. Drugs can alter the function of the central nervous system (CNS) to provide
1. Anticonvulsant effects
2. Tranquilization (sedation)
B. Neurotransmitter–receptor relationship
. Neurotransmitters released by a presynaptic neuron combine with receptors on the plasma membrane of a postsynaptic neuron, altering its membrane potential.
1. Neurotransmitters in the CNS include dopamine, γ-aminobutyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin, histamine, glutamate, glycine, substance P, and many neuropeptides.
. Receptors for neurotransmitters are the site of action for exogenous drugs.
a. The neurotransmitter–receptor complex may directly alter the permeability of the cell membrane by opening or closing specific ion channels.
b. Second messengers. The neurotransmitter-receptor complex may initiate a sequence of chemical reactions that alter ion transport across the membrane, thereby altering the membrane potential. Specific intracellular signal molecules, or second messengers, may be generated. The second messenger system sustains and amplifies the cellular response to drug–receptor binding (see Chapter 1). The vast majority of these neurotransmitters have G protein-coupled receptors (GPCRs).
C. Blood–brain barrier (BBB)
. Circulating drugs must cross BBB in order to gain access to the neurons of the brain.
1. Drugs that are lipid soluble, small in molecular size, poorly bound to protein, and nonionized at the pH of cerebrospinal fluid (CSF) will cross BBB most readily.
2. The BBB tends to increase in permeability in the presence of inflammation or at the site of tumors.
3. The BBB is poorly developed in neonates; hence, chemicals can easily gain access to the neonatal brain.
A. General features
. Only a few of the anticonvulsant drugs available for human use have been proven to be clinically useful in dogs and cats.
a. Some of the drugs are too rapidly metabolized in dogs to be effective, even at high dosages.
b. Clinical experience and pharmacokinetic data are unavailable for many of these compounds in cats. Cats are generally assumed to metabolize drugs more slowly and poorly than dogs.
2. Mechanism of action
. Anticonvulsant drugs stabilize neuronal membranes.
a. They may act directly on ion channels, resulting in hyperpolarization of the neuronal membrane.
b. They activate GABA-gated Cl− channels increasing the frequency of Cl− channel opening produced by GABA, thereby evoking hyperpolarization of the neurons.
3. Therapeutic uses. Anticonvulsant drugs reduce the incidence, severity, or duration of seizures.
. Plasma concentrations of anticonvulsant drugs should be adequate to ensure an effective concentration in the brain. Treatment for at least five half-lives must occur before stable plasma levels of these drugs are achieved; thus, serum analyses for drug concentrations are beneficial.
(1) Trough concentrations should be within the therapeutic range.
(2) Peak concentrations should be below toxic levels.
b. Drugs with long-elimination t½ are more convenient to use in veterinary medicine because owners are usually only able to administer the drug 2–3 times daily.
5. Adverse effects
a. Withdrawal symptoms, seizures, or status epilepticus may follow rapid cessation of administration of these drugs.
. A lowered seizure threshold, precipitating seizures in an otherwise well-controlled patient, may follow the administration of other drugs, such as
(1) Phenothiazine tranquilizers (e.g., acepromazine)
(2) Some antiparasitic drugs (e.g., pyrantel, levamisole, pyrethroids, methoxychlor, lindane, and anticholinesterases).
(3) Metoclopramide, a dopamine receptor antagonist, is used to increase gastrointestinal (GI) motility.
c. Enzyme induction
(1) Phenobarbital, primidone, and phenytoin increase the cytochrome P450 enzymes of the liver. This enzyme induction may increase the biotransformation of other endogenous and exogenous chemicals.
(2) Membrane-bound enzymes (e.g., alkaline phosphatase) can also be induced, leading to increases in serum concentrations that could be mistaken as an indication of liver injury.
is the most common adverse effect of anticonvulsant therapy in dogs. It develops in 6–15% of dogs treated with primidone alone or in combination with phenytoin.
