Neuropharmacology Flashcards

Flashcards covering anticonvulsants, behavior modifying drugs, and treatment of urination disorders from Dr. Villarino's lecture notes on Neuropharmacology.

Diazepam (lipid solubility)

High lipid solubility, allowing for fast distribution to the CNS, making it the treatment of choice for acute seizures. 

Increases GABA activity - inhibitory NT

Metabolized by the liver

Diazepam (half-life)

Short half-life, requiring frequent administration, thus not suitable as a sole maintenance drug and may require a Constant Rate Infusion (CRI).

Diazepam (adverse effects in dogs)

Sedation (all species).

Binds to plastic

Diazepam (adverse effects in cats)

Sedation, and a rare but fatal idiosyncratic hepatic necrosis that develops early in the course of treatment.

Anesthetic agents (refractory seizures)

Used for extremely refractory seizure cases (e.g., Propofol, Isoflurane). Propofol may cause seizures in cats.

First-line maintenance anticonvulsant

Phenobarbital is typically considered a first-line agent for long-term seizure control.

Second-line maintenance anticonvulsant

Potassium Bromide (KBr) and Levetiracetam are examples of second-line agents for long-term seizure control.

Phenobarbital (mechanism of action)

Acts on GABA-gated chloride channels to increase Cl- permeability, hyperpolarizing neuronal cells, and also inhibits glutamate activity (excitatory neurotransmitter).

Met by cyp 450 (increase: chloramphenicol, ketoconazole, cimetidine)

Large T1/2 = 10 days to steady state

Phenobarbital adverse effects

Polyuria, polydipsia, polyphagia (PU/PD/PP), sedation, and ataxia, which may decrease after a few weeks of initiating therapy.

Dose-related hepatic toxicity (higher risk with plasma concentrations > 30 ug/dL), necessitating monitoring of liver enzymes and function; should not be used if bile acids are elevated.

Can cause immune-mediated neutropenia and/or thrombocytopenia. Bome marro

Bromide (mechanism of action)

Traverses chloride channels, resulting in hyperpolarization (inhibition) of neurons; not metabolized.

Potassium Bromide (KBr)

An oral form of bromide used as a maintenance anticonvulsant.

T1/2 dog = 25 days - 4 mo SS

T1/2 = 10 days - 7 week SS

Sodium Bromide (NaBr)

An injectable form of bromide used as a maintenance anticonvulsant.

Bromide (other adverse effects)

Polyuria, polydipsia, polyphagia (PU/PD), GI signs, pancreatitis, and fatal respiratory distress in 30-50% of cats (contraindicated in cats).

Levetiracetam (Keppra)

An anticonvulsant that interferes with glutamate release by binding to SV2A in the presynaptic vesicle; primarily eliminated renally with no hepatic metabolism.

T1/2 dog = 4 hr cat - 5-6 hr

Levetiracetam (clinical use)

Increasingly used as a first-choice antiepileptic for dogs and cats due to minimal side effects (rarely sedation, vomiting, ataxia) and safety for the liver, though tolerance can develop in some dogs.

May see tolerance build up in dog

Polypharmacy (anticonvulsants)

The use of multiple anticonvulsant drugs, typically initiating with phenobarbital or KBr and adding a second (or third/fourth) drug if seizures persist or side effects are unacceptable.

Behavior Modifying Drugs (mechanism)

Most affect CNS neurotransmitters such as serotonin, dopamine, norepinephrine, and GABA.

Clomipramine (mechanism of action)

Inhibits noradrenaline reuptake (+++) and serotonin reuptake, a tricyclic antidepressant.

Clomipramine (clinical use)

FDA-approved for separation anxiety; extra-label uses include fear, aggression, obsessive-compulsive disorders, self-mutilation, and excess barking; full effect takes several weeks.

Clomipramine (adverse effects)

Narrow therapeutic window; can range from mild (sedation, GI disturbances, lethargy) to fatal (cardiac arrhythmias, hypotension, hypoxia, CNS depression, coma, death at higher doses).

Clomipramine (drug interactions)

Inhibitors or inducers of CYP450 enzymes can alter its concentration; should not be combined with selegiline or other drugs that potentiate norepinephrine or serotonin activity due to risk of serotonin syndrome. 

