Drugs Affecting the CNS PDF

Drugs that affect the CNS Prepared by: Dr. Louis Voltaire A. Pagalilauan INTRODUCTION › Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. These include medications used to...

Drugs that affect the CNS Prepared by: Dr. Louis Voltaire A. Pagalilauan INTRODUCTION › Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. These include medications used to treat a wide range of neurologic and psychiatric conditions as well as drugs that relieve pain, suppress nausea, and reduce fever, among other symptoms. In addition, many CNS-acting drugs are used without prescription to increase the sense of well-being. Due to their complexity, the mechanisms by which various drugs act in the CNS have not always been clearly understood. In recent decades, however, dramatic advances have been made in the methodology of CNS pharmacology. It is now possible to study the action of a drug on individual neurons and even single receptors within synapses. The information obtained from such studies is the basis for several major developments in studies of the CNS. First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission. While a few agents such as general anesthetics and alcohol may have nonspecific actions on membranes (although these exceptions are not fully accepted), even these non–receptor-mediated actions result in demonstrable alterations in synaptic transmission. CLASSES OF DRUGS ACTING ON THE CNS Narcotic is any substance which produces insensibility or stupor from which simple stimuli produce temporary arousal (Narcosis) Hypnotic is narcotic agent used to induce sleep, a state which may be considered physiological and from which the subject can be easily aroused by a wide variety of stimuli (Hypnosis) Sedative is a narcotic agent which is used to calm a nervous vicious or excited subject. Most sedatives cause drowsiness (Sedation) Ataractic or tranquilizer is a substance which produces sedation without at the same time causing drowsiness (Ataraxia) Neuroleptic is a tranquilizer which is used in human beings in treatment of psychoses. It is powerful agent in animals to produce sedation (Neuroleptanalgesia) Anesthetic agent is any substance that produces controllable and reversible loss of consciousness and an absence of response to noxious stimuli.(Anesthesia) Dissociative agent is a substance which produces in human beings a feeling of dissociation from surroundings, unconsciousness, catalepsy, vivid dreams and analgesia. It is used in animals to produce a state of thought resembling anesthesia in which the animal does not show response to stimuli. (Catalepsy)  Analgesic agent is any substance that temporarily abolishes the sensation of pain (Analgesia) Anticonvulsant- any agent that inhibit excessive motor stimulation at the CNS. CNS Stimulant- any agent that increase CNS stimulation. HYPNOTICS, SEDATIVES, AND TRANQUILIZERS Sedation, hypnosis, and ataraxia are regarded as stages of increasing depth of a continuum of CNS depression.  These terms are used interchangeably to refer to drugs that calm the animal and promote sleep but not necessarily induce sleep, even in high doses. There are certain agents, such as the barbiturates, may be used as sedative, hypnotic, and general anesthetic. The depth of CNS depression varies directly with the dose administered. Tranquilizer-Sedative group a. Phenothiazine derivatives b. Butyrophenone derivatives c. Benzodiazepines Sedative-Hypnotic group a. Barbiturates b. Chloral hydrate c. α- adrenergic agonist  BLOOD–BRAIN BARRIER (BBB) Circulating drugs must cross BBB in order to gain access to the neurons of the brain. 1. Drugs that are lipid soluble, small in molecular size, poorly bound to protein, and nonionized at the pH of cerebrospinal fluid (CSF) will cross BBB most readily. 2. The BBB tends to increase in permeability in the presence of inflammation or at the site of tumors. 3. The BBB is poorly developed in neonates; hence, chemicals can easily gain access to the neonatal brain. A. PHENOTHIAZINE TRANQUILIZERS 1. These includes : Acepromazine, Promazine, Chlorpromazine 2. Mechanism of action: a. While the exact MOAs are not fullyunderstood, the phenothiazines block post-synaptic dopamine receptors in the CNS and may also inhibit the release of, and increase the turnover rate of dopamine b. Depress portions of the RAS which assists in the control of body temperature, basal metabolic rate, emesis, vasomotor tone, hormonal balance and alertness. c. Varying degrees of anticholinergic, antihistaminic, antispasmodic and alpha-adrenergic blocking effects. 3. Pharmacologic Effects a. Respiratory effects- depression of respiration b. Cardiovascular effects i. Hypotension due to 1-adrenergic blockade and decrease in sympathetic tone ii. Sinus bradycardia and 2nd degree heart block may occur iii. Reflex tachycardia c. Gastrointestinal motility i. Depressed ii. Emesis is also suppressed due to interference at the CRTZ d. Blood – decreased PCV e. Metabolic effects – decrease body temperature due to vasodilation, dec. muscular activity and depression of thermoregulatory center of the brain 4. Therapeutic Uses a. Primarily used for tranquilization, no analgesic effect b. Antiemetics c. Used before induction of anesthesia, may reduce dose anesthetic agent and reduce incidence of arrhythmia caused by myocardial sensitization of catecholamine. 5. Contraindications a. Epileptic animals or those susceptible to seizures. b. Patients with hypovolemia or shock c. Patients with tetanus or strychnine intoxication due to effects of extrapyramidal system d. Giant breeds, boxers and greyhounds may be extremely sensitive (terrier breeds are somewhat resistant) e. Avoid in animals with moderate to severe liver dysfunction or portacaval/ portal cavalshunt. f. 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.  ACEPROMAZINE Very small doses useful in the treatment of behavioral problems in dogs and horses Given IM or IV, even after IV, it takes about 20 min to develop effect. CHLORPROMAZINE Has been largely superseded by acepromazine. It is less potent than acepro but with longer duration of action. Do not use it in cattle as pre-anesthetic medication because it may cause relaxation of the cardia resulting in regurgitation. It can be used in cesarean section and other obstetrical operations without serious effect on the fetus. B. BUTYROPHENONE TRANQUILIZERS 1. Preparations: Droperidol and Azaperone 2. Mechanism of action: a. Like phenothiazine, butyrophenone produced peripheral alpha1 adrenergic receptor blockade b. Binds to dopamine receptors in CNS and reduce membrane effect of normally released dopamine 3. Pharmacologic effect a. These agents reduce motor activity but may produce cataleptic effect b. Myocardial contractility is not altered. They may prevent the fatal cardiovascular effects of catecholamine and reduce mortality from stress and trauma c. Azaperone may produce -adrenergic blockade hence can produce hypotension d. Minimal effect on respiration 