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Anticonvulsants, Sedatives and Behavior-modifying drugs Assoc. Prof. Ivan Lambev: www.medpharm-sofia.eu I. Anticonvulsants (Antiepileptic or Antiseizure Drugs) EPILEPSY is due to sudden, excessive depolarization of some or all cerebral neurons. This may be: ●localized (focal or partial) seizure ●spread to cause a secondary generalized seizure ●affect all cortical neurons simultaneously (primary generalized seizure). Estimates of lifetime seizure frequency vary from 0.5% to 5.7% in dogs and 0.5% to 1.0% in cats. Although many different types of seizures occur in dogs and cats, a universally accepted classification system has not been established. The most frequently recognized seizure type is the generalized seizure. Anticonvulsant drugs are evaluated primarily on their efficacy in the control of such seizures. Generalized seizure Partial seizures are also called focal seizures (the electrical storm is affecting only a part of the brain). A partial seizure may stay localized or it may expand to the whole brain and cause a tonic-clonic seizure. Because the seizure starts in only a part of the brain, an underlying disease or injury is highly suspected. Cluster seizures are more than one seizure within a 24-h period. Status epilepticus is a continuous seizure, or two or more discrete seizures between which there is incomplete recovery of consciousness, lasting at least 5 min. True epilepsy originates from a nonprogressive intracranial disorder. Symptomatic epilepsy is caused by progressive intracranial disease. Disorders that induce seizures may arise either outside the nervous system (extracranial) or within the nervous system (intracranial). Extracranial causes may be subdivided into those that originate outside the body (e.g. toxic agents – lead, organophosphates) and those that originate within the body but outside the nervous system (e.g. hypoglycemia, liver disease). Intracranial causes of seizures are divided into progressive and nonprogressive diseases. Progressive diseases include inflammation (e.g. granulomatous meningoencephalitis), neoplasia, nutritional problems, (e.g. thiamine deficiency), infection (e.g. feline infectious peritonitis, cryptococcosis, distemper), anomalous disorders (e.g. hydrocephalus, intra-arachnoid cyst), trauma and vascular diseases. Nonprogressive diseases include true epilepsy, such as inherited, acquired or idiopathic epilepsy. Inherited epilepsy is caused by a genetically determined intracranial disorder. Acquired epilepsy is caused by a previously active intracranial disorder, which is no longer active. Idiopathic epilepsy is where the cause and mechanism for the seizures are unknown. Therapy for symptomatic epilepsy requires not only control of seizures but also specific therapy for the underlying disease. Therapy is most effective when the underlying disease is diagnosed in a timely manner, before anticonvulsant therapy is initiated. ADRs may limit the usefulness of an anticonvulsants; therefore, it is essential to study the mechanisms of action and drug interactions in the species in which the drug is to be used. Immediate, short-term (acute) anticonvulsant therapy is required to treat status epilepticus, cluster seizures and seizures resulting from some toxicities. Chronic anticonvulsant therapy is used in the management of epilepsy, where seizures are longer than 3 minutes’ duration, are cluster seizures or occur more frequently than once every 4–6 weeks. Anticonvulsants are most effective when started early in the course of a seizure disorder. Anticonvulsant drugs are contraindicated in animals with extracranial causes of seizures, except these with portosystemic shunts and in animals with toxicities. Animals with seizures from a progressive intracranial disease may require additional therapy to treat the underlying disease (e.g. neoplasia or inflammation). Successful anticonvulsant therapy depends on the maintenance of plasma concentrations of drugs within a therapeutic range. The elimination half-life of drugs varies considerably between species. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Antiepileptics inhibit the neuronal discharge or its spread in one or more of the following ways: (1) Enhancing GABA synaptic transmission (2) Reducing cell membrane permeability to voltage-dependent sodium channels (3) Reducing cell membrane permeability to calcium T-channels GABA •Barbiturates •Bromides •Benzodiazepines •Valproates (Depakine Chrono®) •Gabapentin •Levetiracetam •Topiramate Na+ •Carboxamides (Carbamazepine) •Valproates •Hydantoins (Phenytoin) •Lamotrigine •Topiramate Antiseizure drugs, induced reduction of current through T-type Ca2+ channels. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006) Few of the antiseisure drugs, used for the treatment of epilepsy in people, are suitable for use in animals. This is due to differences in the pharmacokinetics of drugs in animals. Phenobarbital and bromide are appropriate for management of chronic seizure disorders of cats and dogs. Few of the antiseisure drugs, used for the treatment of epilepsy in people, are suitable for use in dogs and cats. This is largely due to differences in the pharmacokinetics of drugs in animals. Pharmacokinetic data for, and/or clinical experience with, many anticonvulsant drugs are lacking in cats. Phenobarbital and bromide are considered the anticonvulsant drugs most appropriate for management of chronic seizure disorders of cats and dogs. BARBITURATES (enzyme inducers) Phenobarbital (phenobarbitone), methylphenobarbital and primidone (it is metabolized to phenobarbital) are still used for generalized seizures but sedation is usual. Primidone and its active metabolites Basic & Clinical Pharmacology – 10th Ed. (2007) Cl− Hyperpolarization Phenobarbital is available as oral (tablets or elixir) or injectable