Neuroscience Chapter on Neurotransmitters

Drugs Acting on the Central Nervous System

• Drugs can alter CNS function to provide anticonvulsant effects, tranquilization (sedation), and analgesia.
• Neurotransmitters in the CNS include dopamine, GABA, acetylcholine, norepinephrine, serotonin, histamine, glutamate, glycine, substance P and many neuropeptides.
• Neurotransmitters combine with receptors on the postsynaptic neuron, altering membrane potential.
• Receptors for neurotransmitters are the site of action for exogenous drugs.
• The neurotransmitter-receptor complex may directly alter the cell membrane permeability by opening or closing ion channels or initiate a sequence of chemical reactions altering ion transport across the membrane to change membrane potential.
• Second messenger molecules and systems are generated and sustain and amplify the cellular response to drug-receptor binding.
• Many neurotransmitters have G protein-coupled receptors (GPCRs).
• Circulating drugs must cross the blood-brain barrier (BBB) to gain access to the neurons in the brain.
• Drugs that readily cross the BBB are usually lipid-soluble, small in molecular size, poorly bound to protein, and nonionized at the pH of cerebrospinal fluid (CSF).
• The BBB is typically poorly developed in neonates.
• The BBB tends to increase permeability at sites of inflammation and tumors.
• Only some anticonvulsant drugs available for human use are clinically useful in dogs and cats.
• Some drugs are rapidly metabolized in dogs even at high dosages.
• Cats generally metabolize drugs more slowly and poorly than dogs.
• Anticonvulsant drugs stabilize neuronal membranes directly acting on ion channels inducing hyperpolarization of neuronal membranes.
• Anticonvulsant drugs activate GABA-gated CL-channels increasing the frequency of CL-channel opening.
• Anticonvulsant therapeutic uses reduce the incidence, severity, and duration of seizures.
• Anticonvulsant adverse effects include seizures or status epilepticus following rapid cessation of administration, enzyme induction, and hepatoxicity.

Barbiturates

• Phenobarbital is an oxybarbiturate.
• Barbiturates activate GABA-gated Cl- channels causing hyperpolarization of the neurons.
• Phenobarbital limits the spread of action potentials, increasing seizure threshold.
• Often used for long-term seizure control but administration until onset of effect is slow (~20 minutes).
• GI absorption is practically complete in all animals, and maximum levels occur in dogs between 4-8 hours.
• Common side effects include sedation, polydipsia, polyuria, and polyphagia.
• Dogs develop tolerance to sedative effects after 1-2 weeks.

Primidone

• Primidone is a deoxybarbiturate (an analog of phenobarbital).
• Primidone slowly absorbed in dogs.
• Metabolism to phenobarbital is slower in cats.
• Prolonged use of Primidone in dogs can cause decreased serum albumin and elevated serum liver enzymes and can ocasionally cause severe liver damage.

Pentobarbital

• Pentobarbital is an oxybarbiturate.
• Used to terminate seizures, but the therapeutic dose commonly induces anesthesia.
• Known for rapid onset (~<1 minute) after IV injection and short duration of action.
• Causes CNS depression, irritating when administered perivascularly.

Phenytoin

• Phenytoin is a hydantoin derivative.
• Phenytoin stabilizes neuronal membranes and limits development and spread of seizure activity.
• Its effect includes reduction of Na+ influx during action potential, reduction of Ca2+ influx during depolarization, promotion of Na+ efflux and inhibition of seizure activity.
• K+ movement out of the cell during action potential may be delayed, increasing refractory period and decreasing repetitive depolarization.
• Phenytoin is used as an anticonvulsant, however, because of its short half-life, its use in dogs may be impractical.
• Recommended for treating digitalis-induced ventricular arrhythmias.

Benzodiazepines

• Diazepam, midazepam, clonazepam, and lorazepam are used as anticonvulsants.
• Effective for status epilepticus (continuous seizure activity).
• Used as maintenance anticonvulsant in cats but use is limited in dogs due to rapid drug tolerance development.
• Benzodiazepines activate GABA-gated Cl- channels potentiating the channel opening activity of GABA resulting in hyperpolarization of the neurons.
• Cats given Diazepam is usually given orally for seizure control, dogs is given IV for status epilepticus and cluster seizures, Diazepam can be used as maintenance anticonvulsant, given that it has a short half-life (2-4 hours).
• Common side effects include changes in behavior, depression, and aberrant demeanor.
• Cats may develop acute fatal hepatic necrosis.
• Midazolam has a shorter elimination half-life (77 minutes in dogs—shorter than Diazepam’s ~3 hours), easily crosses the BBB.
• Used for anticonvulsives for status epilepticus, muscle relaxant, tranquilizer and appetite stimulant.
• Clonazepam has limited value as a maintenance anticonvulsant because of rapid tolerance development.
• Common side effects include GI disturbances (e.g., vomiting, hyper-salivation).
• Lorazepam mechanism of action similarly involves activating GABA-gated Cl- channels.
• Lorazepam can be used orally (cats) for seizure control, intravenously for status epilepticus and seizures cluster, and as a maintenance anticonvulsant (dogs) due to short half-life (2-4 hours).