4. Therapeutic Uses a. DROPERIDOL i. 400 times more potent in dogs than chlorpromazine ii. Has the most potent anti-emetic activity which is about 1,000 times more active than chlorpromazine iii. Droperidol is used in combination with fentanyl (an opioid analgesic) to produce a state called neuroleptanalgesia. iv. Fentanyl-droperidol is contraindicated in food producing animals b. AZAPERONE i. Most suitable for sedation for pigs, produces a reliable sedation within 15 mins of IM administration, effects last for 2-3 hr. However, it may cause violent excitement in horses ii. Indicated when mixing feeder or weanling pigs C. BENZODIAZEPINES 1. Preparations: Diazepam, Midazolam, Zolazepam 2. Mechanism of action: a. The mechanism of action of the benzodiazepines seems to be a potentiation of the gamma amino butyric acid (GABA) transmitter. Benzodiazepine binds with one portion of GABA receptor.This enhances the binding of naturally released GABA to the other portion of receptor. b. Activation of GABA results in increase chloride ion movement into a neuron causing hyperpolarization of membrane and inhibition of membrane depolarization. 3. Pharmacologic effects a. They are not general neuronal depressants. Awareness usually persist, and relaxation enough to allow surgery cannot be achieved b. Cardiovascular effect minimal c. Depressed ventilation d. Muscle relaxation 4. Therapeutic uses a. DIAZEPAM (Valium) i. The most widely used in veterinary medicine. It has an anticonvulsant, sedative, hypnotic and tranquilizing effects. ii. Diazepam is used clinically to control convulsions of any origin, to control behavioral problems in pets, and to control restlessness during the postoperative state.In dogs, it is administered IV for the control of status epilepticus and cluster seizures. It is not used orally in dogs as a maintenance anticonvulsant because it has a short t 1/2 of 2–4 hours and its tendency to develop tolerance in this species due to drug metabolism. iii. Pre-anesthetic sedation with diazepam is particularly useful when used prior to ketamine anesthesia to reduce hallucination which occurs with this drug iv. Appetite stimulant in cats and for urine marking and anxiety in cats but also administered orally for seizure control. The longer t 1/2 and lower incidence of developing tolerance make diazepam clinically useful for long term seizure control in cats. Note: This drug may also significantly adsorb to IV solution plastic bags, infusion tubing and plastic syringes. Diazepam is well absorbed after intrarectal administration, and thus can be used as an at-home treatment of animals with cluster seizures. Other benzodiazepines are not well absorbed after this route. b. MIDAZOLAM i. It is more potent than diazepam for its anticonvulsant/sedative effects, but its duration of action is shorter than diazepam. c. LORAZEPAM (Ativan) i. Very long acting and with slow onset of actionii. Its maximum effect can be attained at 30-40 min after IV injection and 40-50 min after oral administration iii. Unlike diazepam, lorazepam following IM injection is not painful iv. It is four times as potent as diazepam. It may be used clinically as a premedication before ketamine anesthesia, but diazepam is preferred d. ZOLAZEPAM is available in combination with tiletamine, a dissociative agent.  5. Reversal. Flumazenil is a specific competitive antagonist for benzodiazepine receptors and has minimal agonist activity. D. BARBITURATES 1. They have been extensively used in veterinary medicine as sedative-hypnotic (lower doses) and as general anesthetic (higher doses) 2. According to duration of action, barbiturates may be a. Long-acting- e.g. Phenobarbital (Luminal) and barbital (Veronal) b. Short-acting- eg. Pentobarbital (Nembutal) and Secobarbital (Seconal) c. Ultra short-acting- eg Thiopental (Penthotal), Thiamylal (Surital and Methohexital (Brevane) 3. Mechanism of Action a. Barbiturates potentiate the GABA induced increased in chloride ion conductance mimicking the action of benzodiazepines but acting at a different site. It decreases the dissociation rate of GABA from the receptor. b. Barbiturates act at the reticular activating system. May also inhibit the release of excitatory neurotransmitter (acetylcholine, norepinephrine and glutamate)  4. Pharmacokinetics a. The agents have varying lipid solubility and this affect the immediate distribution to the brain. Thiobarbiturate is highly lipid soluble hence it readily redistribute in the body. b. Barbiturates binds to proteins c. Metabolism is high initially when there is increase plasma concentration, slows down as concentration decrease d. May accumulate in fat. Repeat dose result to high concentration in fat compartment and when drug administration stopped, accumulated stores may return to blood stream resulting to prolonged elevation of plasma drug level and prolonged recovery from anesthesia. 5. Pharmacological Effects a. The peripheral nervous effects of barbiturates include i. Selective depression of transmission in autonomic ganglia and reduction of nicotinic excitation by choline esters ii. They cause an increased neurotransmitter release at the neuromuscular junction (NMJ) but with concurrent decrease in the sensitivity of the postsynaptic membrane iii. There is also slightly depressed reflexes.  b. CNS i. Low doses may cause sedation or excitement ii. Moderate doses causes general anesthesia iii. High doses lead to profound CNS depression c. There is poor analgesic activity; pain perception and reaction still present until the moment consciousness is lost. In fact, small doses of barbiturates are hyperanalgesic (enhance perception of pain). Barbiturates cannot be relied upon to produce sedation or sleep in the presence of even a moderate pain d. Respiratory effects: depression of respiratory drive and of mechanism responsible for the rhythmic character of respiration e. Cardiovascular effect: slight cardiac depression, cardiac arrhythmias and vasodilation due to secondary histamine release f. The barbiturates confer tolerance to all general CNS depressants including ethanol. This means that chronic treatment with barbiturates induces the biotransforming enzyme causing reduced effects of other CNS depressants.  