Sedatives and IV Anesthetics Part II

Question 1

Name a dissociative anesthetic?

Answer 1

ketamine

Question 2

Name a Barbiturate?

Answer 2

Thiopental

Question 3

Name 3 Non- Barbiturates?

Answer 3

• Propofol
• Alfaxalone
• Etomidate

Question 4

Definition of general anesthesia?

Answer 4

Drug-induced central (CNS) depression resulting in unconsciousness in which the patient cannot be aroused by painful stimuli, and sensory, motor & autonomic reflex functions are attenuated

Question 5

Definition of Dissociative anesthesia?

Answer 5

Drug-induced dissociation of the thalamocortical and limbic systems
resulting in a catatonic state

The eyes remain open and swallowing reflexes remain functional

Skeletal muscles maintain tone

Sensory input is dissociated from perception

Question 6

Name the stages of Anesthesia?

Answer 6

1. Analgesia
2. Excitement phase
3. Surgical anesthesia
4. Medullary paralysis
5. Death

Question 7

Phase characterized by characterized by voluntary motor excitement and state of analgesia

• The animal is conscious
• The animal may urinate or defecate

Answer 7

Analgesia

Question 8

Phase characterized by characterized by involuntary excitation or delirium
Loss of consciousness & voluntary control
Signs of CNS stimulation rather than depression

Answer 8

Excitement phase

Question 9

Phase characterized by plane of surgical anesthetic depth is reached
Consciousness, pain sensation, & most neuromuscular reflexes are
abolished

Respiratory, CV, thermoregulatory function are depressed

• Light
• Medium
• Deep

Answer 9

Surgical anesthesia

Question 10

Phase characterized by characterized by paralysis of vital centers in medulla

Answer 10

Medullary paralysis

Question 11

Phase characterized by respiratory failure and/or CV collapse of resuscitative intervention not immediate

Answer 11

Death

Question 12

MOA of Dissociative anesthetics?

Answer 12

Non-competitive NMDA receptor antagonist

Inhibits activation by glutamate of ligand-gated ion channels

Antagonism at glutamate receptor of NMDA subtype

Suppresses central sensitization

In conjunction with opioids

Subanesthetic doses adequate for analgesia

Question 13

The _____ receptor is thought to be a crucial part of the mechanism of CNS hypersensitisation and dorsal horn wind up–> neuropathic pain

Treats hyperalgesia in response to repetitive afferent stimulation

Answer 13

NMDA

Question 14

What part of the nociceptive pathway does NMDA antagonist fit under?

Answer 14

Pain Modulation

Question 15

Give me an example of a dissociative anesthetic?

Answer 15

Ketamine

Question 16

How is dissociative anesthetics distributed?

Answer 16

rapidly distributed to wide array of tissues including the brain

lipid soluble so crosses the BBB

Question 17

Route of ADM. for dissociative anesthetics?

Answer 17

Usually given IV, can be given IM

Acidic pH may cause pain on injection

Readily absorbed from the injection site

decent transmucosal bioavail (~40%)

Question 18

dissociative anesthetics are metabolized by the _____ and excreted in the ____. What species do we worry about with renal excretion?

Answer 18

metab. in the liver

excreted in the urine

Cats have more renal excretion than other species —> CAUTION with renal insufficiency

Question 19

dissociative anesthetics induction of anesthesia?

Answer 19

within a few minutes (3-5)

Question 20

dissociative anesthetics duration of anesthetic effects?

Answer 20

20-45 minutes

Question 21

dissociative anesthetics recovery?

Answer 21

2-10 hours (very long)

Question 22

What are the 2 duel effects that dissociative anesthetics have on the central nervous system?

Answer 22

1. Depression of the thalamocortical system (sensory perception)
2. Activation of limbic system, dissociation (emotional/behavioral/memory)

Question 23

What stages are induced by amnesia and anesthesia through CNS stimulation and catalepsy?

Answer 23

Only stages 1 and 2 of anesthesia

Consciousness not lost completely —-> don’t disturb the animal!

Question 24

Define catalepsy?

Answer 24

a medical condition characterized by a trance or seizure with a loss of sensation and consciousness accompanied by rigidity of the body.

Question 25

With dissociative anesthetics, what is taking place through out the body with catalepsy?