preparation (i.v./i.m.). • For the chronic treatment of seizures in dogs dosing should begin at 2–5 mg/kg/12 h orally. Cats: 1.5–2.5 mg/kg/12 h orally. In some dogs or cats, the starting dosage may result in ADRs. Should these adverse effects not resolve after 2 weeks of therapy, a reduction in dose may be indicated. Steady-state serum phenobarbital concentrations should be determined after 3 weeks of therapy. If a patient’s seizures are adequately controlled, then serum concentrations may be determined again after 3–6 months. If a patient’s seizures are not adequately controlled after 3 weeks of therapy, the dose of phenobarbital may be increased by 25% and serum concentrations should be determined again after 3 weeks of therapy at this higher dose. Dogs are refractory to phenobarbital therapy when seizure activity or unacceptable effects persist when plasma concentrations reach 35 µg/mL. In dogs, phenobarbital elimination half-life decreases when administered chronically (47.3 h when administered for 90 days versus 88.7 h). It increases its own rate metabolism (autoinduction). Therefore the drug concentration of phenobarbital is expected to decrease in animals receiving chronic therapy after 3–6 months of therapy. In contrast, in cats, repeated phenobarbital administration does not alter serum steady-state concenation. • Reductions in dosage should be made gradually as physical dependence may develop and withdrawal seizures may occur as serum levels decline. Therapy should not be discontinued abruptly, except in animals that develop fulminant liver dysfunction. Phenobarbital should be avoided in animals with hepatic dysfunction. • Phenobarbital may be administered IV for the treatment of toxic seizures or status epilepticus; however, a lag time of 20 min may be observed prior to maximal effect. Bromides have been used as a sole therapy, particularly in dogs with hepatic dysfunction or in patients with mild seizures. Bromides is best suited for noncompliant owners because of its long half-life (> 2 weeks). Bromides is not recommended in cats. The elimination of bromide in cats is faster than in dogs. Bromide does not affect hepatic enzymes. Bromide toxicity appear to be dose dependent and include polyphagia, vomiting, anorexia, constipation, pruritus, muscle pain, sedation and pelvic limb weakness. ● Asthma (may be fatal) is associated with bromide administration in cats. ● Ataxia and sedation are the major dose-limiting adverse effects in dogs. ● High-dose bromide therapy has been associated with thyroid dysfunction in humans and rats. Hydantoins: Phenytoin is approved for control of epileptiform convulsions in dogs. IV injection of the drug causes a drop in arterial pressure and is not advised. Phenytoin is a potent inducer of hepatic metabolizing enzymes affecting itself and carbamazepine, warfarin, adrenal and gonadal steroids, thyroxine, tricyclic antidepressants, doxycycline, vitamin D, folate. Drugs that inhibit its metabolism are: valproates, co-trimoxazole, chloramphenicol, NSAIDs. Benzodiazepines: In dogs, the use of diazepam is limited to treatment of status epilepticus, because of the rapid development of tolerance. In cats, diazepam is effective as an acute and chronic anticonvulsant. Status epilepticus •An IV bolus of diazepam should initially be given at a dosage of 0.5–1 mg/kg. Onset of its activity occurs about 2–3 min after administration. This dosage may be repeated 2–3 times. Midazolam. Since it is water soluble, it is much less irritating with IV or IM administration. Others: Clorazepate and Lorazepam. Carboxamides (enzyme inducers): Carbamazepine Although there are isolated reports of the use of carbamazepine as an anticonvulsant in dogs, appropriate studies of its clinical efficacy in canine or feline seizure control are lacking. The rapid metabolism in dogs makes it unsuitable as an anticonvulsant. Valproates (enzyme inhibitors): Valproic acid (Depakine Chrono®) Since it is not possible to attain therapeutic blood levels even with high-dose therapy or sustainedrelease formulations, valproic acid is of limited usefulness in dogs. Reports of the clinical use of valproic acid in cats are lacking. Additional studies are necessary to evaluate the efficacy of this drug. Dicarbamates: They have dual mechanism of action as a: • positve modulatar of GABAA receptors • blocker of NMDA receptors Felbamate does not cause sedation and may be added to phenobarbital and/or bromide without potentiation of the sedative effect of these drugs. Analogs of GABA Gabapentin has the advantage of not undergoing hepatic metabolism. Although there are anecdotal reports of gabapentin as an anticonvulsant in dogs, studies of its clinical efficacy in dogs and cats are lacking. Pyrrolidone derivatives Levetiracetam is used primarily in dogs as an anticonvulsant. There are no reports on its use clinically in dogs although there is a clinical trial underway at North Carolina State University. II. Sedative drugs in VM • Typical Neuroleptics • Benzodiazepines • α2-adrenergic agonists • Herbal sedatives All sedatives depress CNS. CLINICAL APPLICATIONS Sedatives may be used to relieve anxiety or to provide chemical restraint. They facilitate the handling of patients, allowing thorough examination or positioning radiography. Sedatives are also used for preanesthetic medication. Their use renders the patient more tractable, improves staff safety and helps the placement of i.v. catheters. There are benefits for the patient too: By reducing fear and anxiety prior to induction of anesthesia, the potential for catecholamine-induced arrhythmias is reduced. Many sedatives do not possess analgesic activity and in these cases they should be combined with an opioids. The sedative and opioid act synergistically to enhance sedation; thus lower doses are required and the risk of ADRs is reduced. In addition, the sedative