Valproic acid and sodium valproate

• Valproic acid is a derivative of carboxylic acid and structurally unrelated to other anticonvulsant drugs.
• Effective in controlling seizures in dogs when given orally.
• Short half-life makes it impractical for long-term use in dogs. It is usually considered a second- or third-line anticonvulsant in dogs.
• Potential usefulness as an adjunctive therapy in some dogs.
• Use and clinical value in cats not determined.
• Potential adverse effects include Gl disturbances, hepatoxicity (including liver failure), central nervous system effects (e.g., sedation and ataxia), dermatologic effects (e.g., alopecia, rash), and hematologic effects (e.g., thrombocytopenia, leukopenia, anemia).

Gabapentin

• Gabapentin is a synthetic GABA analog that crosses the BBB affecting anticonvulsant effects.
• Its mechanism of action involves increase in GABA content in neurons and inhibition of voltage-dependent Ca2+ channels in neurons; this reduces neuronal Ca2+ levels, which thereby inhibits excitatory neurotransmitter release, e.g., glutamate.
• Useful as an adjunct therapy for refractory or complex partial seizures, or for chronic pain treatment in dogs and cats.
• Administered orally.
• Common side effects include sedation, ataxia, and mild polyphagia.

Levetiracetam

• Levetiracetam is used as an adjunct therapy for refractory canine epilepsy and well tolerated in dogs. An initial prospective trial in cats was favorable.
• Levetiracetam inhibits hypersynchronization of epileptiform burst firing and propagation of seizure activity.
• It binds to synaptic vesicle protein 2A in neurons, and this interaction with neuronal vesicular protein may account for levetiracetam's anticonvulsant effect.
• Common side effects include minimal changes in behavior, drowsiness, and Gl disturbances (vomiting and anorexia).
• Withdrawal of this drug should be slow in order to prevent "withdrawal" seizures.

Felbamate

• Felbamate is a dicarbamate drug used orally to treat refractory epilepsy in dogs.
• Felbamate does not induce sedation at clinical doses, useful to control obtunded mental status due to brain tumor or cerebral infarct.
• It blocks NMDA receptor-mediated neuronal excitation, and enhances inhibition of GABA-mediated neuronal inhibition and also inhibits voltage-dependent Na+ and Ca2+ channels.
• Potential adverse effects include liver dysfunction (hepatotoxicity), reversible bone marrow depression (thrombocytopenia, leukopenia), and keratoconjunctivitis sicca, and generalized tremor effects.

Zonisamide

• Zonisamide is a sulfonamide-based anticonvulsant drug or adjunct therapy to control refractory epilepsy in dogs with minimal adverse effects,
• It's administered orally (twice daily).
• Its mechanism of action involves inhibiting voltage-dependent Na+ and Ca2+ channels of neurons to induce hyperpolarization and decreased Ca2+ influx.
• Potential adverse effects are not extensively studied in cats.

CNS Stimulants (Analeptics)

• Doxapram is CNS stimulant used to arouse animals from inhalant and parenteral anesthesia or anesthetic overdose.
• Doxapram mechanism of action involves directly stimulating medullary respiratory centers, and probably through activation of carotid and aortic chemoreceptors.
• Depth of anesthesia is reduced but the effect may be transient.
• Doxapram is not effective in reviving seriously depressed neonates and not a good substitute for endotracheal intubation and ventilation.
• High doses of doxapram may induce seizures and also cause hypertension, arrhythmias, and hyperventilation leading to respiratory alkalosis.

Tranquilizers, Atacics, Neuroleptics, and Sedatives

• These terms are commonly used interchangeably to refer to medications that calm and promote sleep but do not always cause sleep
• Neuroleptic means to "take hold of nerves."
• Used as pre-anesthetic medications enabling a use of less general anesthetic

Phenothiazine Derivatives

• Phenothiazine derivatives include acepromazine, promethazine, chlorpromazine, fluphenazine, prochlorperazine, and trimeprazine.
• These drugs affect the CNS at the basal ganglia, hypothalamus, limbic system, brain stem, and reticular activating systems.
• They block dopamine, α1-adrenergic, and serotonergic receptors.
• CNS effects include tranquilizing effects, decrease in spontaneous motor activity, hypotension due to α1-adrenergic receptor blockade and reflex sinus, antiarrhythmic and inotropic effects.
• Respiratory depression, decreased Gl motility, and inhibition of emesis are common.
• Effects on blood: decrease in packed cell volume.
• Metabolic effects: hypothermia, hyperthermia, hyperglycemia, and hyperprolactinemia are seen.

