Adjunct to Anesthesia

Adjunct to anesthesia One of a number of drugs or techniques used to enhance anesthesia but that are not classified as anesthetics. Adjuncts to anesthesia include: - Pre-anesthetic medication - Muscle relaxants

Preanesthetic medications help both anesthetist and animal because it makes induction and maintenance of anesthesia easier for the anesthetist, safer, and comfortable to the patient. It's given usually before anesthesia but sometimes at/or immediately after the induction of anesthesia.

Pre-anesthetic medication groups 1. Anticholinergics 2. Antiemetics 3. Antihistamines 4. Barbiturates 5. Benzodiazepines 6. Opioids Or 1. Anticholinergics 2. Tranquilizers drugs 3. Narcotics drugs. 4. Sedative drugs and adrenergic agonist. 5. Neuroleptanalgesics Or 1. Anticholinergics 2. Tranquilizers 3. Opioids 4. Alpha2-Adrenergic Agonists 5. Alpha2-Adrenergic Antagonists 6. Tranquilizer-Opioid combinations

Examples: Page 1 of 25 Anticholinergics Alpha2-Adrenergic Agonists Atropine Sulfate Xylazine Hcl (Anased, Rumpun) Glycopyrrolate (Robinul – V) Detomidine (Dormosedan) Tranquilizers Medetomidine (Dormitor) Acepromazine Maleate Alpha2-Adrenergic Antagonists Droperidol Yohimbine (Yobine) Diazepam (Valium) Tolazoline (Priscoline) Midazolam (Versed) Atepmizole (Antisedan) Flumazenil (Romazicon) Tranqulizer-Opioid combinations Opioids Fentanyl Citrate – Droperidol (Innovar – vet) Morphine Sulfate Etrophine – Acepromazine (Immobilon LA) and Etrophine – Methotrimeperazine (Immobilon SA) Meperidine Hcl (Demerol, Pethidine) Methadone Hcl (Methadone, Dolophine) Oxymorphone Hcl (Numorphan) Fentanyl Citrate (Sublimaze) Carefentanil Citrate (Wildnil) Sufentanil and Alfentanil (Sufenta and Alfenta) Etrophine Hcl (M – 99) Agonist – Antagonist Opioids Butorphanol Tartrate (Torbutrol, Torbugesic) Bupernorphine (Buprenex, Temgesic) Pentazocine Lactate (Talwin)

Groups of pre anesthetic drugs 1. Anti cholinergic drugs. 2. Tranquilizers drugs. 3. Narcotics drugs. 4. Sedative drugs and adrenergic agonist. 5. Neuroleptanalgesics

Aims of Pre-medications: 1- To relieve anxiety, fear and resistance to anesthesia. 2- To decrease unwanted side effect of anesthetic agents. These effects may require modification depend on the species of animal and on the drugs used they include:- Vomiting (mainly in dogs and cats), poor quality of recovery, bradycardia, salivation and excessive muscle tone. 3- To reduce the dose of anesthetic in many but not in all cases, drug combination may have a lower side effect than a high dose of anesthetic. 4- To provide extra analgesia.

So: Preanesthetic drugs are used to prepare patient for induction and contribute to maintenance and smooth recovery from anesthesia. Specifically, these drugs are chosen to: 1- Calm the patient. 6- Decrease gastric fluid and acidity. Page 2 of 25 2- Induce sedation 7- Suppress or prevent vomiting or regurgitation. 3- Provide analgesia and muscle 8- Decrease anesthetic requirements. relaxation. 4- Decrease airway secretion and 9- Promote smooth induction and salivation. recovery from anesthesia. 5- Obtund autonomic reflex responses.

Anticholinergic drugs An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. Anticholinergics inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, etc. Anticholinergics are divided into three categories in accordance with their specific targets in the central and/or peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers. Anticholinergics are classified according to the receptors that are affected:  Antimuscarinic agents operate on the muscarinic acetylcholine receptors. The majority of anticholinergic drugs are antimuscarinics.  Antinicotinic agents operate on the nicotinic acetylcholine receptors. The majority of these are non-depolarizing skeletal muscle relaxants for surgical use that are structurally related to curare. Several are depolarizing agents.

of 25 Examples of common anticholinergics: Anti-Muscarinic agents Anti-Nicotinic agents Atropine Ipratropium (Atrovent) Bupropion (Zyban, Wellbutrin) - Ganglion blocker Benztropine (Cogentin) Orphenadrine Dextromethorphan - Cough suppressant and ganglion blocker Biperiden Oxitropium (Oxivent) Doxacurium - Nondeplorizing skeletal muscular relaxant Chlorpheniramine Oxybutynin (Ditropan, Hexamethonium - (Chlor-Trimeton) Driptane, Lyrinel XL) Ganglion blocker