may counteract some of the undesirable effects of the opioid, such as vomiting or excitement. Where high doses of a very potent opioid are combined with a sedative the degree of CNS depression may be sufficient to permit minimally invasive surgery. Such combination is termed neuroleptanesthetics. NEUROLEPTICS (Antipsychotics, (Antischizophrenic drugs in humans) Typical Neuroleptics (with extrapyramidal motor symptoms as ADRs) - Phenothiazines - Butyrophenones - Thioxanthenes, etc. Used in VM Atypical antipsychotics (lack of extrapyramidal motor symptoms in rats) Schizophrenia: >> DA and >> 5-HT in human brain •Anxiety Mood •Impulse Cognitive function •Irritability Appetite •Obsessions & Sex Compulsions Aggression •Memory Dopamine Serotonin (DA) (5-HT) •Attention •Plesure •Reward •Motivation •Motor control • • • • • The effects of DA and 5-HT on the brain functions Neuroleptics – mechanism of action The therapeutic potency of the most neuroleptic drugs (especially Typical Neuroleptics) correlates strongly with their D2-receptor blocking activity in CNS. D1-receptor family: D2-receptor family: Distribution and characteristics of DA receptors in the central nervous system Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006) Main effects in humans (1) CNS. In normal individuals antipsychotics produce neuroleptic syndrome – indifference to surroundings, paucity of thought, psychomotor slowing, emotional quietening, reduction in initiative. In psychotic patients neuroleptics reduce irrational behaviour, agitation and aggresiveness. Hyperactivity, hallucinations, and delusions are suppressed. The sedative effect is produced immediately while the antipsychotic (neuroleptic) effect develops after weeks. Tolerance develops only to the sedative effect. The thermoregulatory centre is turned off, rendering the patient poikilothermic – cold-blooded (body temperature falls if surroundings are cold and the contrary). The medullary, respiratory and other vital centres are not affected, except of very high doses. It is very difficult to produce coma with neuroleptics. Antiemetic effect is exerted through the CTZ. Neuroleptics, except thioridazine, have this effect. (2) ANS. Neuroleptics have varying degrees of alphaadrenergic blocking activity and produce hypotension (primarily postural) especially after parenteral administration. Anticholinergic property of neuroleptics is weak. The phenothiazines have weak H1-antihistaminic and anti-5-HT actions but Promethazine has strong sedative and H1-antihistaminic action. (3) Endocrine system. Neuroleptics consistently increase prolactin release by blocking the inhibitory action of DA on pituitary gland. This may result in galactorrhea and gynecomastia. They reduce gonadotropins, ACTH, GH and ADH secretion. Typical Neuroleptics (D2-blockers) Phenothiazines, used in VM as sedative drugs •Acetylpromazine (Acepromazine) •Chlorpromazine •Prochlorperazine (10) •Promazine •Promethazine (2) Phenothiazines Type 1 (aliphatic side chain) Chlorpromazine, Promazine, Promethazine Type 2 (piperidine side chain): Acepromazine Thioridazine Type 3 (piperazine side chain) Prochlorperazine Trifluoperazine Clinical applications Acepromazine is used to facilitate the handling or restraint of patients and is often employed as a premedicant prior to general anesthesia. In low doses it has a general calming effect. Increasing the dose induces a degree of sedation, which is more apparent in dogs than cats. Phenothiazines do not possess analgesic activity and must be combined with an opioid. The antiemetic effects of phenothiazines are of benefit in such combinations. Phenothiazines also can protect the myocardium against adrenaline-induced fibrillation. Some phenothiazines, such as prochlorperazine, are used principally for their antiemetic properties. Others, such as promethazine, are used primarily for their potent antihistamine H1-blocking activity. Phenotiazines are ineffective in motor sickness as antiemetics. Dogs and Cats Chlorpromazine • Largactil® in France (1952) • 50–1000 mcg/kg i.v., i.m., s.c. • 3 mg/kg p.o. Metabolism Phenothiazines are metabolized by hepatic microsomal enzymes. Prolonged duration of action may be observed in patients with impaired liver function. Metabolites are excreted primarily in urine. Adverse Drug Reactions (ADRs) ● Extrapyramidal signs (restlessness, rigidity, tremor, catalepsy). ● Diminish the seizure threshold. ● Modification of thermoregulatory mechanisms at the level of the hypothalamus, which may lead to hypothermia. This effect is compounded by peripheral vasodilation and is significant in small patients with large surface area. Catalepsy (to take (strange posture) ● The main cardiovascular adverce effect of phenothiazines is peripheral vasodilation and a consequent fall in blood pressure, which is mediated mainly through α1-adrenergic blockade. The hypotension is generally well tolerated in healthy animals. Marked hypotension has also been described in excessively fearful dogs given acepromazine. ● Phenothiazines have a spasmolytic (M-cholinolytic) action and will reduce GI motility in the dogs. Contraindications and precautions ● Hypovolemia, shock and patient with history of seizures. Known drug interactions ● The CNS-depressant effects of phenothiazines will potentiate the CNS-depressant effects of concomitantly administered drugs (e.g. opioid analgesic). Phenothiazines are mild cholinesterase inhibitors and may therefore enhance the action of suxamethonium. They may potentiate the toxicity of organophosphates. Butyrophenones in VM • Fluanisone (with Fentanyl = Hypnorm®) • Droperidol (with Fentanyl = Innovar-Vet®) • Azaperone (Stresnil®) •Haloperidol The butyrophenones are structurally similar to GABA. They offer greater potency and fewer autonomic ADRs in comparison with phenothizines. Fluanisone Droperidol Clinical applications Azaperone