The liver should be evaluated every 6–12 months for signs of toxicity, including
(a) Elevated serum enzyme concentrations, particularly alanine transaminase (ALT) and glutamyl transferase activity.
(b) Rising serum phenobarbital concentrations in dogs receiving a constant dosage.
(c) Decreasing serum albumin concentrations.
(d) Elevated postprandial serum concentration of bile acids.
(2) If hepatotoxicity is detected, the dosage of primidone or phenobarbital should be decreased and KBr therapy implemented.
a. Chemistry. Phenobarbital is an oxybarbiturate.
b. Mechanism of action. Barbiturates activate GABA-gated Cl− channels, thereby evoking hyperpolarization of the neurons.
c. Pharmacologic effects
(1) Phenobarbital limits the spread of action potentials and thus elevates the seizure threshold.
(2) Most barbiturates have anticonvulsant effects, but phenobarbital is unique in that it usually produces this effect at lower doses than those necessary to cause pronounced CNS depression (sedation).
d. Therapeutic uses. Phenobarbital is used for the long-term control of seizures. It is not useful for terminating an ongoing seizure because the time span from administration until the onset of effect is too long (~20 minutes).
(1) When given orally, its GI absorption is practically complete in all animals. Peak levels occur in 4–8 hours after oral dosing in dogs.
(2) It is widely distributed throughout the body, but because of its lower lipid solubility, it does not distribute as rapidly as most other barbiturates into the CNS. The amount of phenobarbital bound to albumin is 40–50%.
(3) The oxybarbiturates are primarily metabolized in the liver. The major metabolite of phenobarbital is a parahydroxyphenyl derivative that is inactive and excreted in the urine.
(4) Hepatic cytochrome P450 enzyme activity is increased by chronic administration of barbiturates, producing increased rates of barbiturate metabolism as well as increased metabolism of other drugs.
(5) Hepatic cytochrome P450 enzyme activity is inhibited by certain drugs (e.g., chloramphenicol; see Chapters 1 and 19), thereby decreasing the elimination rate of barbiturates.
(6) The elimination t½: dogs, 32–90 hours; cats, 34–43 hours; horses, 13–18 hours.
(1) Phenobarbital is usually administered orally, but can be injected IV or IM.
(2) A serum drug concentration of 15–45 μg/mL is usually effective in controlling seizures; however, because of phenobarbital’s long t½, 14 days of therapy are required to develop a steady serum concentration.
g. Adverse effects
(1) Sedation, polydipsia, polyuria, and polyphagia are common side effects. Dogs develop a tolerance to the sedative effects after 1–2 weeks, but cats may experience more pronounced sedation with longer duration.
(2) Hepatotoxicity. Chronic administration to dogs may result in elevated serum concentrations of hepatic enzymes, for example, alkaline phosphatase and alanine tranaminase (ALT) and, in a small percentage of cases, liver damage.
(3) Patients on phenobarbital may show a small decrease in serum thyroid hormone levels and an increase in plasma thyroid-stimulating hormone (TSH) levels. The decrease in thyroid hormone levels is attributed to the increase in liver enzymes that metabolize these hormones.
. It was a commonly used antiepileptic drug in dogs, but it is rarely used to control seizures.
a. Chemistry. Primidone is a deoxybarbiturate (an analog of phenobarbital).
(1) Primidone is slowly absorbed after oral administration in dogs, with peak levels occurring 2–4 hours after dosing.
(2) In dogs, primidone is rapidly metabolized by the liver to phenylethylmalonamide (PEMA) and phenobarbital. Primidone, PEMA, and phenobarbital are all anticonvulsants, but the t½ of the first two are too short for them to be effective. The potency of primidone and PEMA is only 1/30 that of phenobarbital. Thus, ~85% of the anticonvulsant activity of primidone is attributable to phenobarbital.
