Sedation

Front 1

Drug class that induces sedation without drowsiness.

- Calming effect

Back 1

TRANQUILIZERS

e.g. phenothiazines, butyrophenones

Front 2

Drug class that induces sleep.

Back 2

HYPNOTIC

e.g. Benzodiazephines (thiopentone, propofol, etc)

Front 3

Drug class that induces sedation with drowsiness.

Back 3

SEDATIVES

- e.g. Alpha-2 Adrenoreceptor Agonists

Front 4

List the four main drug classes used for sedation in vet med, in order of increasing UNRESPONSIVENESS.

Back 4

1. Tranquilizers - sedation without drowsiness

2. Neuroleptic - type of tranquilizer used in treatment on psychoses

3. Sedative - sedation WITH drowsiness

4. Hypnotic - induces sleep

Front 5

What are the most common tranquilizers used in vet med?

Back 5

PHENOTHIAZINES

- Acepromazine/acetylpromazine (ACP) = most commonly used in small animals!

- Others: Chlorpromazine, promazine, etc...

BUTYROPHENONES

- Azaperone = only used in pigs

- Hypnorm = licensed for use in small furies = Fluanisone + fentanyl (full opioid agonist = 100x more potent than morphine)

Front 6

What are the five neurotransmitters involved with CNS physiology?

Back 6

1. Amino acid NT

- Glutamate = excitatory

- y-aminobutyric acid (GABA) = most imp; inhibitory

- Glycine = inhibitory

2. Noradrenaline (NA)

- Controls mood/alertness

3. 5-HT

- NT controls emesis, mood; # of diff receptors

4. Dopamine

- Precursor for NA; D2 most imp receptor wrt to this lecture...

5. Acetylcholine

- Nicotinic & muscarinic rec = diff effects

Front 7

Describe the mechanism of action of phenothiazines, such as Acepromazine (ACP).

Back 7

NON-SELECTIVE, DOPAMINE ANTAGONISTS

- activity in basal ganglia/limbic system and act by inhibiting adenylate cyclase

- Most affect other receptor systems as well (alpha-1 adrenoreceptors, 5-HT1, H1, muscarinic)

Front 8

Briefly describe each pharmacodynamic effect of phenothiazine.

Back 8

1. CNS = Tranquilizer

2. CVS = Arterial hypotension (10-20% dec in ABP)

3. Respiratory = minimal effects except in dyspnoeic animals

4. GIT/Anti-emetic = dec sm muscle activity (anti-muscarinic activity) delaying emptying; dopamine antagonism at chemoreceptor trigger zone (CTZ) effective anti-emetic

5. Antihistamine = promethazine is the most potent

6. Hypothermia = PHERIPHERAL VASODILATION

7. Others = penile prolapse & priapism in stallions, Dec PCV (uptake of RBCs into spleen) & potentiates the effects of other drugs.

Front 9

Describe the effects of Phenothiazines on the Cardiovascular system.

Back 9

1. ARTERIAL HYPOTENSION (10-20% dec in arterial BP)

- Peripheral vasodilation (alpha-adrenergic blockade)

- Direct action on vascular smooth muscle

- Central actions on medulla causing dec sympathetic outflow = dec vasoconstriction

2. MILD TACHYCARDIA

- Response to hypotension

- Anti-muscarinic effect

3. ANTI-ARRHYTHMIC ACTION

- Raises threshold to adrenaline = induced arrhythmias

Front 10

Describe the effects of Phenothiazines on the Respiratory system.

Back 10

Generally minimal . .

- Sedation may worsen degree of respiratory distress in dyspnoeic patients

Front 11

Describe the effects of Phenothiazines on the GIT and Anti-emetic properties.

Back 11

GI EFFECTS:

- Dec GI smooth muscle activity (anti-muscarinic action)

- Delayed gastric emptying

- Dec gastro-esophageal sphincter tone

- Anti-sialagogue

ANTI-EMETIC AGENTS:

- Act centrally via domine antagonism, thus inhibiting the Chemoreceptor Trigger Zone for emesis

Front 12

Promethazine has the most potent antihistaminic action of all the phenothiazines.

True or False?

Back 12

TRUE

Front 13

Phenothiazines have hypothermic effects due to . . .

