Anesthesia - Analgesics

C fibres

- Slow
- Unmyelinated

A-fibres

- Myelinated

Dorsal Root Ganglia

Substantia Gelatinosa of Dorsal Horm

Down/Up regulation

* Down - during fight or flight to suppress pain sensation
* Up - during tissue damage to protect wound

Hyperalgesia

Allodynia

wind-up

Tissue
1) 5 HT
2) Histamine
Systemic
3) Bradykinin
Spinal Chord
4) Substance P
5) Glutamate

1) Decrease inflammatory mediators
2) Decrease transduction or nerves
3) Modify transmission at the DH
4) Modify the central and emotional aspects of pain (vague)

1) Opioids
2) NSAIDs
3) Local anesthetics
4) NMDA antagonists
5) Alpha 2 Agonists

Naturally occuring
1) Morphine
Semi-synthetic
2) Etorphine (Imobilon)
3) Buprenorphine
Synthetic
4) Fentanyl
5) Pethidine
6) Methadone
7) Butorphanol
8) Naloxone

Morphine
Fentanyl
Pethidine
Methadone

* Mu (greek) receptors

* Oral (buprenorphine & codeine)
* IV (except pethidine-> histamine release)
* IM
* SQ
* Intrathecal (epidural/ extradural)

It is cojugated (via gluconization) to morphine-6-glucuronide.

* Both are analgesic

- Excreted in Urine
- Liver metabolized glucuronides hydrolysed in gut

* Morphine reabsorbed (exterohepatic circulation)

1) Sedatation
2) Respiratory depression (more in humans)
3) Chronotropy (decreased HR)
* except pethidine
4) Emesis
5) Dysphoria
6) Histamine release

Brian & Spinal Chord

G-protein coupled receptor (inhibitory for cAMP)

- gamma (OP1) - sedation
- kappa (OP2) - sedation
- mu (OP3) - analgesia

* gamma & kappa give unwanted side effects

Principal Site of Action: Spinal Chord

1) Reduced neuronal excitability
(membrane hyperpolarization)
2) Reduced transmitter release
(inhibition of sub. P and Glutamate release - associated with pain)

1) Analgesia (acute & chronic)
2) Sedation (dysphoria)
3) Decrease CO2 sensitivity in respiratory center
4) Cough suppression
5) Stimulation of vomitting center
6) Reduced GI motility
7) Pupillary constriction (mu & kappa receptors)
8) Histamine release -> Bronchoconstriction & hypotension

- OP3 agonist
- On-set 3-5 min
- Duration 3-4 hrs
- Controled Rate of Infusion (CRI), Extradural (24hr action)

- Partial OP3 agonist/antagonist
- Analgesic for moderate pain
- Fentenyl reversal in exotics

- Partial opioid agonist/ antagonist (more affinity for non-mu receptors)
- On-set 15 min
- Duration 2-4 hours
- Oral Admin (POM)
- Analgesic for mild pain
- Anti-tussive (cough suppressive)

- OP3 agonist
- On-set 10-15 min
- Duration 30-60 min
- Spasmolytic - Decreases Gut spasms (colic)
- Increase HR (+ chronotropy)
- Histamine release IV
-

- OP3 agonist
- On-set rapid "resucue analagesic"
- Duration 15-20min;patch 72hrs

- Narcotic antagonist
* Antagonizes endogenous opioids
- Short duration

- Synth OP3 agonist
- Analgesia for moderate pain
- No emisis

- Hypnorm (mice, rats, rabbits)
- Small Animal Immobilon
- Large Animal Immobilon

Local anesthetics reversibly interfere with action potential generation and conduction, NOT resting membrane potential.

1)Aromatic Ring-Lipid solubility
2)Amide group-hydrophilic
3)Carbon chain linking the two ends - influence drug action

1) Ester (Procaine, Cocaine)
2) Amide (Lidocaine, Bupivicane)

Esters are less stable in solution as the linkage is easily broken. Metabolism of esters produces PABA which can cause allergic reactions (horses; procainepenicillin).

Amides are heat stable and can be stored for longer periods of time.

Local anesthetics are weak bases that are mostly IONIZED in tissues, making them less available to cells.

Examples:
Lidocaine 25% unionized
Bupivicaine 15% unionized

Both have similar anesthetic properties, but:
* Dextrobupivicaine - more cardiotoxic
* Levobupivicaine - less cardio and neuro-toxic

- Injection - near nerves(block)
- Spray
- Cream
- Gel

Infected tissue has a lower pH than normal. This can disrupt the absorption of anesthetic agents.

The vasoconstricting properties of Adrenaline counter act the vasodialating properties of the Lidocaine. This helps to keep the anesthetic in the local area as opposed to being absorbed systemically.

1) Distribution
2) Duration

Lidocaine 65%pb
Distribution - Moderate
Duration - Moderate

Bupivicaine 95%pb
Distribution - Quick!
Duration - Long

Esters - broken down by plasma esterases.

Amides - metabolized by hepatic amidases.

Both are excreted by the kidneys.

1) Ionized form binds to local Na+ gated channels, preventing depolarization.

2) Unionized form penetrates the nerve sheath via the "Membrane Expansion Theory"

In order of sensitivity:
Small > Large
Myelinated > Unmyelinated
Ad fibres > C fibres

Pain sensation is blocked before touch sensation/motor control.

Local anesthetics will preferentially block active fibres with OPEN Na+ channels.

1) CNS - tremors, convulsions & respiratory depression
2) CVS - decrease myocardial contractility, vasodialaiton, hypotension
3) Reduced endothelial repair
4) Tissue irritation
5) Accidental IV admin.
6) Allergic Rxn

- Amide linked
- Anti-arrhythmic (drug of choice for tachycardia)
- Lowers Minimum Alveolar Concentration (MAC) of inhaled anesthetics

- Amide linked
- Extradural
- Long acting (8 hrs)
- Cardiac toxicity
- Not suitable as an Intravenous Regional Anesthetic (IVRA) as QUICK distribution can return drug to heart too fast.

- Amide linkage
- IA (Joint block in Horses)
- Less irritant to tissues than lidocaine, but equi-potent
- Less vasodilation than lidocaine
- Expensive/one use bottle

- Ester linkage
- IV
- added to penicillin to reduce pain on injection
- Causes vasoconstiction
- PABA allergic reactions
- slow onset

- Amide linkage
- Cornial anesthetic for exam.
- Rapid on-set
- Toxic to corneal epithelium
- Reduces healing
* No good alternatives

- Topical for skin
- IV or Cardiac Catheter placement (Rabbit ear or large area)
- On-set time 30-60 min

Blocking glutamate receptors. Glutamate is a known chemical mediator of pain.

Ex: Ketamine

* NMDA antagonist - Ketamine
* Alpha 2 agonist - Medetomidine, Dexmedetomidine

Rimadyl & Metacam
- Decreasing inflammatory mediators in tissue modulate pain.