(3) In cats, the metabolism to phenobarbital is slower and the t½ is very long; thus, primidone should not be used in this species.
c. Administration. In dogs, an oral dose of 4–5 mg of primidone will produce a serum phenobarbital concentration that is equivalent to an oral dose of 1 mg of phenobarbital.
d. Adverse effects. Prolonged use of primidone in dogs may lead to decreased serum albumin and elevated serum concentrations of liver enzymes. Occasionally, serious liver damage occurs.
a. Chemistry. Pentobarbital is an oxybarbiturate.
b. Therapeutic uses
. Pentobarbital will terminate seizures at a dose that produces anesthesia. This dose usually results in significant cardiopulmonary depression but may be the only way to control status epilepticus, if a benzodiazepine fails to work. However, there are two following problems associated with pentobarbital in the treatment of status epilepticus:
(1) IV pentobarbital (2–6 mg/kg) requires 15–20 minutes to take effect; ≥6 mg/kg can cause cardiopulmonary depression.
(2) IV pentobarbital induces paddling reflex activity during recovery; such activity may be confused with continued seizure activity.
. It has a rapid onset (< 1 minute) after IV injection and short duration of action.
(1) It is distributed rapidly to all body tissues with highest concentrations found in the liver and brain. It is ~40% bound to albumin.
(2) It is metabolized in the liver mainly by oxidation via cytochrome P450 enzymes. The t½ in dogs is ~8 hours.
d. Administration. Pentobarbital is administered IV.
e. Adverse effects
Pentobarbital is a CNS depressant; close monitoring and respiratory assistance must be readily available. It may cause excitement during recovery from anesthesia. Hypothermia may develop in animals receiving pentobarbital, if exposed to temperatures <27°C. The barbiturates can be very irritating when administered perivascularly.
1. Chemistry. Phenytoin is a hydantoin derivative.
2. Mechanism of action
. Phenytoin stabilizes neuronal membranes and limits the development and spread of seizure activity.
a. It reduces Na+ influx during the action potential, reduces Ca2+ influx during depolarization, and promotes Na+ efflux. The resultant effect is an inhibition of the spread of seizure activity.
b. K+ movement out of the cell during the action potential may be delayed, producing an increased refractory period and a decrease in repetitive depolarization.
3. Therapeutic uses
a. Phenytoin is an anticonvulsant drug; however, because of its short t½ in dogs, use of phenytoin may be impractical.
b. Because of its lidocaine-like effects, phenytoin has been recommended for the treatment of digitalis-induced ventricular arrhythmias in dogs (see Chapter 8).
a. After oral administration, phenytoin is 40% absorbed in dogs. Phenytoin is well distributed throughout the body and is ~80% bound to albumin in dogs.
b. It is metabolized in the liver and with much of the drug conjugated to a glucuronide form and then excreted by the kidneys. Phenytoin induces hepatic cytochrome P450 enzymes, which may enhance the metabolism of itself and other drugs.
c. The plasma t½ are 3–7 hours in dogs, 8 hours in horses, and 42–108 hours in cats. Because of the pronounced hepatic enzyme induction in dogs, phenytoin metabolism is increased with shorter t½ within 7–9 days after the beginning dose.
(see also IV C)
1. General consideration
a. Diazepam, midazepam, clonazepam, and lorazepam are used as anticonvulsants.
b. They are the preferred drugs for the treatment of status epilepticus (continuous seizure activity lasting >5 minutes or recurrent seizures between which the patient does not fully recover) and cluster seizures (≥2 discrete seizure events within a 24-hour period).
c. They can be used as a maintenance anticonvulsant in cats. However, they have a very limited use as a maintenance anticonvulsant in dogs, because the development of tolerance occurs rapidly in this species due to drug metabolism into inactive metabolites. In contrast, cats metabolize benzodiazepines poorly and thus do not have problems with these drugs as dogs do.
a. Mechanism of action. Benzodiazepines activate GABA-gated Cl− channels to potentiate the channel opening activity of GABA, thereby evoking hyperpolarization of the neurons.
b. Therapeutic uses and administration
. Diazepam is used as an anticonvulsant, muscle relaxant, tranquilizer, and appetite stimulant.
