Drugs Acting on the Central Nervous System

1. Drugs Acting on the Central Nervous System

2. INTRODUCTION Function. Drugs can alter the function of the central nervous system (CNS) to provide • 1. Anticonvulsant effects • 2. Tranquilization (sedation) • 3. Analgesia Neurotransmitters released by a presynaptic neuron combine with receptors on the plasma membrane of a postsynaptic neuron, altering its membrane potential.

3. 1. Neurotransmitters in the CNS include • • dopamine, • • y-a mi no butyric acid (GABA), • • acetylcholine (ACh), • • nor epinephrine, • • serotonin, • • histamine, • • glutamate, • • glycine, • substance P, and many neuropeptides. • 2. Receptors for neurotransmitters are the site of action for exogenous drugs. • a. Theneurotransmitter-receptor complex may directly alter the permeability of the cell membrane by opening or closing specific ion channels.

4. 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. The vast majority of these neurotransmitters have G protein-coupled receptors (GPCRs).

5. Blood-brain barrier (BBB) Circulating drugs must cross BBB in order to gain access to the neurons of the brain 1. Drugs that are cross BBB most readily a. lipid soluble, b. small in molecular size, c. poorly bound to protein, d. no ionized at the pH of cerebrospinal fluid (CSF) 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.

6. ANTICONVULSANT DRUGS • 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 un known in cats. Cats are generally assumed to metabolize drugs more slowly and poorly than dogs.

7. Mechanism of action • Anticonvulsant drugs stabilize neuronal membranes a. They may act directly on ion channels, resulting in hyper polarization of the neuronal membrane. b. They activate GABA-gated Cl- channels increasing the frequency of Cl- channel opening produced by GABA, thereby evoking hyper polarization of the neurons.

8. Therapeutic uses Anticonvulsant drugs reduce the 1. Incidence, 2. Severity, Duration of seizures Adverse effects: 1. seizures, or status epilepticus may follow rapid cessation of administration of these drugs 2. Enzyme induction 3. Hepatotoxicity

9. Barbiturates • Henobarbital • Chemistry.Phenobarbital is an ox barbiturate • Mechanism of action. Barbiturates activate GABA-gated Cl- channels, thereby evoking hyper polarization of the neurons.

10. 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). Therapeutic uses. Phenobarbital is used for the long-term control of seizures. • Phenobarbital is usually administered orally • 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). • When given orally, its Gl absorption is practically complete in all animals. Peak levels occur in 4-8 hours after oral dosing in dogs.

11. Adverse effects • Sedation, polydipsia, polyuria, and polyphagia are common side effects. • Doge develop a tolerance to the sedative effects after 1-2 weeks

12. Primidone • Primidone is a deoxybarbiturate (an analog of Phenobarbital). • Primidone is slowly absorbed after oral administration in dogs • In cats, the metabolism to Phenobarbital is slower • 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.

13. Pentobarbita • Pentobarbital is an oxybarbiturate 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 • It has a rapid onset (<1 minute) after IV injection and • short duration of action. Adverse effects • Pentobarbital is a CNS depressant irritating when administered perivascularly.

14. Phenvtoin • Phonation is a hydration derivative • Mechanism of action: Phonation 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, 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.

15. Therapeutic uses • Phenytoin is an anticonvulsant drug; however, because of its short11/2 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

16. Benzodiazepines • Diazepam, midazepam, clonazepam, and lorazepam are used as anticonvulsants. • Drugs for the treatment of status epilepticus (continuous seizure activity lasting >5 minutes or recurrent seizures between • They can be used as a maintenance anticonvulsant in cats. • 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, because the development of tolerance occurs rapidly in this species due to drug metabolism into inactive metabolites.

17. Diazepam • Mechanism of action. Benzodiazepines activate GAB gated Cl' channels to potentiate the channel opening activity of GABA, thereby evoking hyper polarization of the neurons. • Therapeutics uses • In cats, it is administered orally for seizure control developing tolerance make diazepam • In dogs, it is administered IV for the control of status • epilepticus and cluster seizures. • In dogs as a maintenance anticonvulsant because it has a short 11/2 of 2-4 hours

18. Adverse effects (1) Changes in behavior (irritability, depression, and aberrant demeanor) may occur after receiving diazepam. (2)Cats may develop acute fatal hepatic necrosis

19. Midazolam • Therapeutic uses. Midazolam is used as an • Anticonvulsant for status epilepticus, muscle relaxant, tranquilizer, and appetite stimulant the same way as diazepam • Pharmacokinetics. Midazolam has a shorter • elimination 11/2 of 77 minutes in dogs, which is shorter than diazepam (~3 hours). Readily crosses BBB • Adverse effects. Midazolam may cause mild respiratory depression, vomiting, restless behavior, agitation, and local irritation.