6. Therapeutic Uses a. PENTOBARBITAL Na i. Widely used in small animals as a general anesthetic. In large animals it is used in combination with chloral hydrate and magnesium sulfate. Duration of anesthesia- 30-60 mins. ii. Aside from anesthetic use, it may be given as an antidote to certain poisonings that cause CNS excitation such as with strychnine and with atropine. iii. Pentobarbital may be given to dogs and cats for sedation by oral, IV, and IP routes. When given IM or injected extravascularly, it causes tissue irritation iv. It is a major active ingredient in several euthanasia solutions  b. THIOPENTAL Na/ THIAMYLAL i. It is used in all species of animal only as IV injection for induction of anesthesia which lasts for only 10-30 minutes, and with or without pre_x0002_medication with phenothiazine tranquilizers ii. It can also be combined with muscle relaxants, Note that IV administration of ultrashort- acting barbiturates follows the same pattern as that of pentobarbital, but the effect is more immediate iii. Thiopental may cause transient apnea. Laryngospasm or bronchospasms may be fatal when present; always have the animal endotracheally intubated c. PHENOBARBITAL i. Has the slowest onset on action but have prolonged duration (6-12 hours), hence only use at subanesthetic dose ii. Primarily used as anticonvulsant d. PRIMIDONE i. Primidone is a deoxybarbiturate (an analog of phenobarbital). ii. In dogs, primidone is rapidly metabolized by the liver to phenylethylmalonamide (PEMA) and phenobarbital. Primidone, PEMA, and phenobarbital are all anticonvulsants. iii. In cats, the metabolism to phenobarbital is slower and the t 1/2 is very long; thus, primidone should not be used in this species. E. CHLORAL HYDRATE 1. It is a white translucent crystalline with pungent melon-like smell. It is soluble in water and decomposes in the presence of alkali. 2. Mechanism of Action a. In the body chloral hydrate is reduced to trichloroethanol that is believe to be responsible for the pharmacological effects 3. Pharmacologic Effects a. It causes a marked hypnotic effect; free of excitatory properties. b. General anesthesia may be produced with large doses but recovery from anesthesia is very slow c. CNS: cerebral depression, reflex is diminished but not so much in horses d. Poor analgesic capabilitye. Cardiovascular effect: At hypnotic doses, it causes little depression of blood pressure and pulse. At anesthetic dose, it can cause severe depression of vasomotor center of the brain f. Respiration: Depression of respiratory rate 4. Therapeutic uses a. Use mainly for large animal, particularly horses b. For basal narcosis: given orally by stomach tube after starvation or by IV using 7% solution (5.9/45 kg for horses 400-585 kg). Give 20 min before inducing anesthesia. Narcosis after oral route varies. IV administration to effect is preferred. c. For anesthesia: 127-275 mg/kg, administer by IV only to horses and cattle. Inject for over 5-10 min by infusion. It may be given in combination with magnesium sulfate, or with magnesium sulfate and pentobarbital F. α2-ADRENERGIC AGONIST 1. Preparations: Xylazine, Meditomidine Detomidine 2. Mechanism of Action: α2-adrenergic agonist stimulates centralreceptors, reducing the release of transmitter at the nerve terminals. 3. Pharmacologic Effect a. CNS i. The brain is the site of action for sedative and analgesic effect. The spinal cord is the site of producing analgesia and muscle relaxation by blocking interneural transmission ii. It can potentiate the effect of opioids, barbiturate and inhalant anesthetics iii. Hypnotic effect is due to the depression of main adrenergic nucleus (Nucleus coeruleus, NC) of the brain involved in sleep, analgesia and autonomic function b. Cardiovascular effects i. Blood pressure initially will increase due to direct action of drug-receptor at blood vessel causing vasoconstriction. The blood pressure returns to normal after 30 minutes due to decrease CNS sympathetic output, and decrease norepinephrine release ii. Arrryhtmia due to sinus bradycardia that is responsive to anticholinergic drugs c. Respiratory effect: Decreased respiratory rate and tidal volume d. Gastrointestinal effects: In cats, it can cause emesis with subsequent decrease in GI tract motility e. Animals treated with xylazine may also show hyperglycemia due to decreased insulin secretion. Avoid in diabetic patients 4. Therapeutic Uses a. Ruminants are most sensitive to xylazine, analgesia is present only in deeply sedated ruminants, use of local anesthetic is recommended b. Analgesic for horses c. Xylazine is used for pre-anesthetic sedation in combination with other agents to produce anesthesia such as acepromazine d. Occasionally used to induce vomiting in cats e. Use of xylazine in combination with ketamine should be used only in young healthy animals because this combination synergistically suppressescardiopulmonary function of the animal. 4. Therapeutic Uses a. Ruminants are most sensitive to xylazine, analgesia is present only in deeply sedated ruminants, use of local anesthetic is recommended b. Analgesic for horses c. Xylazine is used for pre-anesthetic sedation in combination with other agents to produce anesthesia such as acepromazine d. Occasionally used to induce vomiting in cats e. Use of xylazine in combination with ketamine should be used only in young healthy animals because this combination synergistically suppressescardiopulmonary function of the animal. 5. Contraindication a. In animals receiving epinephrine b. Xylazine should not be given to animals (particularly mares and ruminants) within the last month of pregnancy, since it may induce abortion. c. Xylazine should not be given to dehydrated animals or those with urinary obstruction because of its potent diuretic effect. d. 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 GI tract. General Anesthesia Anesthesiology is the art and science of administration of anesthesia. Anesthesia is the condition induced by pharmacological and other mean that results to the production of reversible loss of sensibility and in some cases consciousness. Objectives : 1. To minimize or eliminate pain 2. Relax muscle and facilitate patient restraint during surgical, obstetrical and other medical, diagnostic and therapeutic procedures. Types: 1. General anesthesia, the subject loses consciousness with lowered sensitivity to stimulifrom the environment and diminished motor response to such stimuli. 2. Local or regional anesthesia, only certain region of the body loses perception of pain or motor response to stimuli. There is no loss of consciousness. Routes and Administration of Anesthetics 1. Inhalation- drug is administered in a semiclosed or closed system (anesthetic gas machine) a. The depth of anesthesia is easily controlled and monitored b. Elimination of anesthetic drugs is by expiration 2. Intravenous- good for barbiturates which would be first preceded by atropine a. It offers the advantage of ease of induction, prompt recovery with lack of nausea and vomition; does not interfere with the operative areas, as would an inhalant anesthetic.  