Anesthesia Pharmacology

Pharmacology Study Notes

Why Pre-Medicate?

  • Calms patient: Pre-medication can provide a calming effect on the patient, making procedures less stressful.

  • Analgesia and muscle relaxation: Primarily used for pain relief and to relax muscles prior to anesthesia.

  • Anesthetic/MAC sparing: Pre-medication can reduce the amount of general anesthetic needed, known as MAC (Minimum Alveolar Concentration) sparing.

  • Improved vital system stability: Helps in stabilizing vital signs during anesthesia.

  • Improved recovery: Ensures a smoother recovery process for the patient post-anesthesia.

Routes of Administration

  • Routes: SQ (subcutaneous), IM (intramuscular), IV (intravenous), PO (oral)

  • Attribute and Relative Ranking:

    • Onset of Action: IV > IM > SC > PO (IV is the fastest)

    • Duration of Action: SC > IM > IV (SC lasts the longest)

    • Severity of Effects: IV > IM > SC (IV has the most profound effects)

Pre-Medication Drugs

  • Sedatives and Tranquilizers:

    • Alpha 2 agonists

    • Phenothiazines

    • Benzodiazepines

  • Analgesics:

    • Opioids

    • NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

  • Muscle Relaxants:

    • Benzodiazepines

  • Anticholinergics:

    • Atropine

    • Glycopyrrolate

Anesthesia Student Tip

  • Tip #24: When staff asks for the mechanism of action of benzodiazepines, avoid referring to it as "magic".

Anticholinergics

  • Drugs: Atropine, Glycopyrrolate

  • Synonyms:

    • Parasympatholytics

    • Anti-muscarinics

    • Known as "Drying Agents"

Mechanism of Action (MOA)

  • Inhibit the parasympathetic nervous system.

  • Act as competitive antagonists to acetylcholine at postganglionic muscarinic receptors in the peripheral nervous system (PNS).

Indications During Anesthesia

  • Increasing heart rate to treat or prevent bradycardia, but only when necessary.

  • Reduction of salivary and airway secretions, as thickened secretions can cause respiratory distress.

Contraindications

  • Tachycardia

  • Congestive heart failure, HCM, and other cardiac diseases

  • Glaucoma

  • Constipation/ileus

Atropine vs. Glycopyrrolate

General Attributes

  • Heart Rate Increase:

    • Atropine: +++

    • Glycopyrrolate: +

  • Lipid Solubility:

    • Atropine: Lipid soluble, easily absorbed IM, SC, PO, crosses blood-brain barrier (BBB) and placental barrier.

    • Glycopyrrolate: Water soluble, poorly absorbed IM, SC, PO, does not cross BBB and placental barrier.

  • Onset of Action and Effects:

    • Atropine: Rapid onset of anti-sialagogue effects (+++), ocular effects (++), smooth muscle relaxation (+++).

    • Glycopyrrolate: No significant anti-sialagogue effects (0), ocular effects (+), smooth muscle relaxation (+).

Usage Recommendations

  1. Use atropine for rapid-onset bradycardia treatment.

  2. Use glycopyrrolate to avoid cardiovascular adverse effects unless blood pressure is normal, in which case withhold anticholinergic treatment for bradycardia.

Other Indications for Anticholinergics

  • Bronchodilation

  • Mydriasis (dilation of pupils)

  • Decreased GI motility

  • Relaxation of lower esophageal sphincter

  • Organophosphate toxicity

    • Note: Atropine is ineffective in rabbits due to high levels of atropinase; glycopyrrolate should be used instead.

Benzodiazepines

  • Benzodiazepine Abuse Statistics: 30% of prescription drug overdose deaths in 2013 involved benzodiazepines, compared to 70% involving opioids.

  • Drugs: Diazepam, Midazolam, Zolazepam

General Effects of Benzodiazepines

  • Mechanism of Action: GABA-ergic effects; they act as GABA receptor agonists.

  • Main Effects:

    • Sedation/hypnosis (species dependent)

    • Muscle relaxation (central acting)

    • Anti-convulsant

    • Reduction of induction drug dose

  • Benefits: Minimal cardiovascular and respiratory effects.

  • Cons: No analgesic effect; typically combined with an opioid.

GABA Receptors

  • GABA (Gamma Aminobutyric Acid): Main inhibitory neurotransmitter in the central nervous system (CNS).

  • Receptor Effects: Most anesthetic drugs exert effects via GABA receptor agonistic actions (e.g., barbiturates, propofol, alfaxalone).

Clinical Applications of Benzodiazepines

  • As pre-medication: Lack of analgesic and strong sedative effects; must be combined with another drug.