is used exclusively in pigs as a sedative/premedicant or to reduce fear and aggression in recently mixed groups of pigs. It is not recommended for use in small animals. Fluanisone and droperidol are marketed in combination with fentanyl. The butyrophenones are potent antiemetic agents and are particularly effective in inhibiting opioid-induced vomiting. Similarly to phenothiazines, butyrophenones provide protection against adrenaline-induced arrhythmias. Azaperone ® (Stresnil ) 2 mg/kg IM Effect lasts 6 h. 4000 mg/100 ml ADRs of butyrophenones ●Muscle tremors and rigidity (in high doses). ●Excitement reactions after i.v. administration. ●Butyrophenone and fentanyl combinations may cause salivation and defecation. These effects can be reduced by anticholinergic premedication. Contraindications and precautions ●Shock and hypovolemia ●Patients with a history of seizures ●Butyrophenone–fentanyl combinations should also be avoided in patients with respiratory disease and renal or hepatic dysfunction. Known drug interactions ●Butyrophenones potentiate the action of other CNS-depressant drugs such as general anesthetics and analgesics. ●Concomitant use of adrenaline (epinephrine) is contraindicated. Benzodiazepines They are classed primarily as anxiolytic drugs although high doses may cause sedation and sleep. A wide range of benzodiazepines are available for use in people. Benzodiazepines do not induce reliable sedation in normal healthy animals. Their anxiolytic action may increase excitement and render patients more difficult to handle. However, in very young, very old and critically ill patients benzodiazepines may produce effective sedation and their relative lack of ADRs is an advantage in such “high-risk” groups. Benzodiazepines have also been used to calm distressed or restless patients in the postoperative period. Benzodiazepines do not have analgesic activity and should not be used to compensate for pain control. Benzodiazepines may be used to induce general anesthesia in combination with other drugs, typically the dissociative anesthetics. The anticonvulsant and musclerelaxant properties of the benzodiazepines counteract some of the less desirable effects of the dissociative drugs, reducing muscle tone and decreasing the incidence of seizures. Benzodiazepines may be used specifically for their anticonvulsant action and diazepam is a drug of choice in the treatment of status epilepticus. The ability to relax skeletal muscles may also have specific indications such as the treatment of tetanus and relief of urethral spasm. Benzodiazepines will stimulate appetite in anorexic cats. All actions of the benzodiazepines can be reversed by the specific benzodiazepine antagonist flumazenil. Most drugs used in insomnia act as agonists at the GABAA-receptor and have effects other than their direct sedating action, incl. muscle relaxation, memory impairment, and ataxia, which can impair performance of skills such as driving. Clearly those drugs with onset and duration of action confined to the night period will be most effective in insomnia and less prone to unwanted effects during the day. Transmitters: waking state and sleep. During the sleep dominates GABA. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) In animal dominates REM phase of sleep! In high doses benzodiazepines may cause sedation and sleep. In contrast to barbiturates which prolong phase NREM-sleep, benzodiazepines restore normal age ratio between the phases of sleep, facilitate and shorten the sleep time. Benzodiazepines have a euhypnotic effect (eu = good). The most used BENZODIAZEPINES in VM as Sedatives, and Euhypnotics: • Bromazepam • Diazepam • Midazolam (t1/2 2 h) • Triazolam (t1/2 3 h) Benzodiazepines in clinical use enhance the effectiveness of GABA by increasing the frequency of the opening of the chloride ions. They cause hypopolarization. A model of the GABAA receptor-chloride ion channel macromolecular complex Basic & Clinical Pharmacology – 10th Ed. (2007) Benzodiazepines (BDZs) Zolpidem, Zopiclone + GABAAsite + + Cl+ Barbitu- rate sate Ethanol Adapted from Bennett and Brown, Clinical Pharmacology – 9th Ed. (2003) Barbiturates Clorazepate Biotransformation of benzodiazepines Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) Adverse effects ●Therapeutically doses of benzodiazepines have a minimal effect on RS and CVS. However, high doses cause slight reductions in blood pressure. ●Benzodiazepines enhance the depressant effects of the opioids. ●Fulminant hepatic failure has been reported in cats treated with repeated oral doses of diazepam. ●Flumazenil (i.v.) is the treatment of choice if overdose happened. ●Adverse CV, such as arrhythmias, have been reported following the rapid i.v. injection of diazepam. ●Congenital abnormalities have been reported in babies born to women given diazepam during the first trimester of pregnancy (PRC D). ●Dependence and tolerance are features of long-term benzodiazepine use in people. Physical signs of withdrawal (nervousness, loss of appetite and tremor), have also been documented in animals. Green Reception Form for Prescribing of Benzodiazepines. Durability: 7 days. The recipe is stored in licensed pharmacies 10 years! Contraindications and precautions Benzodiazepines should be used with caution in: ● Patients with hepatic encephalopathy, especially those with portosystemic shunts. ● Patients during early pregnancy Known drug interactions ● Benzodiazepines potentiate the CNS-depressant effects of propofol and barbiturates. Melatonin is the hormone produced by the pineal gland during darkness. It is released mainly at night. The impressive nature of the diurnal rhythm in melatonin secretion has stimulated interest in its use to reset circadian rhythm to prevent jet-lag on long-haul flights and for blind or partially sighted people who cannot use daylight to synchronize their