3. Intramuscular- good for dissociative anesthetics 4. Oral – good for sedation of vicious or wild animals wherein anesthetics are incorporated in meats or other baits Balanced Anesthesia. It is the used of multiple drugs in low dosage to take advantage of desirable features of selected drugs while minimizing the potential for harmful depression of homeostatic mechanism Components 1. Sensory blocking – loss of sensitivity to pain (analgesia). Example of agents: Nitrous oxide, Morphine, Meperidine, Fentanyl, Xylazine, Enflurane, Ketamine) 2. Motor blocking- muscle relaxation diminish motor response to noxious stimulation. Agents that produce a. relaxation - Xylazine; b. Slight relaxation – Ethyl chloride; c. Medium – Chloral hydrate, Isoflurane, Enflurane, Halothane, Barbiturate 3. Mental blocking – loss of awareness (unconsciousness) and no recall of events at the conscious level (amnesia) a. Ataraxia – Phenothiazine derivatives; Ketamine b. Light sleep – Fentanyl-droperidol c. Delirium – all that produces deep sleep 4. Reflex blocking – minimize autonomic nervous system response to noxious stimuli a. Blocking undesirable reflexes – Atropine b. Respiratory circulatory and digestive reflexes - Barbiturates  STAGES OF ANESTHESIA Stage I: Induction or Stage of Voluntary Excitement a. Consciousness still present b. Forcible efforts to avoid being anesthetized c. Breath-holding, but may not be observed in all cases d. Fear and apprehension leading to increased respiratory rate and pulse rate e. Pupillary dilatation (mydriasis) f. Urination and defecation Stage II: Stage of Involuntary Excitement a. Loss of consciousness b. Reflex response to stimuli such as exaggerated limb movement may become violent necessitating restraint c. Pronounced vocalization d. Unpredictable degree of violence which bears no relationship with the normal temperament of the animal, some may pass quietly through this stage e. Irregular respiration; sometimes breath holding f. Persistent pharyngeal reflex which becomes progressively depressed  Stage III: Surgical Anesthesia Plane 1 a. Irregular automatic breathing b. Limb movement stops c. Side to side movement of the eyeballs d. Disappearance of palpebral, conjunctival and corneal reflexes e. Brisk pedal reflex may still be present f. May be adequate for minor surgery Plane 2 a. Laryngeal reflex persist until the middle of plane 2 b. Eyeballs fixed in the center in the horse, cats, sheep and pigs, downward in dogs c. Pedal reflex becomes sluggish d. Progressive muscle relaxation e. Adequate for all surgical procedure except abdominal surgery Plane 3 a. Breathing still automatic but the respiratory rate increases while the depth decreases b. Noticeable pause between inspiration and expiration Stage IV: Overdose a. Complete paralysis of the thoracic muscles, only the diaphragm functions b. Jerky diaphragmatic movement c. Respiratory movement gasping in nature d. Wide papillary dilatation ASSESSING DEPTH OF ANESTHESIA Useful Signs in Assessing Anesthetic Depth 1. Cardiovascular system : heart rate, arterial blood pressure, color of mucus membrane, capillary refill time 2. Respiratory system: rate, ventilatory volumes, character of breathing, PCO2 3. Eye: position and movement, Pupil size and response to light, palpebral reflex, corneal reflex 4. Muscle: jaw and limb tone, presence or absence of gross movement, shivering or trembling 5. Others: body temperature, swallowing, coughing, vocalization, urine flow, salivation  PRE-ANESTHETIC MEDICATION Drugs used before actual induction of anesthesia are called pre- anesthetic agents Objectives: a. Mitigate fear and apprehension b. Minimize salivation that may cause aspiration pneumonia (induce by cholinergic blocking agents) c. Reduce pain and discomfort specially during stages I an II d. Improve the response to and recovery from general anesthesia. The pre-anesthetic agents include: a. Tranquilizers – acepromazine, promazine b. Analgesics – morphine, meperidine c. Anesthetics - Xylazine, ketamine d. Anticholinergic – atropine A. INJECTABLE ANESTHETICS 1. Dissociative Anesthetic 1. Dissociative agents include Phencyclidine, Tiletamine and Ketamine 2. These agents cause cataleptic, analgesic, and anesthetic action without hypnotic effect 3. Dissociative Anesthesia. The different levels of CNS seem to become dissociated from one another. The thalamoneocortical portion is depressed and the limbic system is enhanced. a. Catalepsy is a characteristic state of immobility accompanied by loss of postural reflexes but without impairment of consciousness in which the extremities appear to be paralyzed by motor and sensory failure. The cataleptic state is also known as dissociative anesthesia b. Spontaneous involuntary muscle movement and purposeless tonic-clonic movements of extremities occur during anesthesia. These signs may be mistaken for signs of inadequate level of anesthesia. c. Many reflexes (palpebral, laryngeal, pharyngeal) are maintained d. Somatic analgesia is good but poor visceral analgesia. 4. Pharmacologic Effects a. Cardiovascular effect: in healthy animal they increase sympathetic tone, hence may increase or maintain heart rate. The blood pressure and cardiac output are increased b. Respiratory effects: respiration is depressedcausing arterial oxygen tension to decrease c. CNS effects: increase cerebral blood flow and intracranial pressure, dilation of pupil d. Effects on fetus: it can cross the placenta  5. Preparation a. PHENCYCLIDINE. It acts primarily on the CNS either by stimulation or by depression. The overall effect varies considerably with species. It is not recommended anymore for general use in veterinary medicine. b. TILETAMINE i. It is a cataleptic agent for cats. Given at 0.1 –1 mg/kg, it causes salivation, lacrimation, mydriasis and ataxia, recovery within 1-1.5 hours ii. There is no loss of consciousness, causes seizures and clonic muscular reaction during deep anesthetic state iii. There is analgesia of the skin. Swallowing, pedal and palpebral reflexes are not abolished. Muscle relaxation is absent iv. Unconsciousness is induced with a dose of 10 mg/kg. Intramuscular injection causes pain. Tiletamine is now available in 1:1 fixed combination with zolazepam, an analogue of diazepam. This mixture is used as general anesthetics. c. KETAMINE i. Mechanism of Action: Inhibits the polysynaptic actions of the excitatory neurotransmitters ACh and L- glutamate in the spinal cord and Methyl-aspartate in the brain. ii. Pharmacokinetics: Metabolized in liver, metabolites are excreted in the urine iii. Administration: It is available in preparation for IV and IM injections iv. 11-33mg/kg IM 2. Barbiturates B. INHALATION ANESTHETICS 1. Inhalation anesthetics are either gas or volatile liquid. Most of them require special breathing device for delivery into the alveoli. 2. The efficacy of gaseous anesthetic depends on the threshold concentration of the drug in the brain which is also dependent on the concentration of drug that is absorbed in the blood from the alveoli. a. Laws that govern the diffusion of inhalant anesthetics in the blood and its uptake to the brain:  i. Dalton’s law: the greater the concentrations of anesthetic gas in the alveoli, the greater the partial pressure (tension) ii. Therefore, as the inhalant anesthetic is inhaled, an anesthetic partial pressure is established within the alveoli. Increasing the inspired concentration of anesthetic increases the partial pressure in the alveolus. iii. Henry’s Law: The greater the partial pressure of the anesthetic gas, the greater its solubility in the blood. iv. The drug diffuses from the alveoli to the blood and is circulated in all parts of the body. Removal of anesthetic from the alveolus is affected by the solubility of anesthetic in the body (Blood::gas partition coefficient), cardiac output, and difference of partial pressure between alveolus and venous blood entering the lung. v. The tension of an anesthetic gas in the brain is maintained when its concentration in the alveoli is maintained. Therefore, to maintain anesthesia, a minimum alveolar concentration (MAC) of the anesthetic must be maintained. It follows that the induction of and recovery from anesthesia vi. MAC is the minimum alveolar concentration of anesthetic (1atm) that prevents gross purposeful movement in 50% of the patient response to a standard painful stimulus. It is a measure of potency. 