  • Used in compromised animals where alpha 2 agonists or acepromazine are contraindicated.

  • Administered immediately prior to induction, combined with potent opioids for ASA IV or higher animals.

  • As muscle relaxants to counter ketamine-induced rigidity.

  • For seizure treatment: Commonly administered in tablet form but can be given IV as needed.

Diazepam vs. Midazolam

Diazepam

  • Properties: Lipid soluble, forms precipitates and crystals when mixed with other drugs (only mixes well with ketamine).

  • Administration: Administered only by IV route to avoid irritation to muscle and fat tissues.

  • Potency: Less potent, shorter-acting.

Midazolam

  • Properties: Water soluble, compatible with other anesthetic drugs.

  • Administration: Can be administered IV or IM; easier absorption and systemic availability.

  • Potency: More potent, longer-acting.

Phenothiazines

  • Drugs: Acepromazine, Promazine, Propiopromazine, Chlorpromazine, Methotrimeprazine

Indications for Phenothiazines

  • Mild sedation (premedication or post-op).

  • Anxiolytic/tranquilizing effects.

  • Reduces opioid-induced emesis if administered at least 20 minutes prior.

  • Treats opioid-induced/wind-up pain associated dysphoria.

  • Anxiolytic effects prior to alpha 2 agonists sedation in horses.

Acepromazine General Effects

  • Dose-dependent CNS Depression: Has a ceiling effect; much weaker sedative compared to alpha-2 adrenergic receptor agonists.

  • Acts as an antagonist on multiple receptors; causes some muscle relaxation, primarily smooth muscle.

  • Other Effects: Anti-emetic and anti-arrhythmogenic effects; duration of effects ranges from 4 to 8 hours.

  • No Specific Reversal Agent Available.

Adverse Effects of Acepromazine

  • Hypotension due to massive peripheral vasodilation; this may lead to death in hypovolemic animals.

  • Hypothermia resulting from peripheral vasodilation.

  • Penile prolapse observed in stallions and bulls.

Contraindications for Acepromazine

  • Hypovolemic or hemodynamically unstable patients.

  • Conditions such as Von Willebrand Disease.

  • Hypothermia.

  • Neonates or geriatric patients.

  • Boxers and brachycephalic breeds, as it can worsen brachycephalic obstructive airway syndrome (BOAS).

  • Breeding stallions should avoid use due to risks.

Alpha 2 - Adrenergic Receptor Agonists

  • Drugs: Xylazine, Medetomidine, Dex-medetomidine, Detomidine, Romifidine

General Effects of Alpha 2 Agonists

  • Frequently used in both large and small animals; they provide profound dose-dependent sedation.

  • Considered the most potent group of sedatives available.

  • Notably, pigs are resistant to most sedatives.

  • Other Effects: Induces hypnosis and anesthesia in a dose-dependent manner, reduces gas anesthetic requirements by 50-80%, provides analgesia, and muscle relaxation.

Other Effects of Alpha 2 Agonists

  • Respiratory System: Increased upper airway resistance, lung edema.

  • GI System: Alters gastrointestinal motility.

  • Diuresis: Increase urine output (diuresis).

  • Thermoregulation: Depression of the thermoregulatory center.

  • Metabolic Effects: Hypoinsulinemia/hyperglycemia.

  • Pregnancy Effects: Abortions in the second trimester may occur.

Mechanism of Action of Alpha 2 Agonists

  • Act as competitive agonists at alpha-2 adrenergic receptors, stimulating sympathetic nerves throughout the body including the brain.

  • Suppresses noradrenaline, which leads to sedation (in the brainstem), analgesia (in the brainstem and spinal cord), and a reduction of sympathetic outflow from the brain.

Xylazine

  • Used in most species, especially in horses and cattle.

  • Cattle are more sensitive and may need doses approximately 10 times less than that needed for horses.

  • Duration of Sedation: Typically lasts 20-40 minutes.

Dexmedetomidine / Medetomidine

  • Primarily utilized in small animals but can also be used in equines as a constant rate infusion (CRI).

  • Dose-Dependent Sedation: Higher doses lead to more sedation but also an increased risk of adverse effects.

  • Can reduce the dose by combining with other drugs like opioids.

  • Adverse effects are reduced if administered as CRI; avoid in cardiovascular-compromised patients. May decreases tear production.

Opioids

How Drugs are Classified in the US

  • Schedule 1: No medical use, high potential for abuse (e.g., heroin, LSD, marijuana).

  • Schedule 2: High potential for abuse leading to severe dependence (e.g., cocaine, methamphetamine, hydromorphone).