natural rhythm. Ramelteon (in humans) – analogue of melatonin Alpha-2-Adrenoceptor agonists as Sedatives • Xylazine: 3 mg/kg i.m. in dogs and cats • Detomidine • Romifidine • Medetomidine, Dexmedetomidine Clinical applications α2-Adrenoceptor agonists may be classed as sedative-hypnotics with additional muscle-relaxant and analgesic properties. They are widely used for chemical restraint and premedication in small and large animals. The level of sedation induced by α2-agonists is more predictable than that achieved with phenothiazines or benzodiazepines. In most countries detomidine is only licensed for use in the horse. Xylazine, medetomidine and romifidine are generally licensed for use in cats and dogs. Xylazine, medetomidine and romifidine Detomidine The sedative, analgesic and musclerelaxant effects of the α2-agonists are mediated at central α2-receptors (prejunctional inhibitory receptors!), which inhibit noradrenaline exocytosis. (+) Detomidine α2-Adrenoceptors are G protein-coupled receptors linked to the cAMP second messenger system. Their activation inhibits adenylate cyclase and reduces cAMP, opens K+ channels and reduced Ca2+ .Three different α2-adrenoceptor subtypes have been identified: α2a, α2b and α2c: α2a-adrenoceptors mediate sedation, analgesia and hypotension while the α2b-adrenoceptors mediate vasoconstriction and hypertension (i.e. postsynaptic α2-adrenoceptors are probably of the α2b subtype). α2-Agonists undergo extensive first-pass metabolism after oral administration. These agents have also been administered into the epidural space to achieve analgesia. In a study conducted in dogs, epidural administration of 15 µg/kg Medetomidine produced analgesia for 4–8 h. α2-Agonists are lipid-soluble drugs that are therefore widely distributed. Medetomidine is very lipophilic. Adverse effects ● Alterations in body temperature, both increased and decreased, have been reported in animals sedated with α2-agonists. In small animal patients, centrally mediated hypothermia appears to be the predominant finding. ● There are anecdotal reports of dogs responding unexpectedly, and in some cases aggressively, to touch, despite appearing heavily sedated. A similar phenomenon is recognized in the horse and studies in indicate that α2-agonists may induce cutaneous hypersensitivity. ● Bradycardia is common and heart rates frequently fall by 50% or more following administration of sedative doses. This effect has been attributed to a central decrease in sympathetic drive and thereby a predominance of vagal tone, although a baroreceptor response to hypertension may also contribute. Bradycardia may also be accompanied by alterations in rhythm. Sinus arrhythmia, sinoatrial block and first-, second- and third-degree atrioventricular blocks occur not infrequently. ● Activation of peripheral postsynaptic α2- and α1-receptors (α2-agonists are not specific) leads to vasoconstriction. In contrast, activation of central and peripheral presynaptic α2-receptors causes vasodilation through reductions in NA release and sympathetic outflow. The balance of these effects influences blood pressure. The vasoconstrictive effects predominate initially, resulting in a period of hypertension. This is followed by a more sustained fall in arterial blood pressure as the central effects become more important. ● Vomiting is a frequent occurrence following i.m. administration of α2-agonists. It is most common with xylazine, especially in cats, in which the incidence may approach 50%. It is mediated centrally through direct activation of receptors in the chemoreceptor trigger zone (CTZ). ● Overall, α2-agonists depress gastrointestinal motility and prolong gut transit times. This parasympatholytic effect has been attributed to reduced release of ACh from cholinergic nerve terminals innervating the GI. Reductions in salivary and gastric secretions may also occur. Known drug interactions ●α2-Agonists act synergistically with opioids and inhalation anesthetics. ●Fatalities have been documented in horses sedated with detomidine that concurrently received i.v. Sulfonamides. Herbal sedatives Randomized clinical trials have shown some effect of valerian in mild to moderate insomnia, and hops, lavender and some other plants too. The valerian extract contains valeopotriates, which possess GABA-mimetic action. Combined phytoprepartions for oral applications are: Benosen®, Dormiplant®, ReDormin® •Valerian •Extracts contain valeoptriates (GABAA-mimetics) Genetics… Humulus lupulus (Hop) - Strobuli Lupuli The species is a main ingredient of many beers. Extracts contain phytoestrogens, humuleine, linalool, tannins. Leonurus cardiaca (Throw-wort) - Folia Leonuri Melissa officinalis (Lemon balm) - Herba et foliae Lavandula angustifolia (Lavender) Avena sativa (Oat) https://dogtv.com/ III. Behavior-Modifying Drugs (BMDs) Most information on BMDs is derived from human literature and thus cannot necessarily be extrapolated directly to other animal species. Establishing a diagnosis Before prescribing any drug to modify an animal’s behavior, it is important that the veterinarian has made a diagnosis based on a thorough physical examination and behavioral history. Client consent and compliance As most medications used in veterinary behavioral therapy are not registered for use in animals, it is even more important that the rationale for drug use and potential side effects should be clearly explained and the owner should give informed consent to the use of the drug on their pet. A signed consent form is recommended to ensure that a client has understood the implications of the treatment program, possible side effects and likely length of treatment required (> 2 months). Pretreatment screening Blood tests prior to prescribing medication are strongly recommended. A minimum database should include a complete blood count, biochemistry and urinalysis. As