Lecture Notes: Drugs Acting on the Central Nervous System (CNS) PDF

DRUGS Acting on the Central Nervous System (CNS) Date: 09/24/2024 Lecture 12: Tranquilizers/Sedatives/Stimulants Anait S. Levenson, M.D., Ph.D. Office Hours: By Appointment (send me an email) Email: [email protected] Tranquilizers Learning Objectives: ▪ Tranquilizers (Sedatives)...

DRUGS Acting on the Central Nervous System (CNS) Date: 09/24/2024 Lecture 12: Tranquilizers/Sedatives/Stimulants Anait S. Levenson, M.D., Ph.D. Office Hours: By Appointment (send me an email) Email: [email protected] Tranquilizers Learning Objectives: ▪ Tranquilizers (Sedatives) ✓ Tranquilizers: Classification ✓ Receptors, Mechanism of Action, Pharmacological Effects, Therapeutic Uses, Adverse Effects ✓ Phenothiazine Derivatives ✓ Benzodiazepines (BZDs) ✓ α2-Adrenergic Agonists ✓ Butyrophenone Derivatives ✓ Opioids ▪ CNS Stimulants (Analeptics) ✓ Pharmacological and Adverse Effects ✓ Doxapram: most frequently used ✓ Accidental Toxicity in Pets ✓ Abused use in humans  Tranquilizers, Neuroleptics, and Sedatives Medicines that calm the animals and promote sleep but do not necessarily induce sleep, even in high doses. Cause analgesia, sedation, decreased sympathetic tone, euphoria. Tranquilizers and sedatives in pets can be used for a variety of reasons including helping to relax while grooming getting x-rays drawing blood for tests having surgery These drugs are available by prescription from veterinarian only.  Tranquilizers, Neuroleptics, and Sedatives Mechanism of action: affect the CNS at the basal ganglia, hypothalamus, limbic system, and brain stem. CNS depressants acting through dopamine, adrenergic, serotonin, opioid and GABA receptors Therapeutic Uses: CNS tranquilizers are used to calm the animals for easy handling as pre-anesthetic medications (allowing less general anesthetic) anti-emetics anti-allergic Pharmacological effects: Cardiovascular Respiratory GI Bradycardia Hypoventilation motility Hypotension respiratory rate Tachycardia Adverse Effects: various, depending on existing condition  Tranquilizers / Sedatives ❑ Phenothiazine derivatives: MOA: Block dopamine action and reduce action of serotonin ❑ Benzodiazepines: MOA: Enhance inhibitory effect of GABA ❑ α2-adrenergic agonists: MOA: Stimulate α2-adrenoreceptors, which inhibit NE release ❑ Butyrophenone derivatives: MOA: Block dopamine receptors ❑ Opioids: MOA: Stimulate opioid receptors [mu (µ), kappa (κ), and delta (Δ)]  Tranquilizers / Sedatives ❑ Phenothiazine derivatives: Block dopamine and/or serotonin receptors Dopamine Antagonists Postsynaptic: D1-like R (D1, D5) D2-like R (D2, D3, D4)  Tranquilizers: Phenothiazine Derivatives ❖ Chlorpromazine ❖ Acepromazine (ACE) ❖ Promazine ❖ Triflupromazine Pharmacological effects: ( drugs effect on body, PK and PD of the drug) ▪ Effects are due to depression of brain stem and connections to the cerebral cortex ▪ All phenothiazines decrease spontaneous motor activity (grooming, rearing, sniffing) ▪ The induced tranquilization is NOT accompanied by analgesia Therapeutic effects refer to the responses after a treatment, desirable/beneficial effects Adverse effects are side effects that can be adverse or mild side effects ▪ Drowsiness ▪ Dizziness ▪ Dry mouth ▪ Constipation  Chlorpromazine First drug developed with specific antipsychotic or tranquilizer action (1950) Appearance: white to slightly creamy odorless bitter tasting crystalline powder Administration: IM or IV, well absorbed and distributed throughout the body Rapidly absorbed after PO, undergoes extensive metabolism in the liver and kidneys Pharmacological effects: CNS Cardiovascular ✓ Sedation, IV gives pick in 10-20 min Effects on myocardium: ✓ Antagonizing effect on apomorphine-induced emesis in dogs but not cats ✓ Reduction of contractility ✓ Endocrine effects: blocking release of FSH and LH, in plasma prolactin ✓ Arrhythmias ✓ May inhibit release of other hormones Adverse effects: Produces extrapyramidal signs (movement disorders) in cats and dogs May cause hyperesthesia and marked excitement in horses and may cause prolapse in the penis Contraindication: In patients with hypovolemia or shock, carefully used in animals with hepatic dysfunction In horses, may cause severe CNS excitation/depression, seizures, death In dogs, combination with atropine is recommended to overcome bradycardia effect  Chlorpromazine Sedation/ restraining Species Dose Route (mg/kg) Dogs 3 PO 0.5 IM Cats 3 PO 0.5 IM Swine 1 IM Sheep and goats 2.2 PO 1-4 IM 1 - 2.2 IV Pre-anesthetic medication Species Dose (mg/kg) Route Dogs and cats 1.1 