20. Clonazepam • Therapeutic uses. The uses are the same as diazepam without distinct advantages over diazepam. Clonazepam alone has very limited value as a maintenance anticonvulsant because of the rapid development of drug tolerance. • Adverse effects. Tolerance to the anticonvulsant effects in dogs, Gl disturbances, including vomiting, hyper-salivation, and diarrhea/ constipation may occur.

21. Lorazepam • 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. • 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.

22. Adverse effects • Transient sedation at the beginning of therapy may occur. • Gl effects. Stomach irritation can produce nausea and vomiting. Vomiting, anorexia, and constipation are indications of toxicity. • Polydipsia, polyuria, polyphagia, lethargy, irritability, and aimless walking are additional adverse effects of Br- • Pancreatitis may be precipitated by Br-. • Severe asthma can be seen in Br—treated cats

23. Valproic acid and sodium valproate • Valproic acid is a derivative of carboxylic acid. It is structurally unrelated to other anticonvulsant drugs. • Therapeutic uses a.In dogs, valproic acid is effective in controlling seizures when given orally, but its short 11/2 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.

24. Adverse effects a. Gl disturbances and hepatotoxicity. Vomiting, anorexia, and diarrhea, which may be diminished by administration with food. Hepatotoxicity, including liver failure, is a potential adverse effect in dogs. b. CNS effects (sedation, ataxia, behavioral changes, etc.), c. Dermatologic effects (alopecia, rash, etc.), hematologic effects (thrombocytopenia, reduced platelet aggregation, leukopenia, anemia, etc.), pancreatitis, and edema.

25. Gabapentin. It is a synthetic GABA analog that can cross BBB to exert its anticonvulsant effect. • Mechanism of action. GABA content in neurons is increased by gabapentin. 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). • 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. • Adverse effects. Sedation, ataxia, and mild polyphagia are noticeable side effects. Abrupt discontinuation of gabapentin may cause seizures.

26. Levetiracetam. 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 • Mechanism of action. Levetiracetam inhibits hypersynchronization of epileptiform burst firing and propagation of seizure activity. • It binds synaptic vesicle protein 2A • In the neuron; the interaction with this neuronal vesicular protein may account for levetiracetam's anticonvulsant effect • Adverse effects. It has little side effects, which include changes in behavior, drowsiness, and Gl disturbances (vomiting and anorexia). Withdrawal of this drug should be slow in order to prevent "withdrawal" seizures.

27. Felbamate 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. • 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.

28. Adverse effects. a. Liver dysfunction, it should not be given to dogs with a liver disease • hepatotoxicity, • Reversible bone marrow depression is rarely seen in dogs. These dogs may • have thrombocytopenia and leucopenia. • Keratoconjunctivitis sicca and generalized tremor are rarely seen side • effects of felbamate in dogs.

29. Zonisamideis a sulfonamide-based anticonvulsant drug or an adjunctive therapy to control refractory epilepsy in dogs with minimal adverse effects. It is administered orally twice a day. • 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. • Mechanism of action. Zonisamide inhibits voltage-dependent Na+ and Ca2+ channels of neurons to induce hyperpolarization and decreased Ca2+influx • Adverse effects. Zonisamide has high safety margin in dogs. The reported side effects include sedation, ataxia, and anorexia.

30. CNS STIMULANTS (ANALEPTICS) • Doxapram is used most frequently in veterinary medicine as a CNS stimulant. • 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. • Therapeutic uses • 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. • Doxapram is not effective in reviving a severely depressed neonate and is not a good substitute for endotracheal intubation and ventilation. • Adverse effects. • High doses of doxapram may induce seizures. • Hypertension, arrhythmias, seizures, and hyperventilation leading to respiratory alkalosis can happen.

31. TRANQUILIZERS, ATARACTICS, NEUROLEPTICS, AND SEDATIVES • 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''; narcoleptic 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 pre-anesthetic medications, these drugs enable the use of less general anesthetic.