1. The anesthetic dose required to anesthetize 95% of animals is approximately 1.2-1.4 times the MAC. Surgical anesthesia levels are achieved by obtaining alveolar concentration equal to 1.4 -1.8 times the MAC. 2. The more lipid soluble the anesthetic, the lower the MAC, the higher the potency. 3. Hypothermia, hypotension, hypoxemia, senility, pregnancy, and concurrent administration of opioids and tranquilizer may decrease the MAC for some patients. vii. Blood::gas partition coefficient is the measure of the amount of anesthetic that can be dissolved in blood. The higher the BG partition coefficient the longer the induction of anesthesia. List of inhalant anesthetic with highest to lowest BGPC: Methoxyflurane > Halothane > Enflurane > Isoflurane > Sevoflurane > NO PREPARATIONS A. Diethyl Ether 1. Properties a. Transparent colorless; boiling point (bp) is 35 oC b. Lighter than chloroform but 2x heavier than air c. Possibility of explosion is great without good room ventilation d. Decomposed by air, light, and heat e. May cause death if liquid is aspirated into the nasal passages 2. Pharmacological effects a. Nervous effects: i. Initial excitement; delirium during induction, then brain depression. Medullary center is not paralyzed by anesthetic dose. b. Respiratory effects: i. Irritation to mouth, pharynx, and respiratory tract ii. Stimulation of salivation; dangerous if saliva is aspired into the respiratory tract iii. Coughing and breath holding iv. Unless the patient is deeply anesthetized, ether cannot, and should not be introduced in the middle of the operation without provoking coughing, breath, holding or laryngospasm c. Cardiovascular effect: depression of the cardiovascular system antagonized by reflex release of epinephrine d. Neuromuscular effect: Curare like effect at the neuromuscular junction, depresses impulse transmission in the spinal cord 3. Clinical use: for induction and maintenance of anesthesia especially in small laboratory animals B. Chloroform 1. Properties a. Heavy sweet smelling liquid; neither inflammable nor explosive b. Vapor is not irritating and easily decomposed by air and light c. A powerful anesthetic just 0.035% in blood causes anesthesia, 0.06% is fatal 2. Pharmacologic Effects a. Respiratory effects i. Depress sensitivity to carbon dioxide ii. Breathing slowed and shallow iii. Respiratory failure may occur during anesthesia b. Cardiovascular effects i. Effects are complex because the heart, medullary centers and peripheral blood vessels are all affected ii. Cardiac failure may occur during induction C. Halothane 1. Properties a. Not inflammable nor explosive, decomposes slowly unlike ether and chloroform b. Relatively safe. Danger may lie on restricted use by in experienced anesthetist in the belief that nothing ever goes wrong with halothane. 2. Pharmacologic Effects a. Respiratory effects i. Not irritating to the respiratory mucosa ii. Inhibits respiratory secretions iii. Decrease tidal volume b. Cardiovascular effects i. Blood pressure falls, pulse slow, maybe due to ganglionic block or to direct depressant effect on myocardium and to CNS depressant effect on vasomotor center. ii. Increases the sensitivity of the myocardium to epinephrine which may lead to ventricular fibrillation. c. Neuromuscular effects i. Has minimal neuromuscular effect, may potentiates nondepolarizing muscle relaxants, but antagonizes depolarizing relaxants ii. Relaxes smooth muscle and may interfere with normal involution of uterus after cesarean hysterotomy d. Other effects: May cause hepatic dysfunction; even to other persons in the operating room. D. Enflurane 1. Properties a. Halogenated ether, potent, nonflammable, non-explosive inhalation anesthetic b. Resembles methoxyflurane in structure but physical properties are closer to those of halothane c. Vapor does react with soda lime. Soda lime is part of the induction apparatus; it removes carbon dioxide from exhaled air d. Has a low blood/gas partition coefficient, so that induction and recovery are rapid. 2. Pharmacologic Effects a. Nervous effect: twitching or seizure activity; can be abolished by reducing alveolar concentration; can be prevented by pre-medication with a narcotic analgesic, e.g. morphine b. Respiratory effects: causes dose dependent respiratory depression c. Cardiovascular effects i. Dose-dependent depression of cardiovascular function ii. Inhibits epinephrine secretion by adrenal medulla; this may account for hypotension iii. Subcutaneous injection of epinephrine for hemostasis during surgery does no cause serous cardiac irregularities d. Neuromuscular effects i. When muscle relaxation is needed do not try to induce it by increasing the dose of enflurane, instead, use a muscle relaxant such as pancuronium ii. Non-depolarizing muscle relaxants are compatible with enflurane E. Methoxyflurane 1. Properties a. Halogenated ether, non-flammable, nonexplosive inhalation anesthetic b. Stable and does not decompose by air or light 2. Pharmacologic Effects a. Respiratory effects: i. Minimal stimulation of respiratory tract secretion ii. Depresses respiration to a degree proportional to depth anesthesia b. Cardiovascular effects i. Resembles ether in cardiovascular effects ii. Hearty rate and rhythm, not altered until deep anesthesia is attained iii. Sensitizes the myocardium to effects of epinephrine c. Metabolic effects: Can cause polyuric renal dysfunction due to release of free fluoride ion during its metabolism in the body F. Nitrous Oxide 1. Properties a. A colorless gas with a faint rather pleasant smell b. Non, toxic not inflammable, not explosive but can support combustion of other agents even in the absence of free oxygen c. A weak anesthetic used only in combination with other agent having greater narcotic effects 2. Pharmacologic effects a. Nervous effects i. The potency in the horse is only 50% of that in human ii. Its analgesic property enables excessive dosage of more potent agents to be avoided and concurrent cardiopulmonary depression minimized b. Respiratory Effects: No depressant effect, conscious animals do not object to breathing nitrous oxide c. Cardiovascular effects i. Negative inotropic effect has been observed experimentally; but clinically no harmful cardiovascular effect ii. Seems to stimulate sympathoadrenal system. This explains hypotension during halothane/oxygen anesthesia than during anesthesia with halothane vaporized in nitrous oxide-oxygen mixture. d. Other effects: Bloat, Diffusion hypoxia. When the supply of oxygen is turned off immediately following completion of surgical procedure, nitrous oxide remaining in the lungs is absorbed instead of atmospheric oxygen resulting in hypoxia. G. Isoflurane 1. Properties a. Halogenated methyl ethyl ether inhalant anesthetic cleared for veterinary use in dogs and horses. b. A colorless liquid with a characteristic, pungent odor. c. It is a stable compound that does not require additives to maintain shelf life; however, it is supplied in a brown bottle. 