  • Schedule 3: Moderate to low potential for abuse (e.g., ketamine, anabolic steroids).

  • Schedule 4: Low potential for abuse (e.g., Xanax, Valium).

  • Schedule 5: Lowest potential for abuse (e.g., tramadol, cough preparations).

Mechanism of Action of Opioids

  • Act on opioid receptors being the site of action; they provide the strongest systemic analgesics.

  • Best suited for acute pain management; they allow for greatly reduced doses of concurrently used anesthetics.

  • Minimize cardiovascular effects making them suitable for ASA III-IV patients when used as needed (PRN).

Effects of Receptor Types

  • Mu Receptors: Provide strong analgesia, sedation, and can lead to respiratory and cardiovascular depression, nausea, vomiting, and euphoria.

  • Kappa Receptors: Provide weak analgesia, sedation, or dysphoria.

Opioid Classification

  • Pure Agonists: Maximum stimulation of Mu receptors (e.g., morphine, fentanyl).

  • Partial Agonists: Partially stimulates Mu receptors (e.g., buprenorphine).

  • Mixed Action: Agonists at kappa, antagonists at Mu (e.g., butorphanol).

  • Pure Antagonists: Fully antagonize Mu receptors (e.g., naloxone, naltrexone).

Potency vs. Efficacy

  • Potency: Compares the effect versus the dose required to achieve that effect among drugs.

  • Efficacy: Compares the strength or severity of the effect obtainable among drugs.

Partial Agonists / Antagonists

  • Buprenorphine and Butorphanol: Exhibit complex pharmacological effects.

  • Analgesic Effects: Show plateaus at higher doses; limited in treating mild to moderate pain.

  • Buprenorphine's higher affinity for Mu receptors may outcompete other pure agonists if injected concurrently.

General Effects of Pure Mu Agonists

  • Analgesia: Excellent for acute pain, not ideal for chronic conditions due to addiction risks.

  • Sedation: Effects vary by species; good in dogs, may cause excitement in cats, horses, and goats.

  • Additional Effects: Decreases overall anesthetic drug requirements; can provide an antitussive effect.

Adverse Effects of Opioids

  • Respiratory Depression: Especially at higher doses or with more potent opioids.

  • Excitement or Dysphoria: Common in felines, goats, equids.

  • GI disturbances: Including vomiting and constipation; histamine release can lead to pruritis; potential for tolerance, addiction, or dependence.

Opioid Indications

  • Pre-medication: They form the analgesic component of most pre-medication combinations.

  • Perioperative Analgesia: Most pure Mu agonistic opioids are short-acting, requiring re-administration or continuous rate infusion (CRI).

Routes of Administration for Opioids

  • Administration Methods: IM, SQ, PO, transdermal, epidural, or spinal.

Morphine

  • Overview: Widely used analgesic; cost-effective with good efficacy and tolerable adverse effects.

  • Indications: Effective for mild to severe pain; onset of action varies: IM (30-45 minutes) and IV (5-15 minutes).

  • Re-administration: Needs to be given every 90-120 minutes for intraoperative analgesia.

  • Adverse Effects: Includes vomiting, constipation, and decreased urine output.

Hydromorphone (and Oxymorphone)

  • Comparison to Morphine: Similar to morphine, more potent with a similar duration of action; does not cause histamine release.

  • Adverse Effects: May cause vomiting, and post-operative hyperthermia is especially likely in cats.

Fentanyl

  • Classification: A full Mu agonist, significantly more potent analgesia than morphine.

  • Duration of Action: Short (20-30 minutes); typically used as CRI or in patch form post-op.

  • Usage: Popular for induction combined with benzodiazepines in compromised canines; presents minimal nausea/GI signs or histamine release.

Buprenorphine

  • Classification: Partial Mu agonist with weaker analgesia and a ceiling effect.

  • Receptor Affinity: Higher affinity for Mu receptors than morphine; impacts efficacy when switching from buprenorphine to morphine.

  • Onset and Duration: Slower onset (20-40 minutes), longer duration (6-8 hours); can be dispensed as a home medication (e.g., paste formulation, Simbadol).

Butorphanol

  • Classification: Mu antagonist and kappa agonist.

  • Analgesic Effect: Provides weak analgesia with a ceiling effect but offers stronger sedation; not recommended to mix with pure Mu agonists.

  • Indications: Useful for calming patients in respiratory distress to facilitate examination and radiographs.

Pure Mu Antagonists

  • Naloxone: Commonly used as an emergency reversal agent for opioid effects.

  • Indications: Effective for severe apnea, bradycardia, and hypotension.

  • Duration of Action: Approximately 30 minutes.