May lead to serotonin syndrome - sever CNS tox with high mortality rate

Fluoxetine (mechanism of action)

A Selective Serotonin Reuptake Inhibitor (SSRI), which increases serotonin levels in the synaptic cleft.

Fluoxetine (clinical use)

Primarily for separation anxiety; also used extra-label for lick granulomas, tail mutilation, dominance aggression, psychogenic alopecia.

Fluoxetine (adverse effects)

Generally fewer and safer than for TCAs (clomipramine).

Fluoxetine (drug interactions)

Can cause serotonin syndrome if administered with TCAs or monoamine oxidase inhibitors; can inhibit hepatic CYP450 enzymes, leading to toxic levels of other metabolized drugs.

May lead to serotonin sydrome

Trazadone (mechanism of action)

A Serotonin Reuptake Inhibitor and Serotonin receptor antagonist (5-HT2A).

Trazadone (clinical use)

Used for separation anxiety, fear of loud noises (thunderstorms, fireworks), post-surgery recovery, travel anxiety, psychogenic stress in clinics, and to facilitate confinement for orthopedic surgery recovery.

Serotonin Syndrome

A potentially fatal condition due to excess serotonin in the CNS, characterized by hypertension, seizures, tremors, hyperesthesia, ataxia, blindness, GI signs, hypersalivation, hyperthermia.

Selegiline (mechanism of action)

An enzyme inhibitor of monoamine oxidase (MAO), which metabolizes serotonin, dopamine, and norepinephrine.

Selegiline (clinical use)

Used for treating canine cognitive dysfunction; full benefit may take several weeks.

Selegiline (adverse effects)

Generally well tolerated in animals and people.

Serotonin sydrome with very high doses

Dexmedetomidine (Sileo®) (mechanism of action)

A selective alpha2 adrenoceptor agonist that reduces norepinephrine levels in the locus coeruleus, preventing its release.

Dexmedetomidine (clinical use)

Indicated for anxiety and fear, particularly fear of noises.

Dexmedetomidine (contraindications)

Not for use in dogs with severe cardiovascular, respiratory, liver, or kidney disease, or in conditions of shock, severe debilitation, or stress; the gel should be absorbed orally and not swallowed.

Urinary retention (treatment goal)

To relax the sphincter and/or contract the detrusor muscle.

Urinary incontinence (treatment goal)

To contract the urethral sphincter.

Detrusor overactivity (treatment goal)

To relax the detrusor muscle.

Detrusor muscle

The smooth muscle component of the bladder wall responsible for bladder contraction.

Internal urethral sphincter

Smooth muscle located at the bladder neck/proximal urethra, part of the involuntary control of urination.

External urethral sphincter

Striated muscle (urethralis) located in the distal urethra, part of the voluntary control of urination.

Alpha1 (α1) receptors (urinary tract)

Located in the urethral sphincter; agonists contract the sphincter, antagonists relax it.

Muscarinic (M) receptors (urinary tract)

Located in the detrusor muscle; agonists contract the detrusor, antagonists relax it.

Nicotinic (N) receptors (urinary tract)

Antagonists relax the external urethral sphincter.

Phenylpropanolamine (PPA)

An alpha1-agonist drug that constricts the urethral sphincter, used for urinary incontinence; adverse effects include hypertension, GI signs, weight loss, restlessness, mydriasis.

Estrogens (Estriol, Diethylstilbestrol)

Used to increase alpha1-receptor sensitivity and number, helping to constrict the sphincter for urinary incontinence.

Prazosin / Tamsulosin

Alpha1-antagonist drugs that relax the urethral sphincter, used for urinary retention; adverse effects include hypotension, weakness/lethargy, GI signs, third eyelid elevation.

Phenoxybenzamine

A non-selective alpha-antagonist that relaxes the urethral sphincter, used for urinary retention.

Bethanechol chloride

A muscarinic agonist drug that contracts the detrusor, used for bladder hypocontractility; adverse effects include SLUDGE-M (salivation, lacrimation, urination, defecation, GI upset, emesis, miosis), tachycardia.

Propantheline

A muscarinic antagonist drug that relaxes the detrusor, used for detrusor overactivity.

Diazepam / Midazolam (urinary tract)

Nicotinic antagonist drugs that relax the external urethral sphincter, used for urinary retention; adverse effects include sedation, paradoxical excitation, increased appetite, hepatic failure in cats (oral).