32. Phenothiazine derivatives include acepromazine, promethazine, chlorpromazine, fluphenazine, prochlorperazine, and trimeprazine. • Mechanism of action. Phenothiazine derivatives affect the CNS at the basal ganglia, hypothalamus, limbic system, brain stem, and reticular activating system. They block dopamine, al-adrenergic and serotonergic receptors

33. Pharmacologic effects CNS effects (1) The tranquilizing effects( depression of the brain stem via blockade of dopamine and 5-HT receptors. • All phenothiazines decrease spontaneous motor activity. Cardiovascular effects 1. Hypotension (al-adrenergic receptor blockade and a decrease in the sympathetic tone) 2. Reflex sinus 3. Antiarrhythmic effects 4. Inotropic effect. • Respiratory effects :Respiratory depression • Gl effects 1. Motility is inhibited 2. Emesis is suppressed • Effects on blood. Packed cell volume decreases • Metabolic effects 1. Hypothermia/hyperthermia 2. Hyperglycemia 3. Hyperprolactinemia.

34. Therapeutic uses • Tranquilization . • Antiemetics . • Prior to use of inhalant anesthetics can reduce • the incidence of arrhythmias sensitization to catecholamines. • Promethazine and trimeprazine are used to control allergy, because they block Hl-receptors.

35. Adverse effects. There is no reversal agent for this class of drugs. • Accidental intracarotid administration in horses results in the immediate onset of seizure activity and, sometimes, death. • They inhibit cholinesterase (ChE) and may worsen the clinical signs of anti-ChE poisoning. They should not be given to animals within 1 month of treatment with an organophosphate compound. • The Hl-antagonistic effect makes phenothiazines an undesirable drug for sedation of animals prior to allergy testing. • Paraphimosis may occur in stallions, which is due to relaxation of retractive penis muscles via al-receptor blockade. Thus, phenothiazines should be used cautiously or avoided altogether in breeding stallions.

36. Contraindications • Anti-ChEpoisoning or suspected treatment with anti-ChEantiphrastic drugs. • History of blood loss and hypotension. • Avoid in animals with moderate to severe liver dysfunction or portacaval shunt. • A2 -Adrenergic agonists These drugs activate a2-adrenergic receptors in the CNS, thereby causing analgesia, sedation, and skeletal muscle relaxation. • Mechanism of action. a2-Agonists activate 012-receptors that are Gi/o-coupled receptors; Gi/o mediates many inhibitory effects on the nervous systems and endocrine glands • High doses of xylazine, detomidine, and romifidine also activate al-receptors.`

37. Pharmacological effects Analgesia. • a2-Receptors are located on the dorsal horn neurons of the spinal cord, they can inhibit the release of nociceptive neurotransmitters, substance P and calcitonin gene-related peptide (CGRP). • a2-Adrenergic mechanisms do not work through opioidergic mechanisms, because crosstolerance is not usually present. a2-Agonist-mediated analgesia is not reversed by opioid antagonists.

38. Sedation. • 1. Ruminants are most sensitive to a2-agonists, followed by cats, dogs, and horses. Pigs are least sensitive to a2-agonists in domestic animals. • 2. High doses of a2-agonists may induce CNS excitation, which is attributable to activation of al-receptors Skeletal muscle relaxation • a2-Agonists produce skeletal muscle relaxation by inhibiting intraneuronal transmission of impulses in the CNS. • • Emesis. It is induced in carnivores and omnivores, and is commonly seen in the cat, and less frequently in the dog.

39. Cardiovascular effects • 1. Bradycardia, • 2. hypertension is due to activation of the postsynaptic a2-receptors of vascular smooth muscle. • 3. hypotension is caused by reduced norepinephrine release by the sympathetic nerve at the vascular smooth muscle • 4. Bradycardia (with or without sinus arrhythmia) is due to decreased norepinephrine release to the myocardium, particularly the SA node. An increase in baroreceptor reflex during hypertension • Renal effects. a2-Agonists induce diuresis through inhibiting vasopressin release Respiratory effects. a2-Agonists cause hypoxemia

40. Neuroendocrine effects. • ct2-Agonists inhibit sympathoadrenal outflow and decrease • The release of norepinephrine and epinephrine. • (1) a2-Agonists inhibit insulin release; this effect is very pronounced in ruminants, • Which results in a moderate to severe hyperglycemia lasting up to 24 hours. • (2) a2-Agonists increase growth hormone release by inhibiting somatostatin release from the hypothalamus and stimulating growth hormone—stimulating hormone release from the median eminence. The a2-agonist-induced growth hormone release is not sustained; consecutive daily drug administration can only maintain increased secretion for <1 week.