most behavior-modifying drugs are metabolized by the liver and renally excreted. It is important to assess liver enzymes and renal function prior to starting treatment. It may be useful in some cases to reassess liver and renal function approximately 4–6 weeks after starting treatment. All animals on long-term behavior-modifying medication should be retested at least every 6–12 months. Clinical applications of BMDs: • anxiety-related problems (incl. fears and phobias) • obsessive-compulsive behaviors • some types of aggression • abnormal sexual behavior • geriatric behavior problems (1) H1-blockers from 1st generation (with sedative and M-cholinolytic effects) •Dimetindene •Diphenhydramine •Chloropyramine •Doxepin (TCA) •Hydroxyzine (anxiolytic!) •Promethazine (with sedative & antiemetic activity) •Cyproheptadine (H1&5-HT2) In VM H1-blockers have proved useful for treating inappropriate urination associated with anxiety, to reduce anxiety and motion sickness associated with car travel and to reduce excessive unexplained nocturnal activity of cats such as pacing and vocalization while the owners are at home. Antihistamines act by competitive inhibition of H1-receptors. They have mild hypnotic and sedative effects. Antihistamines may be effective in the management of pruritus associated with anxiety, but relatively high doses are necessary. Doxepin, a tricyclic antidepressant (TCA), has proved more useful than antihistamines for the treatment of anxiety-related pruritus and self-mutilation. Cyproheptadine is used to treat urine spraying and masturbation in a neutered (castrated) male cats. The use of cyproheptadine as an appetite stimulant in dogs and cats may result from 5-HT antagonism. H1-blockers from 1st generation Cats Dogs Cyproheptadine Cyproheptadine 0.4–0.5 mg/kg/12 h p.o. 0.3–2 mg/kg/12 h p.o. Diphenhydramine 2–4 mg/kg/12 h p.o. Hydroxyzine 2.2 mg/12 h p.o. Diphenhydramine 2–4 mg/kg/12 h p.o. Hydroxyzine 0.5–2.2 mg/12 h p.o. Adverse effects ● Mild CNS depression or sleepiness ● Anticholinergic effects ●Contraindications ● Urinary retention ● Glaucoma ● Hyperthyroidism Known drug interactions ● Comedications with of other drugs that cause CNS depression can produce additive effects. ● MAOIs may intensify the M-cholinolytic effects of H1-histamine antagonists. (2) Neuroleptics as BMDs Typical neuroleptics (D2-blockers) •phenothiazines •butyrophenones and others Atypical neuroleptics (5-HT2- & D4-blockers) Phenothiazines as BMDs They are commonly used in VM as tranquilizers for restraint and sedation or for brief treatment of agitation, alertness to excitement or hypersensitivity, often associated with fear- or anxiety-provoking circumstances or excitement from anticipation. However, they are seldom used in long-term behavioral therapy because of potential extrapyramidal effects. •Acepromazine is used for motion sickness and anxiety associated with car travel. •Acepromazine and chlorpromazine have also been used in the treatment of aggression, to reduce excitement. •Thioridazine was used to control aberrant motor activity in a dog. Butyrophenones as BMDs Haloperidol assists in the control of stress and therefore to prevent injuries when several species of wild African herbivore are handled at game parks. Haloperidol has a slight effect in dogs with obsessive-compulsive disorders and certain types of aggression. It is used long term (up to 9 years) in the management of self-mutilation and feather-plucking in birds. Atypical neuroleptics as BMDs Clozapine is effective in treating aggression in animal models of self-abuse. However, its use in treating aggressive dogs has been disappointing. (3) Anticonvulsants as BMDs Carbamazepine may control some forms of fear aggression in cats and can use to control motor activity in dogs, associated with seizures. (4) Benzodiazepines as BMDs •Alprazolam (Xanax®) •Clonazepam (Rivotril®) •Diazepam (Valium®) •Flunitrazepam •Oxazepam •Lorazepam •Midazolam •Triazolam In cats benzodiazepines are used to treat inappropriate elimination associated with anxiety, urine marking or spraying and fear aggression, as well as to stimulate appetite. They have been used in dogs in the treatment of noise phobias, panic attacks and sleep disorders such as night-time waking. Clorazepate (active metabolite is nordiazepam) because of its longer half-life, may be more suitable for dogs (0.5 – 1 mg/kg/8 h or 2 mg/kg/12 h p.o.). •Alprazolam is used in dogs in the anticipatory phase of thunderstorm phobias and separation anxiety. •Flurazepam is used to treat night-time waking or changed sleep patterns that may be associated with anxiety in companion animals. •Triazolam has also been used to treat some cases of aggression in cats. (5) Azapirones as BMDs Buspirone is a selective partial agonsist of presynaptic 5-HT1A-receptors. It does not produce dependence. It is used in anxiety related problems in cats, including urine marking/spraying and grooming. It is used successfully for travel sickness too. Advantages of buspirone in comparison to benzodiazepines include lack of sedation and a high safety margin. (5) Antidepressants as BMDs In depression there is deficiency of NA and 5-HT in the brain. The effects of DA, 5-HT and NE on the brain functions Monoamine Reuptake Inhibitors α2-adrenergic blockers MAO inhibitors (1) Tricyclic antidepressants (non-selective inhibitors) (1a) Drugs Desipramine Nortriptyline (2) Selective NARIs Reboxetine (1b) Prodrugs Amitriptyline Clomipramine Doxepin Imipramine (3) Selective SSRIs Citalopram, Fluoxetine Escitalopram, Fluvoxamine Paroxetine, Sertraline Mirtazapine Trazodone Selegiline (MAO-B) Moclobemide (MAO-A) The structures of TCAs are similar to phenothiazines. A. The Tricyclic antidepressants (TCAs): ● Block reuptake of NA and 5-HT ● Have antimuscarinic (atropine-like) effects ● Have α1-adrenolytic effects ● Have H1-blocking effects