Back 13

PHERIPHERAL VASODILATION = inc heat loss

Front 14

Describe the other random effects that can result from phenothiazine use, aside from CNS, CVS, Respiratory, GIT/Anti-emetic, Antihistaminic and hypothermic effects.

Back 14

1. Penile prolapse

- Correlates with onset and duration of sedation

- Priapism (persistent erection) in stallions

2. Decreased PCV

- Uptake of RBCs into spleen

3. Potentiate the effects of other drugs

- Reduce induction and maintenance anesthetic requirements!

Front 15

Butyrophenones are chemically unrelated to phenothiazines.

True or False?

Back 15

TRUE - Although they are both tranquilizers, they are chemically UNRELATED!

Front 16

Describe the general pharmacological effects of Butyrophenones.

Back 16

1. CNS - sedative action, antiemetic properties

2. CVS - some vasodilation & hypotension (alpha-1 adrenergic antagonism)

Front 17

Describe the main CLINICAL USES of Phenothiazines.

Back 17

1. Premedication prior to G/A

- By themselves or

- Mixed with opioids (neuroleptanalgesia)

2. Sedation for minor procedures (radiography, ultrasound, etc)

3. Control of motion sickness

4. Calming (fireworks, etc)

Front 18

What is the only Phenothiazine used in vet med?

Back 18

Acepromazine (ACP)

- licensed in dog, cat and horse, with high therapeutic index meaning it's a rather safe drug; requires massive overdose to do harm.

- poor dose-response relationship; sedation effect can be quite unpredictable so only for minor procedures

- lowers mortality rate in horses quite dramatically when used as premedication before surgeries; mechanism unknown

Front 19

When sedating with acepromazine (ACP), if the animal doesn't seem to be sedated enough after initial dose, you can simply top up the amount with additional dosing to reach desired effect.

True or False?

Back 19

FALSE - ACP has a poor dose-response relationship = little correlation between plasma levels and clinical effect.

- Can't just give more because this will only prolong the sedation and increase the risk of side effects, not sedate the animal anymore.

Front 20

What is the percent of oral bioavailability of acepromazine? What is the preferred route of administration? Other route options? Duration? Metabolized by?

Back 20

- ORAL BIOAVAILABILITY = 20-55% reaches systemic circulation; rest isn't absorbed/broken down by liver and excreted in urine

- PREFERRED ROUTE: IM

- OTHER ROUTES: SC, IV

- DURATION: 4-6 hours (dose-dependent)

- METABOLISM: Liver

Front 21

Contraindications of Phenothiazines?

Back 21

1. Breeding stallions & bulls:

- Priapism of the penis can lead to damage/necrosis

2. Hypovolemic (dehydrated) animals

- Hypotension can be precipitous

- If animal falls flat during sedation, check BP and give fluids immediately; probably dehydrated.

3. Care with specific breeds:

- Boxers tend to faint, but still safe; give lower dose

- Giant breeds are more sensitive; again lower dose

4. Kidney-damaged animals

- Hepatic metabolism is main source of breakdown of acepromazine.

Front 22

Vet clinical uses of BUTYROPHENONES.

Back 22

Azaperone (Strensil)

- Used to sedate/modify behavior in pigs during surgical procedure or when introducing new herds of pigs together to deter fighting

Fluanisone + fentanyl = HYPNORM

- Licensed for use in small furies for tranquilizing

- Combined with full opioid agonist = POTENT

Front 23

Describe the pharmacokinetic aspects of Azaperone (stresnil) wrt:

- Preferred route?

- Duration?

Back 23

PREFERRED ROUTE: Deep IM injection

- IV is difficult and doesn't absorb well.

- Leave animal undisturbed for 30 mins, otherwise stress may fight effects

DURATION: 2-3 hours

Front 24

Azaperone is considered a dose-related sedation and results in slight fall in blood pressure.

True or False?

Back 24

TRUE

Front 25

Side effects of Azaperone?

Back 25

Similar to ACP:

- Mild hypotension

- Hypothermia

- Priapism of penis

- Minimal respiratory effects

Front 26

Tranquilizer (neuroleptanalgesia) licensed for use in small furies and mixed with a full opioid agonist, Fentanyl.