Answer 25

- Muscle tone maintained to hypertonic, need to use in combination with muscle relaxant - Pharyngeal and laryngeal reflexes maintained - Eyes open, mydriasis - Light & sound sensitivity

Question 26

With dissociative anesthetics, what is taking place through out the body with analgesia at sub anesthetic doses?

Answer 26

Classified as a dissociative anesthetics, but there is clinical belief that ketamine provides significant analgesia. More somatic analgesia (muscle, skin) than visceral Short duration of action

Question 27

Main dissociative anesthetic cardiovascular effects?

Answer 27

Centrally mediated CV stimulation Direct action on myocardium causes myocardial depression, but net effect is CV stimulation Increased sympathetic tone , Positive inotropic Decreased parasympathetic tone ↑ CO, CVP, & HR ↑ cerebral blood flow Some antiarrhythmic action ↑ ICP & IOP Not recommended for craniotomy or ocular surgery Not recommended for traumatic brain injury or ocular trauma

Question 28

Dissociative aesthetic effects on respiration?

Answer 28

Safe respiratory profile Low anesthetic doses stimulate respiration  Bronchodilation Decreased airway resistance good for asthmatic patients Increased airway secretions Very large doses depress respiration

Question 29

Dissociative aesthetic effects on GI?

Answer 29

Stimulation of salivary secretion

Question 30

What class is Ketamine?

Answer 30

Schedule III non-narcotic controlled substance

Question 31

Does ketamine have excitatory effects? What happens with lower doses

Answer 31

Ketamine in anesthetic doses is known to have excitatory side effects, and causes a hallucinations in people At lower doses Ketamine does not act on primary pain, but on CNS hypersensitization

Question 32

Can I use ketamine on it's own for analgesic?

Answer 32

Not recommended for use as a sole analgesic Ketamine is used at subanesthetic doses in combination with opioids in the acute pain setting and has been shown to reduce tolerance to opioids

Question 33

Name another dissociative anesthetic and some general info?

Answer 33

Tiletamine (dissociative) + zolazepam (benzodiazepine) combined in a fixed ratio Similar to ketamine + diazepam L-O-N-G recovery (hours) Only the zolazepam is reversible

Question 34

Can we use dissociative anesthetics with chemical restraint?

Answer 34

Chemical restraint and anesthesia for minor procedures Rarely ever used alone

Question 35

What makes up kitty magic? When is ketamine commonly used

Answer 35

Ketamine + Dexmedetomidine + Buprenorphine = Kitty Magic | ketamine is safe for handling fractious cats commonly used for high volume spay/neuter clinics

Question 36

What is triple drip?

Answer 36

Dissociative anesthetics are Part of ‘Triple Drip’ in large animals Guaifenesin (GG) + Xylazine + Ketamine Form of total intravenous anesthesia (TIVA)

Question 37

Best dissociative analgesia constant rate infusion drugs?

Answer 37

Fentanyl + Lidocaine + Ketamine (FLK) Morphine + Lidocaine + Ketamine (MLK)

Question 38

Dissociative anesthetics role in acute pain?

Answer 38

Reduction of post operative pain hypersensitivity Reduction of short term tolerance to opioids Prevention of opioid-induced hyperalgesia (OIH) Reduction in dose of post operative opioids

Question 39

Advantages of Ketamine?

