Sedation

Question 1

Definitions

Answer 1

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)

Question 2

Phenothiazines

Answer 2

tranquilizer

acepromazine/acetylpromazine (ACP)- commonest pre-anaesthetic used in UK

Question 3

CNS physiology

Answer 3

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

Question 4

Phenothiazine mechanism of action

Answer 4

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

Question 5

Pharmacodynamics of Phenothiazines

Answer 5

CNS- tranquilizer

CVS, resp, GIT/anti-emetic, antihistamine, hypothermia, others

Question 6

CV effects of Phenothiazines

Answer 6

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

Question 7

Respiratory and GI effects of Phenothiazines

Answer 7

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)

Question 8

Antihistamine and hypothermic effects of Phenothiazines

Answer 8

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

Question 9

Other effects of phenothiazines

Answer 9

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.

Question 10

Butyrophenones

Answer 10

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)

Question 11

Clinical use of phenothiazines (ACP)

Answer 11

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)

Question 12

Acepromazine (ACP)

Answer 12

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

Question 13

ACP: Cautions

Answer 13

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

Question 14

Clinical use of Butyrophenones- Azaperone

Answer 14

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

Question 15

Other butyrophenones

Answer 15

Fluanisone: not used alone, but in combo with fentanyl=Hypnorm–>pre-med/sedative in small furries

Droperidol: antiemetic in humans

Question 16

Sedatives: Alpha 2 Agonists

Answer 16

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

Question 17

Effects of alpha 2 agonists in CNS

Answer 17

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

Question 18

Effects of alpha 2 agonists in blood vessels

Answer 18

Normally, cAMP inhibits contraction, however, alpha 2 agonists decrease cAMP, therefore get contraction of vascular smooth muscle

Question 19

Specificity of alpha 2 agonists

Answer 19

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

Question 20

Effects of alpha 2 agonists on Blood Pressure

Answer 20

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.

Question 21

Sedative effects of alpha 2 agonists

Answer 21

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

Question 22

Analgesic effects of alpha 2 agonists

Answer 22

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.

Question 23

CV and respiratory effects of alpha 2’s

Answer 23

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

Question 24

GIT, endocrine, urogenital and miscellaneous effects of alpha 2 agonists

Answer 24

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.

Question 25

Uses of alpha 2 agonists

Answer 25

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

Question 26

Xylazine (Rompun)

Answer 26

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

Question 27

Detomidine (Domosedan)

Answer 27

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

Question 28

Romifidine (Sedivet)

Answer 28

used in horses longer duration, up to 3 hours; typical alpha 2 agonist CNS: causes less ataxia in horses- useful for x-rays?

Question 29

Medetomidine (Domitor)

Answer 29

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)

Question 30

L vs. D medetomidine

Answer 30

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

Question 31

Dexmedetomidine (dexdomitor)

Answer 31

active isomer of medetomidine; despite all theoretical advantages, doesn't appear to be significantly clinically different from medetomidine.

Question 32

Alpha 2 ANTAGONISTS

Answer 32

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

Question 33

Hypnotics- Benzodiazepines

Answer 33

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

Question 34

Role of GABA in CNS

Answer 34

main inhibitory NT in CNS 2 receptors: GABA_A and GABA_B GABA_A: ligand gated Cl- channel; mediate fast inhibitory synaptic responses--\>influx of Cl^- --\>hyperpolarization--\> decrease in excitability--\>inhibition

Question 35

Mechanism of action of Benzodiazepines (BZPs)

Answer 35

BZPs potentiate GABA--\> not actually agonists With GABA present, BZPs facilitate opening of GABA activated Cl- channels. BZP binding site is distinct from GABA_A 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

Question 36

General Pharmacological effects of BZPs

Answer 36

CNS: primarily anxiolytic action muscle relaxation: useful in combo with other drugs i.e. ketamine anticonvulsant properties CVS/resp: minimal depression

Question 37

Pharmacokinetics of BZPs

Answer 37

well-absorbed orally; highly plasma protein bound; lipid soluble Metabolism= glucuronidation Side effects -Acute: less dangerous than other hypnotics Few CVS/resp effects

Question 38

BZPs: problem

Answer 38

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.

Question 39

Diazepam (valium)

Answer 39

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

Question 40

Midazolam (Hypnovel)

Answer 40

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.

Question 41

Use of BZPs

Answer 41

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

Question 42

BZP antagonists

Answer 42

Flumazenil: anatagonism of BZPs, sedation reported in dogs, cows, sheep not licensed in animals

Question 43

Neuroleptanalgesia

Answer 43

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

Question 44

Hypnorm

Answer 44

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.