluble
Metabolism= glucuronidation
Side effects
-Acute: less dangerous than other hypnotics
Few CVS/resp effects
BZPs: problem
Excellent anxiolytics, minimal CV and resp. effects–> seems to be ideal agents for sedation/pre-med
BUT, generally BZPs only work well in sicker patients. In healthy animals, get paradoxical excitement, because BZPs disinhibit.
Diazepam (valium)
Administer IV or oral routes; poorly absorbed and painful IM. Can be absorbed rectally (useful in seizures) and get no 1st pass metabolism.
Rapid onset and short duration in IV route
Some active metabolites from hepatic metabolism
Primarily excreted in urine
Insoluble in water: 2 preps to solubilze it
Valium: formulated in propylene glycol–> strictly carrier vehicle–>can irritate veins and cause thrombophlebitis
Diazemuls: emulsion formulation (soyabean oil)–> less vein damage
Midazolam (Hypnovel)
used for infusions
water soluble–> can give IM and it’s not painful
Undergoes conformational change at pH to become lipid soluble (tetomerism)–>can cross BBB
Admin: IV, IM, or orally
Rapidly metabolised, short duration
Similar to diazepam, but 2x as potent; more potent, shorter half life, less likely to accumulate.
Use of BZPs
1) neuroleptanalgesia
2) premed/hypnosis of sick animals
3) control seizures
4) preempt seizures
5) to stimulate appeatite in cats (don’t do this very ofen now d/t possibility of liver damage)
6) occasionally to alter behaviour
7) muscle relaxation- occasionally used for muscle spasmic pain–>helps pain even though not analgesic
nb: no BZPs licensed for use in animals- use under cascade
BZP antagonists
Flumazenil: anatagonism of BZPs, sedation reported in dogs, cows, sheep
not licensed in animals
Neuroleptanalgesia
loosely, any sedative+opioid
condition in which patient, though not entirely unconscious, is insensitive to painful stimuli
Produced by combo of neuroleptic (ACP or butyrophenone) + opioid analgesic
Loosely extended in vet med to include combo of a sedative or hypnotic (alpha 2 agonist, BZP)+opioid analgesic
Licensed prep: hypnorm=fluanisone+fentanyl
Homemade prep: ACP + pethidine, butorphanol; alpha 2+butorphanol etc
Hypnorm
widely used in small furries; given IM or IP (lots of risk of perforation)
Long duration of action d/t large dose of fentanyl. Can be antagonised by “sequential analgesia”
ex: Take X-rays in 15 minutes; afterwards, use opioid partial agonist (buprenorphine) or opioid agonist/antagonist (butorphanol). Knocks fentanyl off mu receptor.
Nalaxone will also antagonize fentanyl, but removes analgesia effect. With “sequential analgesia” still get analgesic effects.
