Drugs Acting on the Central Nervous System PDF

Drugs Acting on the Central Nervous System Mohanad AlBayati Mohanad AbdulSattar Ali Al-Bayati, BVM&S, MS. Physiology, PhD. Assistant Professor of Pharmacology and Toxicology Department of Physiology and Pharmacology College of Veterinary Medicine...

Drugs Acting on the Central Nervous System Mohanad AlBayati Mohanad AbdulSattar Ali Al-Bayati, BVM&S, MS. Physiology, PhD. Assistant Professor of Pharmacology and Toxicology Department of Physiology and Pharmacology College of Veterinary Medicine University of Baghdad Al-Jaderia, Baghdad Phone: 0964 7700766550 E. Mail: [email protected] [email protected]  INTRODUCTION Function. Drugs can alter the function of the central nervous system (CNS) to provide 1. Anticonvulsant effects 2. Tranquilization (sedation) 3. Analgesia  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, serotonin, histamine, glutamate, glycine, substance P, and many neuropeptides. Continue 2. 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. The vast majority of these neurotransmitters have G protein- coupled receptors (GPCRs).  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. nonionized 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.  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. 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. Therapeutic uses Anticonvulsant drugs reduce the 1. Incidence, 2. Severity, 3. Duration of seizures Adverse effects: 4. seizures, or status epilepticus may follow rapid cessation of administration of these drugs 5. Enzyme induction 6. Hepatotoxicity  Barbiturates Henobarbital Chemistry. Phenobarbital is an oxybarbiturate. Mechanism of action. Barbiturates activate GABA-gated Cl− channels, thereby evoking hyperpolarization of the neurons. 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 GI absorption is practically complete in all animals. Peak levels occur in 4–8 hours after oral dosing in dogs. Adverse effects Sedation, polydipsia, polyuria, and polyphagia are common side effects. Dogs develop a tolerance to the sedative effects after 1–2 weeks,  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. Pentobarbital 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 (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. Diazepam Mechanism of action. Benzodiazepines activate GABA-gated Cl− channels to potentiate the channel opening activity of GABA, thereby evoking hyperpolarization 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 t 1/2 of 2–4 hours Adverse effects (1) Changes in behavior (irritability, depression, and aberrant demeanor) may occur after receiving diazepam. (2) Cats may develop acute fatal hepatic necrosis 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 t 1/2 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. 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, GI disturbances, including vomiting, hyper- salivation, and diarrhea/ constipation may occur. 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 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. 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 t 1/2 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.  Adverse effects a. GI 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.  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.  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 GI disturbances (vomiting and anorexia). Withdrawal of this drug should be slow in order to prevent “withdrawal” seizures.  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. Adverse effects. a. liver dysfunction. it should not be given to dogs with a liver disease hepatotoxicity, b. Reversible bone marrow depression is rarely seen in dogs. These dogs may have thrombocytopenia and leucopenia. c. Keratoconjunctivitis sicca and generalized tremor are rarely seen side effects of felbamate in dogs. Zonisamide is 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  CNS STIMULANTS Doxapram is (ANALEPTICS) 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. 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 not effective in reviving a severely depressed neonate and is not a good substitute for endotracheal intubation and ventilation. 3. Adverse effects. High doses of doxapram may induce seizures. Hypertension, arrhythmias, seizures, and hyperventilation leading to respiratory alkalosis can happen.  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”; 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 pre-anesthetic medications, these drugs enable the use of less general anesthetic.  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, α1- adrenergic and serotonergic receptors Pharmacologic effects CNS effects (1) The tranquilizing effects( depression of the brain stem via blockade of dopamine and 5-HT receptors. (2) All phenothiazines decrease spontaneous motor activity. Cardiovascular effects 1. Hypotension (α1-adrenergic receptor blockade and a decrease in the sympathetic tone) 2. Reflex sinus 3. Antiarrhythmic effects 4. Inotropic effect. Respiratory effects :Respiratory depression GI 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. Therapeutic uses a. tranquilization. b. antiemetics. c. prior to use of inhalant anesthetics can reduce the incidence of arrhythmias sensitization to catecholamines. d. Promethazine and trimeprazine are used to control allergy, because they block H1- receptors. Adverse effects. There is no reversal agent for this class of drugs. a. Accidental intracarotid administration in horses results in the immediate onset of seizure activity and, sometimes, death. b. 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. c. The H1-antagonistic effect makes phenothiazines an undesirable drug for sedation of animals prior to allergy testing. d. Paraphimosis may occur in stallions, which is due to relaxation of retractive penis muscles via α1-receptor blockade. Thus, phenothiazines should be used cautiously or avoided altogether in breeding stallions. Contraindications a. Anti-ChE poisoning or suspected treatment with anti-ChE  α2-Adrenergic agonists These drugs activate α2-adrenergic receptors in the CNS, thereby causing analgesia, sedation, and skeletal muscle relaxation. Mechanism of action. α2-Agonists activate α2-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 α1-receptors. Pharmacological effects Analgesia. (1) α2-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). (2) α2-Adrenergic mechanisms do not work through opioidergic mechanisms, because cross-tolerance is not usually present. α2-Agonist-mediated analgesia is not reversed by opioid antagonists.  Sedation. 1. Ruminants are most sensitive to α2-agonists, followed by cats, dogs, and horses. Pigs are least sensitive to α2-agonists in domestic animals. 2. High doses of α2-agonists may induce CNS excitation, which is attributable to activation of α1-receptors Skeletal muscle relaxation α2-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. Cardiovascular effects 1. Bradycardia, 2. hypertension is due to activation of the postsynaptic α2-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. α2-Agonists induce diuresis through inhibiting vasopressin release Respiratory effects. α2-Agonists cause hypoxemia  Neuroendocrine effects. α2-Agonists inhibit sympathoadrenal outflow and decrease the release of norepinephrine and epinephrine. (1) α2-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) α2-Agonists increase growth hormone release by inhibiting somatostatin release from the hypothalamus and stimulating growth hormone— stimulating hormone release from the median eminence. The α2-agonist-induced growth hormone release is not sustained; consecutive daily drug administration can only maintain increased secretion for