(1) In cats, it is administered orally for seizure control. The longer t½ and lower incidence of developing tolerance make diazepam clinically useful for long-term seizure control in cats.
(2) In dogs, it is administered IV for the control of status epilepticus and cluster seizures.
(3) Diazepam is well absorbed after intrarectal administration, and thus can be used as an at-home treatment of animals with cluster seizures. Other benzodiazepines are not well absorbed after this route.
(4) It is not used orally in dogs as a maintenance anticonvulsant because it has a short t½ of 2–4 hours and its tendency to develop tolerance in this species due to drug metabolism.
. Diazepam is dissolved in propylene glycol and Na benzoate for injection.
(a) Because of its poor water solubility, diazepam solution (in propylene glycol) via the IM route is slowly absorbed.
(b) Diazepam is very lipid soluble and rapidly crosses BBB.
(2) Distribution. It is highly (> 85%) albumin bound.
(3) Metabolism and excretion. Diazepam is metabolized in the liver to several metabolites, including desmethyldiazepam (nordiazepam), temazepam, and oxazepam, all of which are pharmacologically active. These metabolites are conjugated to glucuronide and excreted by the kidneys.
(4) The plasma t½ of diazepam: dogs, 2–4 hours; cats, 5.5 hours; horses, 7–22 hours. The plasma t½ of nordiazepam: dogs, ~3 hours; cats, ~24 hours.
d. Adverse effects
(1) Changes in behavior (irritability, depression, and aberrant demeanor) may occur after receiving diazepam.
(2) Cats may develop acute fatal hepatic necrosis after receiving oral diazepam for several days. As a result, some neurologists do not recommend the use of diazepam as a maintenance anticonvulsant in cats.
(3) Complications related to the propylene glycol carrier include venous thrombosis, transient cardiovascular depression, and arrhythmias following rapid IV injection.
. It is more potent than diazepam for its anticonvulsant/sedative effects, but its duration of action is shorter than diazepam
a. Therapeutic uses. Midazolam is used as an anticonvulsant for status epilepticus, muscle relaxant, tranquilizer, and appetite stimulant the same way as diazepam.
. Midazolam has a shorter elimination t½
minutes in dogs, which is shorter than diazepam (~3 hours).
(1) Distribution. At low pH values (<4.0), midazolam is water soluble, but at higher pH values, it is lipid soluble. Thus, in the bottle (pH = 3.5), it is an aqueous solution, but in the body (pH =7.4), it is lipid soluble and readily crosses BBB and cell membranes. A total of 95% of midazolam is bound by albumin.
(2) Metabolism and excretion. Midazolam is metabolized by cytochrome P450 enzymes. An active metabolite α-hydroxymidazolam has less pharmacologic effect than the parent drug. The metabolites are conjugated to glucuronide and excreted by the kidneys.
c. Administration. It is administered IM or IV.
d. Adverse effects. Midazolam may cause mild respiratory depression, vomiting, restless behavior, agitation, and local irritation.
a. Therapeutic uses. The uses are the same as diazepam without distinct advantages over diazepam. It is administered orally or IV. IV administration is for the treatment of status epilepticus. However, clonazepam injectable is not available in the United States. It can be used as an adjunctive therapy to be in combination with phenobarbital in order to reduce the dosage of the latter. Clonazepam alone has very limited value as a maintenance anticonvulsant because of the rapid development of drug tolerance.
b. Pharmacokinetics. It is well absorbed from the GI tract; crosses BBB and placenta. A total of 85% of clonazepam is bound by albumin. It is metabolized in the liver by cytochrome P450 enzymes to several metabolites that are excreted in the urine. Peak plasma levels occur ~3 hours after oral administration. The t½ ranges from 20 to 40 hours in humans. No information is available for animals.
c. Adverse effects. Tolerance to the anticonvulsant effects of clonazepam has been reported in dogs, which is usually noted after weeks of therapy. GI disturbances, including vomiting, hypersalivation, and diarrhea/constipation may occur.
a. Therapeutic uses
(1) It can be administered orally for a short-term at-home treatment of dogs having cluster seizures.