Opioids

• Opioids are used for analgesia (reducing pain), preanesthetic medication (reducing anxiety and stress before surgery), and induction/maintenance of anesthesia.

• Opioid receptors are located in the brain, spinal cord, urinary tract, GI tract, and vas deferens

• There are at least 3 major subtypes of opioid receptors (µ, к, δ).

• Mu (µ)-receptors and Kappa (к)-receptors are located throughout the brain/CNS, and deltas (δ)-receptors reside in the limbic system of the brain.

• Opioids cause analgesic effects by activating and/or antagonizing these receptors.

• Opioids (e.g., morphine) are respiratory depressants decreasing arterial Co2 tension and arterial O2 tension, lowering pH.

• In dogs, opioids will cause panting in an attempt to regulate temperature.

• Cardiovascular effects (e.g., decreased heart rate and hypotension) are often noted.

• Analgesia effect lasts less than that of elimination t.

• GI effects include antidiarrheal and constipation.

• Opioid adverse effects include hyperexcitability, hypotension, cerebral hemorrhage and edema.

• Tramadol, Methadone, Oxymorphone, Hydromorphone, Fentanyl, Alfentanil, Sufentanil, Carfentanil.

Opioid partial agonists

• Butorphanol is a partial agonist for µ receptors but a full agonist for k-receptors.
• Used to reverse μ effects of other opioids such as morphine, and oxymorphone; it maintains some analgesia (k effect) which is 4-7 times more potent than morphine.
• Indicated for analgesia, antitussives, and antiemetics
• Can induce mild adverse effects such as sedation, ataxia, anorexia and diarrhea in dogs and cats; in horses, includes ataxia, sedation, and increased GI motility and ileus (due to prolonged use).

Opioid agonist-antagonist drugs

• Nalbuphine and buprenorphine are opioid agonist-antagonists.
• Nalbuphine is an agonist at the к receptor and antagonist at the μ receptor.
• Buprenorphine is a partial agonist at the µ receptor and an antagonist at the к receptor.
• Naloxone is a long acting μ, κ, and δ receptor antagonist and reverses opioid-induced depression and respiratory depression.
• Naltrexone is a long-lasting opioid receptor antagonist and can be given IV or IM to reverse opioid-induced immobilization/depression, especially in wildlife or large animals.
• It can also treat certain behavioral problems in dogs such as excessive licking or tail chasing.
• Naloxone is relatively free of adverse effects.

Anxiolytic Drugs and Antidepressants

• The pages do not contain detailed information for these categories.

α2-Adrenergic Agonists

• These drugs act on a2 adrenergic receptors in CNS to produce analgesic/sedative/relaxation
• Ruminants, followed by cats, dogs, and horses are most sensitive to a2-agonists; Pigs, least sensitive.
• High doses can induce CNS excitation.
• Produce skeletal muscle relaxation by inhibiting intraneuronal transmission.
• Can induce emesis and cardiovascular effects (bradycardia, hypertension, hypotension).

Xylazine

• Approved by FDA for use in cats, dogs, horses, and wildlife.
• Common adverse effects include GI stasis leading to bloat, bradycardia with sinus arrhythmia/arrest, hypothermia, or hyperthermia.
• Contraindicated in animals with cardiac aberrations, hypotension, shock, renal insufficiency, hepatic impairment, or pre-existing epilepsy

Detomidine

• Approved by FDA for use in horses.
• Common adverse effects include piloerection, sweating, partial penis prolapse, salivation, muscle tremors, CNS excitation.
• IV sulfonamides given in detomidine-treated horses (potentiating fatal dysrhythmias)
• Potent α2-agonist
• Adverse effects are similar to xylazine.

Medetomidine

• Potent and selective a2-agonist—induces a light anesthesia, common in examinations/procedures in some animals.
• Adverse effects are similar to xylazine and detomidine

Romifidine

• For use in horses, has similar adverse effects that of xylazine and detomidine.

Test your knowledge on neurotransmitters and their functions within the central nervous system. This quiz examines key concepts related to drug actions, the blood-brain barrier, and therapeutic effects. Assess your understanding of how these elements interact in the realm of neuroscience.