Answer 39

```  ↓ central hypersensitivity to pain  ↓ chronic pain  ↓ opioid requirements  ↓ respiratory depression  ↑ sense of well-being (human patients)  Anti-inflammatory role in trauma patient ```  Inhibits cytokine production and release both in vitro and in vivo  Ketamine suppressed LPS-induced TNF-alpha, IL-6, and IL-8 production in human whole blood.  May be useful for horses suffering from pain or endotoxemia  Reduced chemotaxis of neutrophils, TNF-α, IL-6  Minimal hemodynamic effects in healthy animals  Ketamine has been associated with lower pain scores and better activity post op  Ketamine associated with improved feeding behavior after surgery  Useful in the critical care and perioperative setting

Question 40

Disadvantages of Ketamine?

Answer 40

 Irreversible  Can’t be used alone, adjunctive therapy with opioids  May be inappropriate for patients with certain cardiac disease  ↑ intracranial pressure  Contraindicated for traumatic brain injury & space-occupying intracranial/brain disease  Pain upon IM injection  Risk of corneal ulceration  Risk of substance abuse

Question 41

Precautions for ketamine uses?

Answer 41

 Pain with IM injection  good for use in cats, but less good for IM use in dogs  Eyes usually remain open  lubricate often, blink reflex delayed for up to hours  Respiratory depression seen at high doses  ‘Rough’ recovery can be seen (usually if used alone)

Question 42

Avoid using ketamine if?

Answer 42

 Contraindication for increased ICP or IOP  Seizures  Not for use in myelography  Certain cardiac disease or hypertension  Hypertrophic cardiomyopathy (HCM) in cats  Hyperthyroidism  Pheochromocytomas  Hepatic insufficiency  Contraindicated for renal disease or failure in cats  Other reported adverse effects:  Muscle tremors and hypertonicity, CNS stimulation & convulsions  Nausea, vomiting, hyper salivation

Question 43

Review in summary for dissociative anesthetics? - Sedation - Anesthetic induction? - Muscle relaxation - Analgesia - CV/Resp? - Other?

Answer 43

 Sedation? Yes Dissociation, used in combination with other drugs Anesthetic induction? Yes, only induction agent with analgesic properties Muscle relaxation? No muscle relaxation by itself Analgesia? Yes, very good Opioid-sparing effect Cardiovascular/Respiratory effects? - Sympathetic stimulation is the main effect! - Minimal respiratory depressive effects - Bronchodilation Other? Cataplexy, lack of blinking/ocular exposure

Question 44

Name a drug example of a barbiturate?

Answer 44

Thiopental

Question 45

Name the drug examples of non-barbiturates?

Answer 45

 Propofol  Alfaxalone  Etomidate

Question 46

Anesthetic drugs that potentiate GABA will create a dose-dependent CNS depression: ?

Answer 46

Sedation  hypnosis  anesthesia  coma  death

Question 47

Thiopental, propofol, alfaxalone, etomidate are all ____ agonists?

Answer 47

GABA

Question 48

What are the Gaba agonists effect on nociception?

Answer 48

- Perception | - Modulation (anticonvulsants)

Question 49

Mechanism of action for injectable anesthetic GABA agonists? Main effects?

Answer 49

Several of the induction agents work by potentiating GABAA receptors Main effects: sedation & hypnosis

Question 50

Barbiturates are thought to ______ the amount of time that GABA remains on the binding site and at higher doses are reported to be able to activate chloride channels without ––– being present The end result of chloride entry into the cell is hyperpolarization

Answer 50

increase without GABA

Question 51

GABA dependent mechanism may be the cause of _______ effects and the GABA independent mechanism may result in _______

Answer 51

anticonvulsant and sedative anesthesia

Question 52

Absorption of injectable anesthetic GABA agonists

Answer 52

 Administered intravenously and orally but IM and SC injection can cause tissue damage  Readily absorbed orally

Question 53

Distribution of injectable anesthetic GABA agonists

Answer 53

Distribution to all tissues and the rate of distribution depends on their lipid solubility More lipid soluble are faster acting (BBB)

Question 54

Metabolism and elimination of injectable anesthetic GABA agonists?

Answer 54

 Metabolized by hydroxylation in the liver  Thiobarbiturates are also inactivated in the brain and the kidney  Barbiturates are enzyme inducers

Question 55

Duration of action of injectable anesthetic GABA agonists?

Answer 55

Duration of action and recovery depends on redistribution and elimination

Question 56

Recovery of injectable anesthetic GABA agonists?

Answer 56

slower in thin animals such as greyhounds or emaciated animals 

Question 57

Barbituates main effects in the CNS?

Answer 57

Sedation, hypnosis, and anesthesia Poor analgesia unless anesthetized Anticonvulsant (- intracranial pressure) Decrease brain metabolism (neuroprotective) sometimes used for head trauma by decreasing metabolic requirements

Question 58

Main effects of Barbiturates in the CVS?

Answer 58