to varying degrees ● Produce sedation in animals In cats TCAs have been recommended as part of the treatment of anxiety-related disorders: inter-cat aggression, fear aggression, excessive licking in obsessivecompulsive disorder, excessive vocalization due to anxiety, urine spraying (with amitriptyline or clomipramine). TCAs with strong antimuscarinic activity have also been used to reduce predation in cats, as ACh is the principal neurotransmitter involved in predatory aggression. In dogs, TCAs have been used as part of the treatment of dominance aggression, fear aggression, separation anxiety, obsessive-compulsive disorders, including acral lick granulomas, fears and phobias (thunderstorm phobia, enuresis, narcolepsy). Amitriptyline has been used in the management of cats with lower urinary tract disease. Imipramine has been used in the treatment of urethral incompetence because of its M-cholinolytic effect. Doxepin and amitriptyline have considerable antihistaminergic (H1-blocking) effects. They are useful in cases where antipruritic or sedating effects are also needed. Amitriptyline Tricyclic Antidepressants 1 – 4 mg/kg p.o. q. 12 – 24 h 0.5 – 1 mg/kg p.o. q. 24 h Doxepin 3 – 5 mg/kg p.o. q. 8 – 12 h in acral lick dermatitis 0.5 – 1 mg/kg p.o. q. 12 – 24 h Adverse effects of TCAs ● Short-term lethargy ● Mild intermittent vomiting ● Increases or decreases in appetite ● Sedation (antihistaminic effect) ● Ataxia ● Atropine-like side effects: – Dry mouth – Constipation (antimuscarinic effect) – Urinary retention – Tachycardia – Cardiac arrhythmias – Decreased tear production – Mydriasis – Disturbances of accommodation Known drug interactions ●Concurrent MAOI administration should be avoided as it may lead to a serotonin syndrome. ●TCAs used with antithyroid medications may increase the potential risk of agranulocytosis. ●As TCAs are strongly bound to plasma protein, their effects may be enhanced by drugs that compete for protein-binding sites (e.g. Aspirin). Contraindications ●Urinary retention ●Concurrent use of hypertensive drugs ●Narrow angle glaucoma ●Seizures ●Cardiac dysrhythmias B. Selective Serotonin Reuptake Inhibitors (SSRIs) Clinical applications Apart from the treatment of depression, SSRIs have been used in panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, chronic pain, social phobias, enuresis and eating disorders (including bulemia neurosa) in humans. In cats, fluoxetine and paroxetine have been used to treat urine spraying, aggression and obsessive-compulsive disorders. In dogs, fluoxetine and sertraline have been used in the treatment of acral lick granulomas. Fluoxetine has also been used to treat obsessive-compulsive disorders, separation anxiety, generalized anxiety or global fear and dominance aggression. Paroxetine has also been used to treat generalized anxiety disorder. Citalopram has been used to treat acral lick dermatitis with a satisfactory result being seen in about 2 weeks. SSRIs Fluoxetine Paroxetine 1 – 2 mg/kg p.o. q. 24 h 1 mg/kg p.o. q. 24 h 0.5 – 1 mg/kg p.o. q. 24 h 0.5 – 1 mg/kg p.o. q. 24 h ADRs of SSRIs ●Mild sedation ●Transient decreased appetite ●Increased anxiety ●Decreased sexual motivation in animals and humans ●Nausea, vomiting, diarrhea, lethargy, weight loss, tremors and agitation in humans. ●The serotonin syndrome is a rare but dangerous complication with features restlessness, tremor, hуperthermia, convulsions, coma and death in humans. Risk is increased by co-administration with MAOIs. C. Monoamine oxidase inhibitors (MAOIs) ● Selegiline (Selective MAO-B irreversible inhibitor) In humans, selegiline has been used in Parkinson’s disease. In VM it has been used in older cats with anxiety, disturbed sleep/wake cycles and excessive vocalization associated with aging. It has also been used to treat generalized anxiety, compulsive licking and several types of aggression, but higher doses are required for cats than dogs. Adverse effects of MAOIs ●Stereotypic behaviors with overdosage ●Vomiting and/or diarrhea ●Hyperactivity or restlessness ●Pruritus, hypersalivation, anorexia, diminished hearing and listlessness in dogs Known drug interactions ●Comedication with ephedrine or opioids is not recommeded. The mechanism is not understood but this interaction can be fatal. (6) LITHIUM Lithium is a monovalent cation that is used in acute mania in humans. It has been used to treat some cases of unpredictable, severe aggression in dogs. It has a narrow therapeutic window. Regular monitoring of its plasma concentration is required. Lithium inhibits hydrolysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylinositides. These intracellular molecules are part of the transmembrane signaling system that is important in regulating intracellullar Ca2+ concentration. ADRs of lithium ●Acute overdose of lithium causes confusion, convulsions, cardiac arrhythmias and death. Known drug interactions ●Diuretics enhance lithium’s action and increase the likelihood of toxicity. (7) Antiadrenergic drugs as BMDs A. Postsynaptic α-blockers Nicergoline has been recommended in dogs with canine cognitive dysfunction syndrome (CCDS) and cerebral insufficiency of vascular origin. These include alteration in sleep/wake cycles and loss of learned behaviors such as house training. It also used in the treatment of aggression associated with aging. Nicergoline has been reported to be beneficial for cats with behavioral problems associated with aging, such as excessive vocalization and restlessness, especially at night. Known drug interactions ●Nicergoline can be expected to have an additive effect if used concurrently with other vasodilators. ●Treatment should be stopped 24 h before induction of anesthesia with xylazine. Because it is an α-antagonist, nicergoline may interfere with the activity of xylazine, reducing or negating its sedative effects. Alternatively, xylazine may