41. Therapeutic uses • a2-Agonists are used as a sedative, analgesic, and immobilizing agent. • They are also used to induce epidural analgesia, • As a preanesthetic, and as a part of the anesthetic combination. • Xylazine - ketamine is a commonly used, but not very safe, parenteral anesthetic combination • Xylazine. It is approved by the FDA for use in the cat, dog, horses, and wildlife, for example, deer and elk. However, it is also frequently used in other species, particularly the cattle. It is administered IM, • IV, or SC

42. Adverse effects • (1) Because of the Gl stasis associated with xylazine administration, bloat may be a result. • (2) Xylazine-induced bradycardia with sinus arrhythmia/arrest can be severe. Close monitoring is needed; in very severe cases, the use of an a2- antagonist may be necessary to save the animal. • (3) Xylazine affects the thermoregulation center in the hypothalamus, thus it produces hypothermia when the ambient temperature is low, and hyperthermia when the ambient temperature is high. Thus, the use of xylazine to immobilize wildlife should be performed with caution and the use of a2-antagonist to control the pharmacological effects of xylazine (or other a2-agonists) in wildlife is a must.

43. Contraindications • (1) Cardiac aberrations • (2) Hypotension or shock • (3) Renal insufficiency • (4) Hepatic impairment • (5) Epilepsy (because xylazine may precipitate seizures in susceptible animals). • (6) Use of xylazine in combination with ketamine should be used only in young healthy animals because this combination synergistically suppresses cardiopulmonary function of the animal.

44. (7) Immediate collapse, convulsions, and sudden death can occur in horses given xylazine into the carotid artery. • (8) A cautious approach should be taken whenever xylazine is used in treatment of colic, because xylazine's powerful analgesic effect can mask the underlying problem and because xylazine can paralyze the Gl tract. • (9) Xylazine should not be given to animals (particularly mares and ruminants) within the last month of pregnancy, since it may induce abortion. • (10) Xylazine should not be given to dehydrated animals or those with urinary obstruction because of its potent diuretic effect.

45. Detomidine (Dormosedan R ). It is approved by the FDA for use in horses. It is administered IM or IV. a. Pharmacokinetics (1) The elimination 11/2 is 1.2 hours for the IV dose and 1.8 hours for the IM dose. (2) Metabolism to detomidine carboxylic acid and hydroxydetomidine glucuronide and thereafter excretion into the urine seems to be the major elimination route.

46. b. Adverse effects (1) Following the recommended dose, piloerection, sweating, partial penis prolapse, and salivation, and occasionally, slight muscle tremors may be seen. (2) Excessive doses of detomidine can induce CNS excitation. The above two side effects of detomidine are also seen with the administration of other a2-agonists. (3) IV sulfonamides should not be used in detomidine-treated horses as potentially fatal dysrhythmias may occur. (4) Detomidine at 400 pg/kg (10x of recommended dose of 40 pg/kg) daily for three consecutive days can produce myocardial necrosis in horses. (5) Other adverse effects seen with xylazine administration may also occur in animals treated with detomidine.

47. Medetomidine (Dormitor R ). It is the most potent and selective a2-agonist available for use in veterinary medicine. It can induce light anesthesia in some individual animals; short examinations/procedures can be performed in these animals Adverse effects. • These are the same as stated in the xylazine section and are the extension of the pharmacological effects of the a2-agonist. However, since • medetomidine is a very potent a2-agonist, the adverse effects can be very severe. Thus, the use of an a2-antagonist, for example, atipamezole may be needed to reverse these adverse effects of medetomidine.

48. Romifidine ( Sedivet R ). It is for IV use in horses. • Adverse effects. The adverse effects of romifidine are similar to those of xylazine and detomidine.

49. Receptors. • Opioid receptors are naturally occurring sites in the body that respond to endogenous opioid neuropeptides (i.e., enkephalins, dynorphins, endorphins). All opioid receptors are Gi/o-coupled receptors that mediate the inhibition of neurotransmission and endocrine secretion (see Chapter 1 for information on G proteins). • The receptors are present in numerous cells/tissues, including the brain, spinal cord, urinary tract, Gl tract, and vas deferens. • Classification. There are at least three receptor subtypes. The following are information on the location of the receptor and effects mediated by the receptor

50. Mu (p) receptors are located throughout the brain and in laminae I and II of the dorsal horn of the spinal cord. Activation of p-receptors causes supraspinal and spinal analgesia, euphoria, sedation, miosis, respiratory depression, chemical dependence, and inhibition of ACh and dopamine release, and decreased Gl motility due to inhibition of ACh release. • Kappa (x) receptors are found in the cerebral cortex, spinal cord, and other brain regions, for example, hypothalamus. Activation of x-receptors results in spinal and supraspinal analgesia, mild sedation, dysphoria, inhibition of vasopressin release to induce diuresis, and miosis. • Delta (6) receptors are located in the limbic system, cerebral cortex, and spinal cord. Activation of 6-receptors results in spinal and supraspinal analgesia, inhibition of dopamine release, and cardiovascular depression.