Hypotension is mainly due to cardiac depression with lesser contribution from vasodilation Hypotension may cause reflex tachycardia Thiobarbiturates may sensitize the myocardium to catecholamine-induced arrhythmias

Question 59

Barbiturates main effects on the respiratory system?

Answer 59

 Dose-dependent respiratory depression (especially at anesthetic dose)  Cats are more sensitive to respiratory depression  Intravenous injection causes more depression than oral administration

Question 60

What's significant about deaths by barbiturates?

Answer 60

This is of primary importance with these drugs and is likely the most common cause of death, due to inaccurate dosing or poor monitoring. Best to intubate and monitor closely (pulse oximetry, designated tech, ECG, capnometry etc...)

Question 61

Skeletal muscle effects of barbiturates?

Answer 61

 Inhibit sensitivity of the motor endplate to Ach  Abdominal muscle relaxation not complete

Question 62

Body temp. effects of barbiturates?

Answer 62

 Hypothermia due to peripheral vasodilation and reduced basal metabolic rate  Decreased temperature can lead to delayed recovery, coagulation abnormalities and ventricular arrhythmias

Question 63

Renal effects of barbiturates?

Answer 63

 Oliguria and anuria due to decreased blood pressure and resulting reduction in GFR  Stimulation of ADH (vasopressin)

Question 64

Uterus and fetus effects of barbiturates?

Answer 64

 Depression of uterine contractions  Depression of fetal respiration

Question 65

Name the non barbiturate drugs?

Answer 65

Propofol Alfaxalone Etomidate

Question 66

Propoflo?

Answer 66

Emulsion containing egg lecithin and soybean oil Ideal for bacterial growth, use or discard within 12-24hr One of the few white liquids that can go IV

Question 67

Propoflo 28?

Answer 67

Benzyl alcohol preservative Once opened stable for 28 days Not labeled for cats

Question 68

Pharmacokinetic for both formulations of propofol?

Answer 68

 Given IV only (slowly to effect over 20 seconds)  Rapid onset (< 1 minute), short duration of action  Widely distributed to all tissues (lipid soluble drug)  Redistribution to muscle then to fat  Metabolism is rapid (hepatic and extrahepatic)  Rapid metabolism allows for repeated dosing/CRI  Metabolites excreted in urine

Question 69

Main effects on different body systems (CNC, cardiovascular, Respir., Muscle)

Answer 69

Central Nervous System  Dose-dependent CNS depression Cardiovascular  Vasodilation w/out reflex tachycardia (cardiac depressant)  Splenic engorgement can be observed Respiratory  Dose dependent respiratory depression  Rate-dependent apnea (e.g. with rapid administration) Muscle  Laryngeal reflexes decreased  Myoclonic movements on induction  After induction generally good muscle relaxation Other  Appetite stimulation  Heinz-body anemia (> 5 days repeated use cats)  Risk of dependence

Question 70

Alfaxalone?

Answer 70

Alfaxalone Neurosteroid which is an analog of progesterone MOA:  GABA agonist Does not bind to usual ‘steroid’ receptors (no effect on glucocorticoid, mineralocorticoid, or sex hormones!!) Approved (Class IV controlled substance) in US 08/2014

Question 71

Alfaxalone compared to propofol?

Answer 71

 Similar pharmacokinetics  Rapid onset, short duration, no accumulation (CRI ok)  Labeled for IV usage only  Sometimes used (off label) IM unlike propofol  Contains no preservative – use within 24h  In other countries labeled shelf life of 7 days Similar pharmacologic effects  Dose dependent CNS depression  No significant analgesia  Good muscle relaxation  Metabolized in the liver (glucuronidation and sulfation)  Cardiac and respiratory depression similar to propofol  Myoclonus can be seen during induction (and if given by non-IV routes), possibly some on recovery  May see increased secretions?

Question 72

Etomidate?

Answer 72

 MOA: Depresses the CNS by enhancing GABA Indicated in patients with significant cardiac disease  Has a sedative hypnotic,and anesthetic effects  No analgesic effect  Good muscle relaxation during anesthesia  May cause excitement or myclonic twitching which can be minimized by pretreatment with benzodiazepenes or opioids Does not have significant cardiovascular effects compared to other IV anesthetics  Inhibits cortisol synthesis  Rapid recovery with no accumulation  Rapid hepatic metabolism  Metabolites excreted in kidney and bile  Can be used as induction agent in the dog & cat  Reported to be better for critical patients

Question 73

Injectable anesthetic GABA agonists clinical uses?

Answer 73

Anesthetic Induction This is stage I and II Generally characterized by excitement Ultra short acting barbiturates can be used to shorten induction Premedications also decrease excitement Procedural sedation Emergency anti-convulsants TIVA

Question 74

Pharmacologic effects propofol and alfaxalone?

Answer 74

Pharmacologic Effects Overview Sedation?  Full anesthesia Muscle relaxation?  Good muscle relaxation Analgesia?  None Cardiorespiratory effects? Respiratory depression and hypotension, Apnea on induction Other?  Myotonia on induction, anticonvulsant