2. Pharmacologic Effects a. Cardiovascular effects i. Isoflurane depresses cardiovascular function and decreases arterial blood pressure in a dose- dependent manner because of a decreased stroke volume and decreased systemic vascular resistance. However, isoflurane-anesthetized animals maintain a higher cardiac output at deeper levels of anesthesia than halothane anesthetized animals because the decrease in stroke volume is counteracted by an increase in heart rate. ii. Catecholamine sensitization and resultant cardiac arrhythmias occur with isoflurane, but to a lesser extent than with other inhalant anesthetics. b. CNS effects i. Isoflurane is a dose-dependent CNS depressant that produces general anesthesia by an unknown mechanism. ii. Body temperature usually decreases unless a supplemental heat source is provided. iii. Cerebral blood flow is unchanged at doses of less than 1.2 MAC. Cerebral blood flow increases at high multiples of MAC, but the vessels are still responsive to carbon dioxide. Thus, controlled ventilation to decrease the arterial carbon dioxide partial pressure will counteract the cerebral vasodilation of deep levels of isoflurane anesthesia. c. Muscular effects. Isoflurane potentiates the non-depolarizing muscle relaxant drugs (e.g., atracurium). d. Hepatic effects. Hepatic function is reversibly depressed. e. Renal effects. Renal function is reversibly depressed, causing a decrease in renal blood flow, glomerular filtration rate, and urine production. Local Anesthetics LOCAL OR REGIONAL ANESTHESIA is a state characterized by reversible loss of perception of pain or other motor response to stimuli in local or regional part of the body, and is not accompanied by loss of consciousness. TYPES OF LOCAL ANESTHESIA 1. Surface or topical anesthesia a. The drug is applied to skin and mucous membrane (eyes, nose, mouth, throat, tracheo-bronchial tree, urinary tract, and gastrointestinal tract) to cause loss of sensory perception b. Application on the mucous membrane may lead to rapid absorption and toxicity c. Most local anesthetic agents are ineffective when applied on unbroken skin because cornified epithelium limits penetration d. Surface local anesthetic agents include: Cocaine, Hexylcaine, Lidocaine Tetracaine, Cyclomethylcaine 2. Infiltration Anesthesia a. Most commonly used for superficial procedures such as skin biopsy and or suturing wounds b. The drug is injected directly into the skin or deeper structures to facilitate surgery or other painful procedures c. Local anesthetics for infiltration anesthesia include: Lidocaine, Mepivacaine, Bupivacaine, Etidocaine, Chloroprocaine 3. Peripheral nerve-block a. The drug is injected into the area immediately surrounding the nerve or group of nerves (plexus) b. The anesthetic diffuses into the nerve trunks and anesthetize the area innervated by these nerves. This technique results in the blockade of the sensory, motor and autonomic pathways surgical procedure, nitrous oxide remaining in the lungs is absorbed instead of atmospheric oxygen resulting in hypoxia c. Agents commonly used for peripheral nerve block include: Lidocaine, Mepivacaine, Bupivacaine 4. Spinal anesthesia (Intrathecal anesthesia) a. Seldom used in animal b. The drug is injected into to CSF of the spinal subarachnoid space c. Anesthesia is due to the action of the drug on the spinal nerve roots and in the dorsal root ganglia, thus causing both sensory and motor blockade with rapid onset d. Local anesthetics for spinal anesthesia include: Lidocaine, Tetracaine 5. Epidural anesthesia a. The drug is injected into the epidural space to the spinal canal posterior to the end of the spinal cord Types of epidural anesthesia i. Caudal epidural 1. Site: Ruminants – sacro-coccygeal junction ;Horse- 1st and 2nd coccygeal junction 2. Sensory innervation will be lost from anus. Vulva, and caudal aspect of thighs 3. It is used in tenesmus, obstetric, perineal, and lower extremity procedures ii. Cranial or high epidural 1. Site: Swine/dog/cat/goat/sheep - lumbo-sacral region 2. Used for laparotomy, pelvic limb surgery or udder amputation, provides 2-4 hours analgesia 3. Animal will go down and should be maintained in sternal recumbency for 10-15 minutes to ensure even distribution of analgesic solution b. Agents commonly used for epidural anesthesia include: Lidocaine, Mepivacaine, Bupivacaine, Etidocaine, Chloroprocaine LOCAL ANESTHETICS are substances which when applied about the nerve terminals or nerve fibers prevent conduction of both sensory and motor impulses in axons and dendrites. 1. Physicochemical properties a. The chemical structure of most anesthetics has three parts: an aromatic ring, an intermediate chain, and an amino group. The intermediate chain, a local anesthetic may be ester or amide. b. Esters : Procaine, Chloroprocaine, Tetracaine c. Amides: Lidocaine, Mepivacaine,Bupivacaine, Etidocaine, Prilocaine 2. Mechanism of Action a. After injection, the uncharged portion of local anesthetic passes through the connective tissues surrounding the nerve fiber and through the plasma membrane to the axoplasm. Inside the neuron, the local anesthetic ionizes b. The cationic form then attaches to the internal sodium gate decreasing the sodium entry and block depolarization. They interact with hydrophobic regions of the nerve cell membrane, and prevent conformational change in the membrane protein necessary for normal impulse formation. c. Local anesthetics affect small non-myelinated nerve fibers more than the myelinated fibers, where they can act only at the nodes of Ranvier d. The order of blockade is as follows: sympathetic outflow -pain -thermal and propioceptive sensations - and lastly, motor activity 3. Pharmacokinetics a. Local anesthetics are administered at the site of action. Initial absorption and distribution reduces pharmacological effects b. Absorption of too much local anesthetic may cause adverse systemic effects. Absorption into the blood circulation may be retarded by incorporation of a vasoconstrictor agent such as epinephrine or phenylephrine c. The ester local anesthetics are hydrolyzed by the pseudocholinestrase in the plasma. Some are hydrolyzed so rapidly that toxic reactions to them are rare. But the local anesthetic effect is shortened. The hydrolytic product paminobenzoic acid (PABA) may cause allergic reactions in some patients. d. Amides, not being susceptible to pseudocholinestrase, are more stable than esters. They are metabolized predominantly by oxidation and then conjugation. 