(2) It is also useful in cats as a maintenance anticonvulsant, and the chances of developing idiopathic hepatic necrosis are minimal.
(3) It may be safely used in individuals with compromised liver function and in geriatric dogs because it does not produce active metabolites.
(1) After oral administration, it is rapidly absorbed from the GI tract in dogs, although, to a lesser degree in cats. The time to peak plasma concentrations is ~2 hours.
(2) Approximately 85% of lorazepam is bound by albumin.
(3) It is primarily metabolized to its glucuronide conjugation in dogs and cats. The formation of the conjugate is much faster in dogs as compared to humans and cats.
(4) It is excreted primarily in the urine and to a lesser extent in the feces of dogs. In cats, the drug is excreted in equal parts in both feces and urine.
(5) In humans, the mean t½ is ~12 hours, whereas t½ of lorazepam glucuronide is ~18 hours. No information is available for animals.
c. Adverse effects. Increased appetite, paradoxical excitation, and anxiety have been reported to occur early in therapy, although they resolve with continued use or by decreasing the dose.
E. Potassium bromide (KBr)
1. Mechanism of action
a. It is hypothesized that Br− enters neurons via Cl− channels, resulting in hyperpolarization of the neuronal membrane.
b. Barbiturates and benzodiazepines, which enhance Cl− conductance, may act in synergy with KBr to hyperpolarize neurons, thus raising the seizure threshold.
2. Therapeutic uses
a. KBr is administered orally to treat refractory seizures in dogs. The use in cats is not recommended, since it evokes severe asthma in this species.
b. It is used in combination with phenobarbital to terminate refractory generalized tonic-clonic convulsions in dogs.
a. Absorption. Br− is quickly absorbed from the GI tract following oral administration.
b. Metabolism. Br− is neither metabolized nor bound to plasma proteins. It has a long t½ (25 days in dogs and 10 days in cats), and it may take up to 6 months to achieve stable plasma Br− concentrations.
c. Elimination. Br− is eliminated exclusively by the kidneys.
4. Adverse effects
a. Transient sedation at the beginning of therapy may occur.
b. GI effects. Stomach irritation can produce nausea and vomiting. Vomiting, anorexia, and constipation are indications of toxicity.
c. Polydipsia, polyuria, polyphagia, lethargy, irritability, and aimless walking are additional adverse effects of Br−.
d. Pancreatitis may be precipitated by Br−.
e. Severe asthma can be seen in Br−-treated cats.
F. Valproic acid and sodium valproate
1. Chemistry. Valproic acid is a derivative of carboxylic acid. It is structurally unrelated to other anticonvulsant drugs.
2. Therapeutic uses
a. In dogs, valproic acid is effective in controlling seizures when given orally, but its short t½ makes it impractical for long-term use. It is a second to fourth-line anticonvulsant that may be useful as an adjunctive treatment in some dogs.
b. Its clinical usefulness in cats has not been evaluated.
a. Sodium valproate is rapidly converted to valproic acid in the acidic environment of the stomach where it is rapidly absorbed from the GI tract. The bioavailability via this route in dogs is ~80% and peak levels occur in 1 hour.
b. It is rapidly and well distributed in the extracellular fluid, with 70–80% bound by albumin in dogs. CSF levels of valproic acid are ~10% of the plasma levels.
c. It is metabolized in the liver and is conjugated with glucuronide. These metabolites and a small quantity of parent drug are excreted in the urine. The elimination t½ in dogs is 1.5–3 hours.