Back 26

HYPNORM

- Fluanisone + Fentanyl

- 100x more potent than morphine

- Profound sedation!

Front 27

Sedative drugs which have central effects as well as effects out in the periphery?

Back 27

ALPHA-2 ADRENORECEPTOR AGONISTS

- Alpha-2 receptors widespread throughout the body (sympathetic NS, vascular endothelium, CNS, platelets, uterus, & gut)

Front 28

Describe the functions of the alpha2-adrenoreceptors throughout the body.

Back 28

Inhibit adenylate cyclase, thus decreasing cAMP & inhibit voltage-gated Ca2+ channels & activate Ca dependent K+ channels.

- Located prejunctionally at synapses and inhibit NT release (NA stimulates alpha2 receptor -> inhibits adenylate cyclase -> inhibits cAMP -> inhibits further NT release)

- Located post-junctionally in vascular smooth muscle = vasoconstriction/contraction

- CNS mediate sedation and analgesia

Front 29

Effects of alpha2-adrenoreceptor agonists in the Central Nervous System?

Back 29

Effects on Function:

- Sedative, analgesic & muscle relaxant

* Mediated by central alpha-2 receptors

* Presynaptic dec NA release

* Depression of neurons in locus ceruleus (conducts signals from low brain stem to upper brain = sedative effect)

- Decrease in sympathetic drive (predominance of vagal tone)

Front 30

Which alpha-2 adrenoreceptor agonist has the greatest specificity?

Back 30

MEDETOMIDINE

Ratio of a2:a1 selectivity = 1620:1

Than, Detomidine > Xylazine

Front 31

What are the two alpha-2 receptor subtypes? Where are each most important within the body?

Back 31

1. Alpha-2A = most imp PRESYNAPTICALLY

2. Alpha-2B = most imp POSTSYNAPTICALLY

Front 32

Effects of alpha-2 adrenoreceptor agonists on blood pressure?

Back 32

1. Dec in Sympathetic Vascular Tone:

- Initial, peripheral, postsynaptic vasoconstriction = hypertension (inc BP)

- Followed by, Peripheral & central presynaptic vasodilation = normalization

2. Bradycardia (slowing of heart)

- Partly reflexive baroreceptor response to vasoconstriction

- Partly due to central dec in sympathetic drive

Front 33

What can be done to offset the effects of bradycardia (dec HR) caused by alpha2-adrenoreceptor agonist sedatives?

Back 33

Use an alpha2-adrenoreceptor ANTAGONIST

* Beware, because this reverses sedation AND ANALGESIA.

Front 34

Describe the sedative effects of alpha2-adrenoreceptor agonists (alpha2s). Licensed?

Back 34

Mild to deep sedation

- Dose-dependent

Licensed in dogs, cats, horses and cattle.

Front 35

Describe the analgesic effects of alpha2s.

Back 35

POTENT analgesic action

- Central action (spinal & supraspinal)

- Dose dependent and shorter than sedation

Front 36

Cardiovascular effects of alpha2s?

Back 36

HYPERTENSION => Hypotension/normotension

- Marked bradycardia (dec HR)

Front 37

Respiratory effects of alpha2s?

Back 37

Mild to moderate depression in dogs, cats & horses

* RUMINANTS = arterial hypoxemia (can be very severe in sheep)

Front 38

GIT effects of alpha2s?

Back 38

* Vomiting in some species

- Zylasine given IM in cats to induce emesis.

* GIT motility is depressed (dec Ach release)

Front 39

Endocrine effects of alpha2s?

Back 39

- Inhibition of ADH = diuresis

- Inhibition of insulin release (alpha2s in pancreas) = hyperglycemia

Front 40

Urogenital effects of alpha2s?

Back 40

Uterine contraction

Front 41

Veterinary clinical uses of alpha2s?

Back 41

- Sedation/premedication

- Offset muscle hypertonicity caused by pre-anesthesia drugs like ketamine (which inc muscle tone)

- Analgesia = horses with colic; during anesthesia

Front 42

Routes of administration for alpha2s?

Back 42

IM, IV, SC & Epidural routes common.

* Oral route = high 1st pass metabolism!