IM Cattle 0.2 - 1 IM 1 - 4.4 IV Swine 1 IM  Acepromazine (ACE) Appearance: yellow, odorless, bitter tasting water soluble powder Administration: IM or IV 10-20 times more potent than chlorpromazine, produces mild to moderate sedation of shorter duration (24 hr) Drug is highly protein bound and has a fair volume of distribution in horses Used as a tranquilizer-sedative for controlling intractable animals and to immobilize large animals Used before surgery or veterinary examinations and procedures (X-ray) or grooming sessions with nervous/excitable animals Sedation/Restrain Species Dose (mg/kg) Route Dogs 0.025 – 0.2 IV 0.1 – 0.25 IM 0.25 - 3 PO Cats 0.05 – 0.13 IM or IV 0.25 - 3 PO Cattle 0.01 – 0.02 IV 0.03 – 0.1 IM Sheep and goats 0.05 – 0.1 IM Horses 0.03 – 0.1 IM or slow IV  Promazine Structurally related to chlorpromazine Administration: IM and IV 10-13 times less potent than chlorpromazine, produces mild to moderate sedation Duration is dose-dependent and can vary within 4-6 hr Sedation/Restrain Species Dose (mg/kg) Route Dogs and cats 2.2 – 4.4 IV or IM Cattle 0.4 – 1.0 IV or IM Horses 0.4 – 1.0 IV 1.0 - 2.0 PO Contraindication: the same as for chlorpromazine and acepromazine  Triflupromazine Used occasionally in animals for sedation Has higher risk of side effects than other phenothiazine derivatives Sedation/Restrain Species Dose (mg/kg) Route Dogs 1.1– 2.2 IV 2.2 – 4.4 IM Cats 4.4 –8.8 IM Tranquilizers: Benzodiazepines (BZDs, Benzos) ❑ Benzodiazepines (BZDs): Bind to GABA receptors and enhance inhibitory effect of GABA GABA-Agonists Activation of GABA-gated Cl- channels  Tranquilizers: Benzodiazepine (BZD) derivatives ❖ Diazepam (ValiumR) ❖ Midazolam ❖ Clonazepam ❖ Zolazepam ❖ Alprazolam (XanaxR) Pharmacological effects: Minimal cardiovascular effects Depressed respiratory effects Muscular relaxation due to effects in spinal cord Uses: As a sedative, anti-anxiety, anti-panic disorders As anticonvulsants in all the domestic species As muscle relaxant when given together with ketamine BZD alone: satisfactory in sheep, goats, neonatal foals NOT reliable in horses, dogs, or cats  Tranquilizers: Benzodiazepine (BZD) derivatives ❖ Diazepam (ValiumR) PK: highly lipid soluble, widely distributed throughout the body, crosses BBB, liver metabolism Used in Vet Med to sedate, reduce anxiety, panic, promote behavioral changes, or induce muscle relaxation Also used as an anticonvulsant (dogs and horses) and as a pre-anesthetic Can be prescribed to dogs, cats, reptiles, sheep, horses, and goat for scanning procedures Used as sedative in horses Used to increase appetite in cats and control behavior disorders Can be used IV in combination with opioids or anesthetics for general anesthesia Administration: oral, IV, or rectal Adverse Effects: Impaired coordination Alprazolam (Xanax) Lethargy Prescription only Rare: aggression and excitement Rare: hepatotoxicity in cats ❖ Clonazepam (stronger than diazepam but has shorter t1/2 ) ❖ Midazolam (used in combination with an opioid in older dogs as a neuroleptanalgesic) ❖ Zolazepam (used exclusively with Tiletamine for anesthesia)(approved for animal use)  Catecholamines and Receptors Catecholamines: Dopamine Norepinephrine (NE, also called noradrenaline) Epinephrine (E, also called adrenaline) Emergency STRESS Production: in the brain, nerve tissues, and adrenal glands Release: in response to emotional or physical stress “fight-or-flight’ response Control: metabolism, heart rate, blood pressure, respiratory functions Receptors: G protein-coupled Adrenergic receptors (α and β)  Tranquilizers: α2- Adrenergic Agonists ❑ α2-adrenergic Agonists: Causing decrease in NE release Stimulating α2-receptors in the heart and blood vessels decreases sympathetic Negative feedback activity leading to decreased heart rate and suppressing further blood pressure. NE release block α2- Agonists 2  Tranquilizers: α2- Adrenergic Agonists ❖ Xylazine (cat, dog, horse, and wild animals) ❖ Medetomidine ❖ Dexmedetomidine (DexdomitorR)(most potent and selective α2-agonist in Vet Med) ❖ Detomidine (horses, IM and IV) ❖ Clonidine Pharmacological effects: Powerful sedation Powerful analgesia Skeletal muscle relaxation due to effects in the CNS Emesis (cats, less in dogs) Reduced both GI motility and secretion (control of diarrhea) Hypertension followed by hypotension, bradycardia Uses: As a sedative, analgesic, and immobilizing agent As a pre-anesthetic, and as a part of the anesthetic combination Xylazine-ketamine combo should be avoided in geriatric, weak, and diseased small animals α2-Adrenergic Agonists Dexdomitor Is