4. Adverse effects
a. GI disturbances and hepatotoxicity. Vomiting, anorexia, and diarrhea may be seen, which may be diminished by administration with food. Hepatotoxicity, including liver failure, is a potential adverse effect in dogs.
b. Other potential adverse effects include CNS effects (sedation, ataxia, behavioral changes, etc.), dermatologic effects (alopecia, rash, etc.), hematologic effects (thrombocytopenia, reduced platelet aggregation, leukopenia, anemia, etc.), pancreatitis, and edema.
. It is a synthetic GABA analog that can cross BBB to exert its anticonvulsant effect.
1. Mechanism of action. GABA content in neurons is increased by gabapentin administration. However, the main effect of gabapentin is due to its inhibition of voltage-dependent Ca2+ channels to decrease neuronal Ca2+ levels, thereby inhibiting excitatory neurotransmitter release (e.g., glutamate).
2. Therapeutic uses. Gabapentin may be useful as adjunctive therapy for refractory or complex partial seizures, or in the treatment of chronic pain in dogs or cats. It is administered orally.
3. Pharmacokinetics. In dogs, oral bioavailability is ~80%. Peak plasma levels occur ~2 hours post-administration. In dogs, elimination is primarily via kidneys, but ≤40% of gabapentin is metabolized by the liver to N-methyl-gabapentin. The elimination t½ is 3–4 hours in dogs. No t½ information is available for cats.
4. Adverse effects. Sedation, ataxia, and mild polyphagia are noticeable side effects. Abrupt discontinuation of gabapentin may cause seizures.
. It is used orally as an adjunctive therapy for refractory canine epilepsy. It is well tolerated in dogs and an initial prospective trial in cats was favorable.
1. Mechanism of action. Levetiracetam inhibits hypersynchronization of epileptiform burst firing and propagation of seizure activity. The exact mechanism is not understood. However, recent evidence suggests that it binds synaptic vesicle protein 2A in the neuron; the interaction with this neuronal vesicular protein may account for levetiracetam’s anticonvulsant effect.
a. It is well absorbed after oral administration and has 100% bioavailability. It is well distributed and minimally (10%) bound by albumin.
b. While not extensively metabolized, the acetamide group of the drug is hydrolyzed to the carboxylic acid metabolite that is apparently inactive. Both the parent drug and metabolites are excreted into urine. The elimination t½ in dogs, ~4 hours and in cats, ~8 hours.
3. Adverse effects. It has little side effects, which include changes in behavior, drowsiness, and GI disturbances (vomiting and anorexia). Withdrawal of this drug should be slow in order to prevent “withdrawal” seizures.
is a dicarbamate drug and is used orally in dogs to treat refractory epilepsy as an adjunctive therapy or a sole anticonvulsant agent for patients with focal and generalized seizures. At clinical doses, felbamate does not induce sedation and thus is particularly useful in the control of obtunded mental status
due to brain tumor or cerebral infarct.
1. Mechanism of action
a. Blockade of NMDA receptor-mediated neuronal excitation.
b. Potentiation of GABA-mediated neuronal inhibition.
c. Inhibition of voltage-dependent Na+ and Ca2+ channels.
a. It is readily absorbed from the GI tract after oral administration, but bioavailability in pups is only 30% that of adult dogs.
b. In dogs, ~70% of felbamate is excreted in the urine unchanged; the remainder undergoes liver metabolism by cytochrome P450 enzymes and conjugation.
c. The elimination t½ is 5–6 hours in adult dogs and 2.5 hours in pups.