Front 43

What are the main alpha2-adrenoreceptor agonists used in veterinary medicine?

Back 43

1. Xylazine (not specific)

2. Detomidine (semi-specific)

3. Romifidine

4. Medetomidine (most specific)

5. Dexmedetomidine (also used in humans)

Front 44

What is the dirtiest alpha2-agonist drug, licensed for dogs, cats, horses and cattle, which isn't used in the UK as much anymore, but is still used on small animals in N. America?

Back 44

XYLAZINE (Rompun)

- "Dirty" because has very low selectivity for alpha2 receptors, which causes inc side effects

- Administered via IM & IV routes

- Duration is short and varies depending on the species, route & dose of drug.

- Metabolized to multiple products that are excreted in urine

- Species differences in sensitivity: Ruminants > Horse/dog > Pig

Front 45

Describe the following pharmacokinetic aspects of XYLAZINE:

- Route of admin

- Duration

- Metabolism

- Selectivity

- Species differences?

Back 45

ROUTES: IM or IV

DURATION: Short - spp, route & dose-dependent

METABOLIZED: to multiple products that are excreted in urine

SELECTIVITY: Very low for alpha2 rec = increased side effects

SPECIES DIFFERENCES: Ruminant (very sensitive)> horse/dog > Pig

Front 46

Describe the pharmacological effects of Xylazine.

Back 46

Typical alpha2-agonist used in small & large animals

CVS: Arrhythmogenic

Urogenital: contraction of uterine smooth muscle

Front 47

________________ used in horses and recently licensed in cattle for standing sedation.

Back 47

DETOMIDINE (Domosedan)

- Imidazole derivative; typical alpha2-agonist

Front 48

Describe the pharmacokinetic aspects of detomidine.

Back 48

- Administered IM or IV

- Longer duration of action than xylazine (1-2 hours in horse)

- Equipotent in horses and cattle (standing sedation)

Front 49

Clinical use of detomidine in vet med?

Back 49

Alpha2-adrenoreceptor agonist

- used for "standing" sedation in horses and cattle.

Front 50

Alpha2-adrenoreceptor agonist used in horses that provides the longest duration of sedation (up to 3 hours)?

Back 50

ROMIFIDINE (Sedivet)

- Causes less ataxia in horses

Front 51

______________ - Cleaner alpha2-agonist, used mainly in dogs, cats, and exotic species, which is very potent & very selective for alpha2 receptors (a2:a1 ratio = 1620:1)

Back 51

MEDETOMIDINE (Domitor)

Front 52

Describe the pharmacokinetic aspects of Medetomidine.

Back 52

- Administered IM, IV, or SC

- Rapid onset & duration up to 3 hours

- Very potent & very selective for alpha2s

- Sedation may be profound

Front 53

Pharmacological effects of Medetomidine?

Back 53

Typical Alpha2-Adrenoreceptor Agonist

CVS: may be antiarrhythmic

- Vomiting in some patients, but less than xylazine.

Front 54

Medetomidine is a racemic mixture of levomedetomidine and dexmedetomidine. Which is the active isomer?

Back 54

DEXMEDOTOMIDINE = active isomer

Levomedetomidine = inactive

- Reduces activity of dexmedotomidine

- Delays metabolism of other hepatically metabolized drugs (e.g. ketamine) = "hangover" effects

Front 55

What is the main alpha2-adrenoreceptor ANTAGONIST used in vet med?

Back 55

ATIPAMEZOLE (Antisedan)

- Specific for alpha2 receptors

- Antagonizes alpha2 agonists awakening the animal from sedation

- Reverses analgesia also

- Licensed for dogs and cats via IM route

Front 56

Benzodiazepines (BZPs) are considered a ____________ class of drug.

Back 56

HYPNOTIC

Front 57

Clinical uses of Benzodiazepines (BZPs) in Vet Med?

Back 57

- Sedative/Premedicant

- Anticonvulsant

* Few side effects which makes it good for use in very young, very old, or very ill animals.

Front 58

What is the main inhibitory neurotransmitter in the CNS?

Back 58

GABA

Two receptor types:

1. GABAa

- Receptor for ligand gated Cl- channels, which mediate fast inhibitory synaptic responses

- Drugs mostly target these GABAa

2. GABAb

Front 59

Describe the mechanism of action of Benzodiazepines (BZPs).