the most potent & Selective α2-Agonist Available for use in Vet Med Tranquilizers: α2-Adrenergic Agonists Xylazine and horses Contraindications: ▪ Immediate collapse, convulsions, and sudden death can occur in horse given Xylazine into carotid artery ▪ Xylazine inhibits insulin release in horses leading to hyperglycemia ▪ Cardiac aberrations, renal insufficiency, hepatic damage, epilepsy ▪ Combinations with ketamine should be use only in young and healthy animals ▪ Should not be given within the last month of pregnancy  Tranquilizers: Butyrophenone derivatives ❑ Butyrophenone derivatives: Block central dopamine D2 receptors Azaperone: Butyrophenone neuroleptic with sedative and antiemetic effects Potent D2 antagonist with some α1-adrenergic, muscarinic-cholinergic and histamine receptors Used as a pre-anesthetic agent prior to general anesthesia or caesarean section Occasionally used as a behavior modifying agent Mainly used in pigs Droperidol: Potent D2 antagonist with some histamine and serotonin antagonist activity More potent than chlorpromazine and promazine in dogs Should not be used with epinephrine Used in combination with fentanyl (opioid) for induction of neuroleptanalgesia Chemical restraining agent in aggressive dogs  Tranquilizers / Sedatives: Opioids ❑ Opioids: MOA: Stimulate opioid receptors [mu (µ), kappa (κ), and delta (δ)] ❖ Morphine ( μ+++; κ +) ❖ Oxymorphone ( μ+++; κ +; δ+) 101 more potent ❖ Fentanyl (μ+++) 102 more potent ❖ Carfentanil (μ+++) 105 more potent NY Zoo Africa  CNS Stimulants (Analeptics) Medicines that stimulate the brain, speeding up both mental and physical processes. They increase energy, improve attention and alertness, and elevate blood pressure, heart rate and respiratory rate MOA: Promotion of neurotransmission Amphetamines enhance release of DA and NE onto the synaptic gap by blocking dopamine and/or NE reuptake Pharmacological effects: CNS stimulants are used primarily in emergency situations during Heart rate anesthesia or to decrease the respiratory depressant effects of Blood pressure opiates and barbiturates; to treat Attention Deficit Hyperactivity Metabolism Body Temp Disorder (ADHD) or hyperkinesis in dogs Doses: 1-5 mg/kg, IV, in dogs and cats 0.5 -1 mg/kg. IV in adult horses 0.02-0.05 mg/kg/min, IV in young animal Adverse Effects: High doses may induce seizures Hypertension, arrhythmias, and hyperventilation Hepatotoxicity  CNS Stimulants Doxapram: Is used most frequently in Veterinary Medicine as a CNS stimulant MOA: stimulates respiration through direct stimulation of the medullary respiratory centers and activation of carotid and aortic chemoreceptors Therapeutic uses: To arouse animals from inhalant and parenteral anesthesia or anesthetic overdose Not effective in severely depressed neonate and is not a good substitute for endotracheal intubation and ventilation Adverse effects: High doses may induce seizures Hypertension, arrhythmias, hyperventilation, and seizures may lead to respiratory alkalosis [a low level of carbon dioxide (CO2) in the blood] Methylphenidate (RitalinR) is used for the treatment of ADHD (hyperactivity) in dogs This drug is not approved for use in animals by the Food and Drug Administration (FDA) but it is prescribed legally by veterinarians as an extra-label drug.  Accidental Ingestion and Intoxication in Pets Signs and symptoms of toxicity in dogs: Agitation Increased heart rate Panting Tremors Increased body T Vomiting, Drooling Seizures Medical use in humans: ADD and narcolepsy. methylphenidate, atomoxetine (ADD), modafinil (narcolepsy), armodafinil, amphetamines, ecstasy Pharmacological effects: Simulant effects on mood and alertness, enhance energy, sociability, and sexual arousal (by increasing dopamine and NE levels in the brain) Side Effects: Headache, insomnia, irritability, elation, agitation, confusion, palpitations, tachycardia, nasal stuffiness, and decreased appetite Liver injury Addictive qualities  Abused: Cocaine, MDMA: “ecstasy” ❖ Cocaine: Binds to dopamine transporter, blocking the removal of dopamine from the synapse. Dopamine accumulates in the synapse to produce amplified signal. Affects also NE and serotonin neurotransmission ❖ MDMA (MethyleneDioxyMetamphetAmine): is an indirect serotonin agonist increasing the amount of serotonin released into the synapse Illegal MDMA labs operating in the US Bonus slide: Abused: Cocaine, MDMA: “ecstasy” COCAINE /CRACK USERS Elevated BP, Respirations, Dilated Pupils Temperature Nosebleeds Nasal Congestion Sniffing Tachycardia Agitation, Anxiety Impaired Movement Anorexia- Weight loss Seizures