3. Adverse effects
. Side effects of felbamate are infrequently seen.
a. The most noticeable side effect is liver dysfunction. Thus, it should not be given to dogs with a liver disease. Because of the potential for hepatotoxicity, it is recommended that serum biochemistry be performed every 6 months for dogs on felbamate therapy.
b. Reversible bone marrow depression is rarely seen in dogs receiving felbamate. These dogs may have thrombocytopenia and leucopenia.
c. Keratoconjunctivitis sicca and generalized tremor are rarely seen side effects of felbamate in dogs.
is a sulfonamide-based anticonvulsant drug that can be used as a sole anticonvulsant or an adjunctive therapy to control refractory epilepsy in dogs with minimal adverse effects. It is administered orally twice a day. However, the cost could be a problem for using this drug in dogs. The drug has not been studied sufficiently in cats to be recommended for this species.
1. Mechanism of action. Zonisamide inhibits voltage-dependent Na+ and Ca2+ channels of neurons to induce hyperpolarization and decreased Ca2+ influx.
a. It is well absorbed from the GI tract after oral administration to dogs.
b. It is evenly distributed in the body after GI absorption and has low protein binding.
c. Most of zonisamide is excreted in the urine, but ~20% is metabolized by the liver. In humans, it is metabolized to acetylzonisamide, 2-sulfamoylacetyl phenol, and glucuronide.
d. The elimination t½ in dogs is ~15 hours.
3. Adverse effects. Zonisamide has high safety margin in dogs. The reported side effects include sedation, ataxia, and anorexia.
is used most frequently in veterinary medicine as a CNS stimulant.
1. Mechanism of action. Doxapram stimulates respiration, which is a result of direct stimulation of the medullary respiratory centers and probably via activation of carotid and aortic chemoreceptors. Transient increases in respiratory rate and tidal volume occur. Detailed mechanism by which doxapram stimulates respiratory center transiently is not known.
2. Therapeutic uses
a. Doxapram is used to arouse animals from inhalant and parenteral anesthesia or anesthetic overdose. The depth of anesthesia is reduced, but the effect could be transient.
b. Doxapram is used for respiratory stimulation in neonates after assisted birth or C-section, and in lightly anesthetized adult dogs to evaluate laryngeal function. Low doses of doxapram increase the respiratory minute volume by stimulating the carotid bodies.
c. Doxapram is not effective in reviving a severely depressed neonate and is not a good substitute for endotracheal intubation and ventilation.
3. Pharmacokinetics. The drug is well distributed into tissues. In dogs, doxapram is rapidly metabolized by the liver and most is excreted as metabolites in the urine within 24–48 hours of administration.
a. IV administration produces an effect for 5–10 minutes.
b. IM administration and topical application to the buccal mucosa are also effective in neonates.
5. Adverse effects. High doses of doxapram may induce seizures. Hypertension, arrhythmias, seizures, and hyperventilation leading to respiratory alkalosis can happen. These effects are most probable with repeated or high doses of doxapram.
These terms are used interchangeably in veterinary medicine to refer the drugs that calm the animal and promote sleep but do not necessarily induce sleep, even at high doses. Ataractic means “undisturbed”; neuroleptic means “to take hold of nerves.” Tranquilized animals are usually calm and easy to handle, but they may be aroused by and respond to stimuli in a normal fashion (e.g., biting, scratching, kicking). When used as preanesthetic medications, these drugs enable the use of less general anesthetic.
A. Phenothiazine derivatives include acepromazine, promethazine, chlorpromazine, fluphenazine, prochlorperazine, and trimeprazine
1. Mechanism of action. Phenothiazine derivatives affect the CNS at the basal ganglia, hypothalamus, limbic system, brain stem, and reticular activating system. They block dopamine, α1–adrenergic and serotonergic receptors.
2. Pharmacologic effects
a. CNS effects
(1) The tranquilizing effects are due to depression of the brain stem and connections to the cerebral cortex (reticular activating system), probably via blockade of dopamine and 5-HT receptors.
(2) All phenothiazines decrease spontaneous motor activity. At high doses, animals will be immobilized in a fixed position for long periods (extrapyramidal symptoms).
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