Pharmacology, Anesthetic Drugs, Cyclohexanones

Front 1

What are the major cyclohexanone drugs?

Back 1

Ketamine and Tiletamine (of Telazol)

Front 2

What original compouds did ketamine come from?

What did these original compounds do?

Back 2

Phencyclidine and Clyclohexamine

Strong and Long-Lasting Psychomimetic effects with High Abuse Potential

Front 3

Unlike all other Injectables, Cyclohexanones produce an anesthesia-like state described as ________ and characterized by ________.

Back 3

Dissociated Anesthesia

Intense Analgesia, Light Sleep, Amnesia, and Catalepsy
(and considerably less euphoria than phencyclidine)

Front 4

How are the cyclohexanones administered?
prepared?

Back 4

IV or IM

Ketamine - mono-drug prep
Tiletamine - in combination with a benzodiazepine

Front 5

pKa of Ketamine?

Back 5

7.5 (weak base)

Front 6

Isoforms of Ketamine?

Back 6

Enantiomers
Racemic used in US
Racemic or S-alone avail in Europe

S is 3-4x more potent than R
S more likely to suppress breathing, S knocks out faster, S has quicker recovery.
during Recovery -S produces less dysphoria, agitation, and locomotion.

Front 7

Why are cyclohexamines so fast to act and recover from?

Back 7

Readily dissolves in H2O
and 5-10x more lipid-sol than Thio

= BBB cross, and quick redistribution

Front 8

Ketamine HCl... whats the deal with that?

Back 8

pH of 3.5 - 5.5 and may cause tissue irritation on IM admin

Front 9

Tiletamine is never given alone..... whats the deal with that?

Back 9

Only formulated with Zolazepam (a benzo-d) --- marketed as Telazol

--reason why coming later

Front 10

What is the main mechanism of action of Cyclohexanones?

Back 10

Inhibit Glutamate-R's -- esp NMDA-R
(Glu is main excitatory of CNS)

Front 11

How do cyclohexanes act upon the NMDA-R?

Back 11

2 ways:

"Use-Dependent" - Open Channel Blockade OR
Hydrophobic - Closed Channel Blockade

Both decrease Glutamatergic activity and contribute to Potent Analgesic props of the drugs

Front 12

How does one open an NMDA-R channel?

Back 12

Special -R requires BOTH a Glutamate and an co-agonist Glycine

Allows Ca and Na to enter cell
Plays a functional role in transmission of nociceptive info.

Front 13

At what dosing level will these analgesic effects of cyclohexanones kick in?

Back 13

Subanesthetic concentrations

Front 14

Do cyclohexones act on other mechanisms/receptors?

Back 14

Yes.... lots - all of which may contribute to the analgesic effects in less significant ways.

Also some indirect CV effects displayed because of NE reuptake inhibition at symp postgangs

Front 15

Why is cyclohexanone said to put you into a "Dissociative Anesthesia"?

Back 15

Effects the CNS by causing a functional and electrochemical DISSOCIATION/Disconnect of the Thalamoneocortical areas (consciousness center) from the Limbic and Subcortical areas

Rather than just General depression of all brain areas - only turns off Thalamoneocortical

Front 16

What are the characteristics of a Dissociative Anesthetic State?

Back 16

Catalepsy, Motionlessness, Eyes Open, Slow Nystagmus
*Protective Reflexes are maintained or hyperactive

EEG different
no Alpha
dominance of Theta
Delta comes on with loss of consciousness

no evidence of epileptic activity
(yet drug has been assoc with clonic seizure)

Front 17

Analgesic effect of cyclohexanones is greater for:

Somatic or Visceral pain sensation?

Back 17

Somatic > Visceral

Front 18

Inhibition of ________ signal transmission through the ________ and the __________ to higher cortical areas is the CHIEF (not only) mechanism underlying cyclohexanone analgesic action.

Back 18

Nociceptive

Medial Medullary RF
and the Medial Thalamic Nuclei

Front 19

ADVERSE EFFECTS:

CNS

Back 19

Increases Electrical Activity and Metabolism/O2 consumption
Potent Vasodilators --> increase intracranial P
Violent Recovery (hallucinatory)

Front 20

ADVERSE EFFECTS:

CNS - so can you give ketamine to a patient with an already increased intracranial pressure?