4. Therapeutic Uses and Preparations a. Local or regional anesthesia b. Control arrhythmias c. Facilitation of general anesthesia d. For ophthalmological use- Benoxinate, Proparacaine e. For delicate mucous membrane and skin-Benzocaine, Hexylcaine, Butamben Analgesics A. OPIOID ANALGESICS a. Opioid refer to all other substances that bind specifically to any of the several subspecies of opioid receptors in the brain and produce some agonistic actions. The endogenous opioids found in humans and other animals are endorphins and enkaphalins. b. Opiates are drug derived from opium. Opium is obtained from milky exudates of incised unripe seed of poppy plant. Papaver somniferum. Opium contains a number of alkaloids but only morphine, codeine and papaverin have clinical usefulness. c. Narcotics –refers to opioid analgesic that induces sleep d. Pharmacologic Effects a. CNS : i. Analgesia without loss of consciousness, other sensory modalities is not depressed. ii. Drowsiness and mental clouding, and excitatory effects generally occurs with extremely high doses. Excitation may be due to indirect effect because of increased release of norepinephrine and increased turnover of dopamine. iii. Nausea and emesis due to direct stimulation of the chemoreceptor trigger zone in the area postrema in the medulla. This can be counteracted by phenothiazine tranquilizers b. Respiration is depressed by virtue of direct effects on the respiratory center in the brain stem. c. Cardiovascular effect: There is no major direct effect on blood pressure or on cardiac rate and rhythm. Most opioids cause the release of histamine which may be responsible for any cardiovascular effect. Morphine produces arteriolar dilatation by a central suppression of adrenergic tone. d. GIT: Opioids delay gastric emptying, enhance segmental contraction of the small intestine and increase sphincter tone. Some opioids have been incorporated in antidiarrheal preparations (Loperamide).  e. Mechanism of actions: a. Opioids bind with opioid receptors in the brain and other tissues. There are several types of opioid receptors. Some of the important ones are : Mu; Kappa receptors; Sigma receptors b. These receptors are widely but unevenly distributed throughout the CNS, highest concentration in the limbic system. f. Pharmacokinetics a. Opioid analgesics are readily absorbed following oral, IM, SC, anal and inhalation administration. b. They distribute to parenchymatous tissues but do not persist in these tissues. They are conjugated with glucuronic acid and excretedin urine mostly as conjugated metabolite. g. Therapeutic uses a. Pain relief b. Sedation and induction of sleep c. Aid in the relief of pulmonary edema d. d. Cough suppression e. Treatment of secretory diarrhea h. Opioid Agonists a. MORPHINE i. Natural Opioid agonist, it may produce nitial excitement, panting, urination and defecation due to stimulation of CRZ at the medulla oblongata ii. Administered SC, IM or IV iii. Analgesia lasts for 4 hours after a single dose b. OXYMORPHONE i. Is a semisynthetic opioid agonist with 10x the analgesic potency of morphine but less pronounced effect on respiratory, cardiovascular and gastrointestinal system c. MEPERIDINE i. Synthetic opioid agonist with milder narcotic and gastrointestinal effects than morphine ii. Some respiratory depression but does not depress cough reflex d. FENTANYL i. 50% times as potent as morphine; very short-acting ii. more commonly used with neuroleptic agents B. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) 1. These agents provide less profound analgesia compared to opiates and are most suitable for mild or chronic low grade pain. They block the cyclooxygenase (PG synthase) necessary for the formation of prostaglandin (PG) which play a role in vasodilation, pain, and edema associated with inflammation. 2. All anti-inflammatory effects are attributed to the stabilization of lysosomal membrane, inhibition of phagocytosis, leukocyte accumulation and synthesis of mucopolysaccharides and histamine. 3. Antipyretic effect is due to the impairment of the pyrogens to raise the set- point of the temperature-regulating mechanism of hypothalamus. 4. Major problem is gastric irritation resulting in vomiting, diarrhea, and gastric hemorrhage 5. Mechanism of Action 1. Prostaglandins, leukotrienes, and their synthesis a. Prostaglandins are produced by a wide array of tissues including lungs, GI tract, kidney, and liver. They are metabolized primarily at the site of action hence resulting in decreased circulating levels of PGs. b. Prostaglandins, prostacyclins, and thromboxanes collectively known as prostanoids are synthesized from the same precursor, arachidonic acid (AA). c. AA is an important component of cell membrane and is released by the action of phospholipase A2 and other acyl hydrolases, which are subject to regulation by hormones and other stimuli. Subsequently, AA undergoes cyclization and oxygenation to prostanoids via the cyclooxygenase (COX) pathway; and to leukotrienes via the lipooxygenase (LOX) pathway. 2. Cyclooxygenase (COX) pathway. Prostanoids are synthesized primarily via the COX pathway; there are two COX isoforms, COX-1 and COX-2. In addition, the recently identified acetaminopheninhibitable COX-3 isoform is found to be expressed in the canine brain. COX-3 participates in the pyresis processes. a. COX-1 is constitutively expressed in several tissues and is termed “house keeping enzyme” because of its essential role in the maintenance of several homeostatic process including gastric mucosal cytoprotection, renal function, vascular homeostasis, platelet aggregation. b. COX-2 is an inducible form because it is expressed at the site of injury, inflammation and in certain pathological states such as osteoarthritis. Interestingly, recent reports indicate that it may also be constitutively expressed in a tissue specific manner including, bone, kidney, and brain and may promote delayedmwound healing. 3. Lipoxygenase (LOX) pathway. AA is converted by 5- LOX to 5- hydroperoxyeicosatetraenoic acid, which is eventually converted to leukotriene B4 (LTB4). LTB4 plays a central role in inflammation, increased microvascular permeability, and chemotactic properties involving neutrophil–endothelial adhesion,and neutrophil aggregation and degranulation. 