reduce the effectiveness of nicergoline. B. Non-selective Beta-blockers NA is released in fear- or anxiety-provoking situations. Blocking some of the effects of NA reduces the physical manifestations of fear and anxiety (muscle tremors, trembling, tachycardia and altered GI motility). β-blockers can have a calming effect on anxious animals. Propranolol have been used to treat some forms of anxiety such as noise phobias in animals. Non-selective Beta-blockers as Sedative, resp. as BMDs Propranolol p.o. Pindolol p.o. 0.5–3 mg/kg/12 h 0.2–1 mg/kg/8 h 0.125–0.25 mg/kg/12 h – (8) Opioid agonists/antagonists as BMDs Agonist: Hydrocodone Antagionists: Naloxone, Naltrexone •Naloxone has a briefly effect. It is used as a diagnostic aid for compulsive disorders. •Naltrexone is longer acting and used therapeutically. •The opioid agonist Hydrocodone is used in some cases of self-mutilation in cats and chronic management of canine acral lick dermatitis. (9) Progestins Synthetic progestins (medrogyprogesterone and megestrol) have been used traditionally in VM in the treatment of problems ranging from roaming, sexual perversion, raucous behavior, obsessive barking, destructiveness, hole digging, car chasing, excessive timidity and poultry killing to urine spraying and aggression. Progesterone and its metabolites act as nonspecific sedatives and have barbiturate-like activity. They are antiandrogenic and act mainly in the medial preoptic area (part of anterior hypothalamus). This area control male sexual behavior and urine marking. Progesterone also interferes with synthesis of estrogen receptors and suppresses the production of testosterone in the reproductive tract of intact animals. However, progestins also suppress male-like behavior in castrated cats. The behavioral and physiological effects of progestins due to inhibition of 5α-steroid reductase. (−) Progestins (10) Pheromones are volatile chemical messengers that are produced in exocrine glands. They are released into the environment by animals to communicate with and alter the behavior of other members of usually the same species. Cats are believed to use facial pheromones to familiarize themselves with their environment. Other uses include calming cats prior to travel by spraying the cat-carrier prior to placing the cat inside, helping cats to become familiar with a new house and in the introduction of a new cat to the household. Additionally, it appears to be useful in stimulating appetite in hospitalized cats. It helps to control undesirable scratching behavior. To date, five functional fractions (Fs) of facial secretions of cats have been identified. The F3 fraction of facial pheromone is thought to inhibit urine marking, enhances feeding in an unknown situation and enhances exploratory behavior in unfamiliar surroundings. The F4 fraction familiarizes and calms the cats. Feliway® contains a synthetic analog of the F3 fraction of feline facial pheromone, along with a cat attractant (the alcoholic extract of the plant Valerian). Feliway® has been advocated for use in cases of urine spraying or anxiety in domestic cats and cheetahs. It has been reported to be help decrease intercat aggression in multi cat households (one of the major causes of urine spraying). Feliway® is also recommended to help cats tolerate clinical examinations during a veterinary consultation. Feliway® Spray (75 ml): for scratching/urine marking, spray daily at a height of 20 cm (cat nose level) in 6–8 prominent locations per room, incl. areas that have been marked with urine. Needs to be used continuously for 21 d for scratching, 30 d for urine marking, 45 d for older cats; for travel: spray cat carrier 15 min prior to introducing the cat. Diffuser: needs to be plugged in the room where the cat spends most of its time. One diffuser covers around 50 m2 (sq m) and lasts approximately 1 month. In multistory houses diffusers need to be placed on each level. The product should be used continuously for 1 to 3 months initially depending on the problem. DAP® (Dog Appeasement Pheromone) is a synthetic analog of the appeasing pheromone that the bitch secretes in the first few days after birth which helps the attachment process of mother to pups. I only cuddle pups but don’t kiss them! DAP® (Dog Appeasement Pheromone) has been used in dogs in the treatment of noise phobias (fireworks, thunderstorms), separation anxiety, motion sickness and helping puppies settle in to their new home. It has also been used successfully in boarding establishments and veterinary hospitals to help decrease anxiety, facilitate handling of dogs and assist dogs to familiarize themselves with the new environment. DAP®: Spray, diffuser and collar are now available. Spray (e.g. for car travel): spray 8–10 pumps of DAP 15 min before effect is required and before introducing the dog into the car or crate. It can also be sprayed onto a bandana and tied around the dog’s neck if the DAP collar is not available. Diffuser: should be placed in the room where the dog spends most of its time. It should not be placed behind furniture or areas that the dog cannot access as many dogs prefer to lie close to the diffuser. It should not be placed under tables as this will prevent circulation through the room. One diffuser covers approximately 50–70 m2 and lasts around 30 days. In multistory houses a diffuser should be placed on each level. The diffuser should be plugged in continuously for at least 30 days. Collar: the collar should be fitted firmly on the dog’s neck (one finger between collar and neck!). Each collars lasts about 1 month. Adverse effects of Phermone-containing preparations: ●None have been reported, although some clients claim that the alcohol vehicle is irritating. ●Caution should be exercised if there are birds in the environment as they are likely to investigate anything new in the environment by sniffing.