Back 20

Yes - as long as normocapnia is maintained by mechanical ventilation.

Front 21

ADVERSE EFFECTS:

CNS - how can you overcome these side effects?

Back 21

Give with and Alpha-2 agonist or muscle relaxer
-diminishes severity of recovery rxn

Front 22

ADVERSE EFFECTS:

CNS -- what do kids call Ketamine?

Back 22

K, Special K, Vitamin K, Kit Kat, Purple K-hole, K-land

Front 23

ADVERSE EFFECTS:

Respiratory System

Back 23

does NOT produce sig. depression of ventilation
Responses to CO2 and hypoxemia are well maintained.
Apneustic Pattern (holding at peak inspiration, shallow/irreg)

Bronchodilatory AND xs saliva/secretions = obstrxn, cough, gag (so giving an Anticholingergic with this is good)

Front 24

ADVERSE EFFECTS:

Cardiovascular

Back 24

Indirectly Sympathomimetic
Increase HR, BP, CO - and promotion of catechol arrhythmias

Depletion of catecholamines --> unmasking of direct CV DEPRESSANT fx

Front 25

Tell me about the PK of cyclohexanones -

Back 25

High Lipid-Sol
High Bioavailability (>90%)
Relevant protein binding (45-55%)

Leading to Rapid Onset, Short Duration (Rapid Distribution), High Clearance, but Long Elimination Half Time

Front 26

Recovery from Dissociative Anesthesia is primarily due to ______ (rather than ______)

Back 26

Redistribution

Metabolism

Front 27

How is Ketamine metabolized?

Back 27

P450s
Ketamine --> Norketamine (still 20-30% active) --> HydroxyNorketamine (Inactive) --> Renal excretion

This happens way more in Dogs than Cats

Front 28

How is Tiletamine metabolized?

Back 28

forms 2 or 3 metabolites excreted in urine.
Plasma t-1/2 is
1.2 hours in DOG
2-4 hours in CAT

Front 29

KETAMINE (Ketaset, Vetalar):

Animals become recumbent within _______, and Anesthesia lasts for about ________.

Back 29

1-3 minutes

15-20 minutes

Front 30

What lasts longer - the anesthesia or the analgesia?

Back 30

Analgesia - woot!

Front 31

KETAMINE (Ketaset, Vetalar):

How long to knock them out if given IM?

Back 31

2-15 minutes

Front 32

Dog, Pig and Horse are more prone to __________ effects of Ketamine than are Cattle and Cats

*what do you do about this?

Back 32

Excitatory

*Co-Admin with tranqs or m-relaxers

Front 33

What is "Triple Dip"?

Back 33

Used as Total IV Anesthesia (TIVA) in horses for short procedures

Ketamine + Guaifensin + Alpha 2 agonist

Front 34

What overall effects does Ketamine have on the body?

Back 34

Apneustic pattern
Increase HR and BP
Analgesia

(when injected into caudal epidural space - analgesic effect equivalent to Bupivicaine)

Front 35

TILETAMINE+ZOLAZEPAM (TELAZOL)

How does it compare to Ketamine?

Back 35

Similar - but has 3x duration and greater analgesic effect.

Front 36

Why is Tiletamine always combined with Zolazepam?

Back 36

Tiletamine causes Catalepsy --- Zolazepam is Anticonvulsive/Muscle Relaxing

Front 37

How long until onset of Dissociative Anesthesia when given:
IV?
IM?

Back 37

2-3 minutes either way!

Front 38

What are the general effecs of Telozol?

Back 38

Dissoc. Anesthesia
Protective Reflexes Maintained
xs salivation/secretions (controlled by atropine or glycopyrrolate)

Increase HR, CO, BP --- at high doses + Apneustic Pattern

Front 39

How is recovery from Telazol?

Back 39

Could be better for dogs:

unfortunately the Zolazepam wears off faster than the Tiletamine in dogs so there can be excitatory responses

Cats:
Zolazepam actually lasts twice as long as Tiletamine so recovery time is 2x as long.
*Tigers - depressed for days, may re-sedate, may have convulsions