Back 59

BZPs potentiate GABA (inhibitory action on CNS)

- Facilitate the opening of GABA activated chloride channels

- BZP binding site is distinct from GABAa site & increases affinity of GABA for its receptor (enhanced agonist effect)

Front 60

Describe the general pharmacological effects of Benzodiazepines (BZP).

Back 60

- CNS - primarily anxiolytic action (muscle relaxation & anticonvulsant properties)

- CVS/RESP - minimal depression

Front 61

Describe the pharmacokinetics of benzodiazepines.

Back 61

- Well absorbed orally = good bioavailability

- Highly plasma protein bound

- Lipid soluble = high = inc distribution = accumulation within tissues likely

- Metabolism = glucuronidation

Front 62

Side effects of Benzodiazepines?

Back 62

Acute - less dangerous than other hypnotics

- Little CVS/respiratory effects

- Paradoxical excitement in healthy patients, rather than sedation...

Front 63

Clinical use of Benzodiazepines?

Back 63

- Excellent anxiolytics (anxiety inhibitors)

- Minimal CV & respiratory effects

- Good sedation in sicker patients (CNS system depressed)

* Would seem to be ideal agents for sedation/premedication, EXCEPT FOR THE PARADOXICAL EXCITEMENT IN HEALTHY PATIENTS; so not used with healthy patients

Front 64

What are the two main types of benzodiazepines?

Back 64

1. DIAZEPAM

2. MIDAZOLAM (Hypnovel)

Front 65

Describe the pharmacokinetic aspects of DIAZEPAM.

Back 65

- Administered via IV, orally, or rectally for epileptic animals

- Rapid onset & short duration (IV)

- Liver metabolism

- Excreted in urine

- Insoluble in Water

Front 66

What are the two DIAZEPAM preparations available?

Back 66

1. "Valium" = formulated in propylene glycol

- May induce thrombophlebitis

2. "Diazemuls" = lipid emulsion formulation

- Better for veins (no thrombosis)

- BUT decreased bioavailability.

Front 67

Water soluble benzodiazepine, which undergoes conformational change at physiological pH to become lipid soluble.

Back 67

MIDAZOLAM (Hypnovel)

Front 68

Describe the pharmacokinetic aspects of MIDAZOLAM.

Back 68

- Administered IV, IM, or orally

- Rapidly metabolized; short duration

Front 69

Describe the pharmacological effects of MIDAZOLAM.

Back 69

Similar to Diazepam, but twice the potency

- Less likely to accumulate because requires only have the dose & is metabolized much faster.

Front 70

Clinical uses of Benzodiazepines?

Back 70

1. Neuroleptanalgesia (a state of quiescence, altered awareness, and analgesia)

2. Premed/hypnosis of 'sick' animals

3. Control seizures

4. Pre-empt seizures

5. Induce eating (cats)

6. Occasionally, to alter behavior

7. Muscle relaxation (often combined w/ ketamine)

* NONE OF BZPs ARE LICENSED IN ANIMALS!

Front 71

None of the benzodiazepines are licensed for use in animals.

True or False?

Back 71

TRUE

Front 72

A condition in which the patient, though not entirely unconscious, is insensitive to painful stimuli.

Back 72

NEUROLEPTANALGESIA

Neuroleptic = "nerve seizing"

Front 73

________________ is produced by the combination of neuroleptic (e.g. phenothiazines, butyrophenones) & opioid analgesic.

Back 73

NEUROLEPTANALGESIA

- Definition in vet med extended to include combinations of sedative or hypnotic (alpha-2 agonists, benzodiazepine) and an opioid analgesic.

Front 74

Licensed neuroleptanalgesia for small furies.

Back 74

HYPNORM - Fluanisone + fentanyl (full opioid agonist)

- Usually given IM or IP

- Long duration of action

- Can be antagonized by "sequential analgesia" (partial opioid antagonist to wake up the animal, but still providing some analgesia)

Front 75

Give two examples of "homemade" neuroleptanalgesia preparations.

Back 75

1. ACP + pethidine

2. alpha2 agonist + butorphanol