6. Preparations Classification of NSAIDs 1. Nonselective COX inhibitors: a. Enolic acids Oxicams: Meloxicam Pyrazolones: Phenylbutazone b. Carboxylic acid Nicotinic acid: Flunixin meglumine Fenamates: Meclofenamic acid Salicylates: Aspirin Propionates: Ibuprofen, Naproxen, Ketoprofen, Carprofen Acetic acid: Etodolac 2. COX-2 selective inhibitors: Coxibs: Deracoxib, Firocoxib 3. Dual inhibitors: (COX/and 5-LOX): Propanamide: Tepoxalin 6.1 ASPIRIN (acetylsalicylic acid) 1. Pharmacokinetics a. Absorbed readily from stomach and upper intestine. b. Primarily conjugated with glucuronic acid. It can be suitable in dogs but can accumulate in cats 2. Therapeutic Uses a. Most commonly used analgesic, antipyretic, and anti-inflammatory drug. It is used primarily for relief of minor pain, particularly of musculoskeletal origin. b. Inhibits platelet agglutination by inhibiting synthesis of thromboxane. Use in the treatment of disseminated intravascular coagulation, pancreatitis, heat stroke 3. Adverse Effect: Aspirin causes gastric irritation which may result in vomiting, gastric hemorrhage and abdominal pain Dog 10-25mg/kg PO q8h Cat – 10mg/kg PO every other day Cattle – 50-100mg/kg PO q12h Horse- 25mg/kg PO q12h initially then 10mg/kg daily 6.2 ACETAMINOPHEN (Paracetamol) 1. It is an aniline derivative with analgesic and antipyretic properties. It is less effective analgesic than aspirin but causes less gastric irritation 2. Can induce hepatic necrosis in cats. Cats often show clinical signs of hypoxia from methemoglobinemia before hepatic necrosis occurs 10mg/kg PO q12h 6.3 IBUPROFEN / CARPROFEN 1. It is a propionic acid derivative. It is one of the safest NSAID but gastric irritation and nephrotoxicity should be regarded as potential hazards Dogs/Cats 2mg/kg PO bid *limit in 2d therapy in cats 6.4 FLUNIXINE MEGLUMINE 1. NSAIDs are effective in alleviating pain that is of somatic and integumental origin, although less effective in relieving visceral pain. Flunixin is an exception; it alleviates visceral pain related to colic. 2. In horses flunixin is effective in producing the longest duration of postoperative analgesia (∼13 hours) followed by carprofen (∼12 hours) and phenylbutazone (∼8 hours). In cattle, it is used for the control of pyrexia associated with respiratory disease and endotoxemia, and for the control of inflammation in endotoxemia and mastitis. 3. Considered more potent analgesic used to alleviate musculoskeletal disorder, gastrointestinal spasm, endotoxic shock. 6.5 PHENYLBUTAZONE 1. It is a pyrazolone derivative. 2. The safety and efficacy profile in addition to its affordability makes it the most commonly used NSAID in the horse. 3. Analgesic and antipyretic actions similar to those of aspirin and its anti-inflammatory properties resemble those of cortisone 4. Treat various lameness, osteoarthritis, nonarticular rheumatism 5. May produce renal necrosis and gastric irritation, may increase bleeding times by decreasing platelet aggregation 6. 3-6mg/kg IV q12h (do not exceed 8.8mg/kg/day) 6.6 DIPYRONE 1. Used as analgesic and antipyretic in small and large animals 2. Use to treat gastrointestinal spasm or hypomotility 3. Adverse effects: agranulocytosis, and leucopenia, increase bleeding and overdose may cause convulsion 6.7 ETODOLAC 1. Etodolac is an indole acetic acid derivative. In dogs, it preferentially inhibits COX-2. 2. It is for the control of pain and inflammation associated with osteoarthritis in dogs. It may be used as an analgesic and anti-inflammatory drug for many other conditions. 6.8. DERACOXIB AND FIROCOXIB 1. It is used in dogs for the treatment of pain and inflammation associated with osteoarthritis 6.9 TEPOXALIN 1. By inhibiting both COX-1 and COX-2 and 5-LOX at the approved recommended dosage in dogs it may have fewer adverse effects on GI tract. 2. It is used to control the pain and inflammation associated with osteoarthritis in dogs.Because it inhibits leukotrienes synthesis, it might benefit allergic conditions in dogs. It is useful to control postoperative pain associated with soft tissue surgery. 2. Anti-inflammatory and anti-allergic effects are due to involution of lymph node, thymus and spleen, inhibition of leukocyte migration and function and stabilization of plasma and lysosomal membrane; decrease capillary permeability. It also induced fibroblast activity, collagen synthesis and tissue repair. 3. Adverse side effects include gastrointestinal ulcers and adrenal suppression and immunosuppression. 4. Preparations: Rapid onset, Short -Acting : Hydrocortisone- 4.4 mg/kg IV, PO Prednisone – 0.2-0.5 mg/kg q12h IV, IM Rapid onset, intermediate acting: Dexamethasone – 0.125 – 1mg/kg IM Triamcinolone Slow onset, long acting Betamethasone Neuroleptanalgesia 1. Neuroleptanalgesia is a condition induced by administration of a combination of an opioid analgesic drug and a neuroleptic tranquilizer drug. 2. At a low dose, the mixture of an analgesic and a tranquilizer can be used as heavy pre- anesthetic medication. 3. At a high dose, it can be used to produce sufficient depression of the CNS (a state called neuroleptanesthesia) for surgery to be performed 4. Neuroleptanalgesia is associated with severe respiratory depression and therefore should not e induced unless facilities for intermittent positive pressure ventilation are available 5. Preparation: Fentanyl and Droperidol tranquilizer mixtures a. They are used in dogs, primates, and small rodents, but contraindicated in cats because fentanyl may cause violent excitement b. These mixtures are used to produce deep sedation with profound analgesia sufficient for minor surgery such as lancing of superficial abscess but inadequate for major surgery. Anticonvulsants MOTOR DEPRESSANT 1. Epilepsy is a disorder of the brain that is characterized by recurring seizures. 2. Seizures, fits and convulsions are synonymous terms to describe the manifestation of abnormal brain function that are characterized by paroxysmal stereotyped alterations in behavior. Seizures can be caused by numerous abnormalities that affect neuronal function of the brain. Seizures with no demonstrable cause require therapy. 3. Preparations a. Phenobarbital: i. This is the drug of choice for control of seizure in dogs and cats. It should be used first in all cases. ii. It depresses the motor center of the cerebral cortex, by inhibiting the initiation of seizures; raises seizure threshold but does not prevent the spread of seizure activity. iii. It has wide spectrum of activity in different types of convulsive seizures. Given IV or orally, onset of action 12 h after oral administration b. Phenytoin depresses motor centers without depressing sensory areas; inhibits the spread of seizure activity. Given orally or IV; poor absorption from gut of dogs. Overdose causes incoordination, depression and gastric irritation. c. Primidone i. Has no hypnotic effect when used at doses with potent anticonvulsant effect in dogs. It is toxic to cats. ii. Often effective when phenytoin and/or Phenobarbital fail. Broken down to Phenobarbital and phenylethylmalon-amide in vivo; all of these have anticonvulsant activity. iii. Toxicity includes hepatotoxicity, polyphagia, polydispsia, sedation and behavioral change. d. Diazepam, a benzodiazepine tranquilizersedative, used to control status epilepticus. Not used for maintenance. It is a good choice for control of seizures incats but not in dogs.