Lecture 5- Nervous System Drug Overview 1

Blood-brain barrier: what crosses best

Lipid-soluble, small, non-ionized, poorly protein-bound substances; BBB compromised with inflammation/injury; poorly developed in neonates.

Definition of seizure

Sudden burst of uncontrolled electrical activity due to excessive neuronal excitation.

General anticonvulsant goal

Stabilize neuronal membrane potential and decrease excitability.

Major inhibitory neurotransmitter

GABA acting on GABA-A receptors.

Major excitatory neurotransmitter

Glutamate acting on NMDA and other receptors.

Ways anticonvulsants decrease excitation

Sodium channel blockers, calcium channel blockers, glutamate antagonists, vesicle release inhibitors.

Ways anticonvulsants increase inhibition

GABA enhancers (benzodiazepines, barbiturates), miscellaneous ASMs.

Diazepam vs midazolam: solubility

Diazepam poorly water soluble; midazolam water soluble.

Diazepam vs midazolam: routes

Diazepam IV/rectal; midazolam IV, IM, SQ, intranasal.

Diazepam vs midazolam: duration

Both short; diazepam limited by redistribution.

Diazepam vs midazolam: major concern

Respiratory and CNS depression.

Diazepam: metabolism

CYP450; active metabolites.

Midazolam: metabolism

CYP450; more rapid clearance.

Benzodiazepine mechanism

Bind BZD site on GABA-A receptor → increase frequency of Cl⁻ channel opening → hyperpolarization.

Barbiturate mechanism

Bind barbiturate site on GABA-A receptor → increase duration of Cl⁻ channel opening; some anti-glutamate effects.

Benzodiazepine indications

Acute seizure control, sedation, anesthetic adjunct, muscle relaxation, behavioral disorders.

Why benzodiazepines are poor for chronic seizure control

Tolerance develops.

Diazepam feline toxicity

Oral diazepam can cause acute fatal hepatic necrosis in cats.

Benzodiazepine contraindications

Liver disease; lipophilicity causes adherence to plastic; precipitation in aqueous solutions.

Phenobarbital mechanism

Enhances GABA-A receptor activity; increases Cl⁻ channel opening duration; some anti-glutamate effects.

Phenobarbital absorption

High oral absorption; peak 4–6 hours.

Phenobarbital distribution

Wide distribution; 40–50% protein bound.

Phenobarbital metabolism

Hepatic CYP450 induction; long half-life (40–90 h dog, 40–50 h cat).

Phenobarbital steady state

10–20 days.

Phenobarbital side effects

Sedation (tolerance develops), PU/PD/PP/panting, hepatotoxicity, ↑ALP, altered bile acids, ↓BUN/albumin, thyroid test interference, bone marrow dyscrasia.

Phenobarbital contraindications

Liver disease.

Phenobarbital drug interactions

Strong CYP450 inducer → increases clearance of theophylline, digoxin, anesthetics, other P450 substrates.

Phenobarbital diet interactions

Low-fat diet increases clearance; alkaline urine increases clearance.

Potassium bromide mechanism

Br⁻ enters neuron via Cl⁻ channels → hyperpolarization → increased seizure threshold.

Potassium bromide synergy

Synergistic with barbiturates and benzodiazepines.

Potassium bromide indications

Maintenance therapy for refractory seizures in dogs/horses; alternative when phenobarbital contraindicated.

Potassium bromide elimination

Renal; not metabolized; competes with chloride.

Potassium bromide half-life

Very long; 3–4 months to steady state without loading.

Potassium bromide diet interaction

High chloride diet increases elimination → lower Br⁻ levels.

Potassium bromide feline toxicity

Severe asthma risk → generally avoided in cats.

Potassium bromide side effects

Sedation, lethargy, irritability, GI upset, pancreatitis risk, PU/PD/PP, neurologic toxicosis, false ↑Cl⁻ on chemistry.

Levetiracetam mechanism

SV2A vesicle release inhibitor → reduces excitatory neurotransmission.

Levetiracetam advantages

Few drug interactions; renal elimination.

Levetiracetam limitations

Short half-life; adherence issues; variable evidence.

Zonisamide mechanism

Sodium and calcium channel blocker; sulfonamide derivative.

Zonisamide limitations

Sulfonamide-related adverse effects; hepatic effects.

Rapid rescue seizure drugs

Diazepam, midazolam.

Immediate recurrence prevention

Phenobarbital, levetiracetam.

Chronic maintenance drugs

Phenobarbital, potassium bromide, levetiracetam, zonisamide.

Equine seizure rescue doses

Diazepam 0.05–0.44 mg/kg IV; midazolam 0.05–0.1 mg/kg IV.

Equine phenobarbital dosing

Loading 5 mg/kg IV; maintenance 2–10 mg/kg PO q8–12h.

Equine bromide dosing

Potassium bromide 60–90 mg/kg PO; sodium bromide 60–90 mg/kg IV.

Definitions: anxiolysis

Reduction in fear/anxiety.

Definitions: tranquilization

Reduced behavioral reactivity without marked drowsiness.

Definitions: sedation

Reduced arousal and activity.

Definitions: analgesia

Reduction in pain perception.

Definitions: chemical restraint

Drug-facilitated control for safe procedure performance.

Acepromazine mechanism

D2, 5HT1/2, α1, H1, muscarinic antagonist.

Acepromazine uses

Light sedation, tranquilization/anxiolysis; no analgesia.

Acepromazine side effects

Splenic engorgement, vasodilation, ↓MAP, penile prolapse/paraphimosis in male horses.

Acepromazine dose

0.01–0.05 mg/kg IM; lasts 6–8 hours.

Equine benzodiazepine uses

Induction adjunct, muscle relaxant, anticonvulsant; neonatal foal sedation.

Alpha-2 agonists: examples

Xylazine, detomidine, romifidine.

Alpha-2 agonists: uses

Sedation, analgesia, anesthesia adjunct.

Alpha-2 agonists: side effects

Bradycardia, arrhythmias.

Alpha-2 agonists: contraindications

Neonates, cardiac disease.

Alpha-2 agonists: human risk

Accidental needle stick → severe sedation.

Butorphanol use

Combined with alpha-2 agonists; prolongs sedation, adds analgesia, reduces coughing.

Romifidine competition rule issue

Sedation/analgesia may mask lameness and pose safety risks; not FDA-approved in US.

Xylazine illicit drug issue

Increasingly found in illicit fentanyl samples; human health concern.

Equine sedation doses

Xylazine 0.2–1 mg/kg IV; detomidine 0.005–0.01 mg/kg IV; romifidine 0.04–0.12 mg/kg IV; butorphanol 0.01–0.1 mg/kg IV.

Buscopan equine use

0.3 mg/kg IV; smooth muscle relaxant for rectal exam.

Lidocaine rectal use

50–60 cc per rectum for exam comfort.

Key exam trap: diazepam in cats

Oral diazepam → acute fatal hepatic necrosis.

Key exam trap: bromide in cats

Causes life-threatening asthma.

Key exam trap: phenobarbital

Strong CYP450 inducer → many drug interactions.

Key exam trap: acepromazine

Causes penile prolapse in male horses.

Key exam trap: alpha-2 agonists

Contraindicated in neonates; profound bradycardia.

Key exam trap: benzodiazepines

Tolerance prevents long-term seizure control.

Key exam trap: bromide diet

High chloride diet → rapid elimination → breakthrough seizures.