Dicyclomine (Dicycloverine) Tolterodine (Detrol, Mecamylamine - Ganglion Detrusitol) blocker and occasional smoking cessation aid Dimenhydrinate(Dramamine) Tiotropium (Spiriva) Tubocurarine - Nondepolarizing skeletal muscular relaxant Diphenhydramine (Benadryl, Trihexyphenidyl Sominex, Advil PM, etc.) Doxylamine (Unisom) Scopolamine Glycopyrrolate (Robinul) Solifenacin Hydroxyzine (Atarax, Tropicamide Vistaril)

The most common plants containing anticholinergic alkaloids are:  Atropa belladonna (Deadly Nightshade), source of atropine  Brugmansia species (Brugmansia)  Datura species (Datura)  Hyoscyamus niger (Henbane)  Mandragora officinarum (Mandrake)

Drug: Atropine Class: Anticholinergic Page 4 of 25 MOA: Competitive blockade of muscarinic receptors DOA: 60–90 min (some species variation) ROA: (IV, I M, SC) Effect: Parasympatholytic: increased heart rate, decreased salivation/secretions, dilated pupils; gastrointestinal stasis, increases physiologic dead space (bronchodilation) Adverse: Tachycardia, arrhythmias, colic (equine) Approved: Dogs, cats, cattle, horses, sheep

Note :  Atropine should not be given to ruminants because it makes their secretion more viscid and therefore more difficult to remove from the mouth and respiratory tract.

Drug: Glycopyrrolate (Robinul) Class: Anticholinergic MOA: Blocks effect of acetylcholine at muscarinic receptors DOA: 2–4 hr ROD: (IV, IM, SC) Effect: Parasympatholytic: increased heart rate, decreased respiratory secretions, increases physiologic dead space (bronchodilation), does not cross placental or blood-brain barrier Adverse: Ileus, sinus tachycardia Approved: Dog, cat

Other anticholinergic agents: Dosage forms Main usage - Scopolamine (hyoscine) (levo-duboisine) - it is used in antidiarrheal medications - Methscopolamine - It is used to control diarrhea. - Aminopentamide (Centrine) - it is used to control vomiting and diarrhea in dogs and cats - Propantheline (Pro-Banthine) - it is used to treat diarrhea - it is used to treat urinary incontinence - It is used to treat bradycardia. - It is used to reduce colonic peristalsis in horses to allow rectal examination. - Pralidoxime (Protopam, 2-PAM) - It is used to treat Organophosphate intoxication.

Tranquilizers drugs:

of 25 Tranquilizers agents: drugs that cause a state of behavioral change in which the patient is relaxed and unconcerned by his surroundings.  Phenothiazine Derivatives Mechanism of action on CNS is not well understood. It has been proposed that they are Dopamine blockers. - They approved for use in wide variety of animals, and for administration by almost any rout. - They are relatively safe drugs to use when administered appropriately. - They should be given with care when used with other CNS depressants because of the additive effect. - Most phenothiazine derivatives are metabolized by the liver and excreted by the kidneys. - They can cause hypotension and hypothermia because of their vasodilator effect (alpha blockade). - They also can induce seizures (by lowering the seizure threshold) in epileptic animals. - They should not be used within 1 month of worming with organophosphate anthelmintic. - The tranquilizing effect may be reduced in an excited animal. Example: * Acepromazine maleat (Acepromazine, Promace) * Chlorpromazine HCl (Thorazine) * Promazine HCl * Prochlorperazine /isopropamide (Darbazine, Compazine) * Propionylpromazine * Methotrimeprazine * Promethazine Drug: Acepromazine (Promace; Acetylpromazine) Class: Phenothiazine tranquilizer (major) MOA: Antiadrenergic, anticholinergic, antihistaminic, antidopaminergic DOA: Dose dependent; 2–3 hr (prolonged in hepatic-compromised, geriatric, and pediatric patients) ROA: (IV, IM, SC, PO) Effect: Calming effect; decreased motor activity; antiemetic; no analgesia Adverse: Hypotension, penile paralysis (equine), decreased seizure threshold, prolonged duration with liver disease; anecdotal reports of profound respiratory and cardiovascular depression in Boxers Approved: Horses, cats, dogs.

of 25  Benzodiazepine derivatives Mode of action: (a) Exert many of their pharmacologic effects by enhancing the activity of CNS inhibitory neurotransmitters and opening chloride channel, thereby hyperpolarizing memberanes; also produce their effects by combining with CNS benzodiazepines receptors (BZ1, BZ2). Effects can be antagonized by the benzodiazepines antagonist Flumazenil. (b) Depress the limbic system, thalamus, and hypothalamus (reducing sympathetic output), thereby inducing a mild calming effect. (c) Reduce polysynaptic reflex activity, resulting in muscle relaxation. (d) Cause minimal CNS depression and produce anti-convulsant effects in most animals; may cause disorientation and agitation after rapid IV administration, particularly in cats. (e) Stimulate appetite and pica.

Example *Diazepam (Valium, Vazepam) * Midazolam

Drug: Diazepam (Valium) Class: Benzodiazepine tranquilizer (minor) MOA: Activates CNS benzodiazepine receptors, which increase inhibitory neurotransmitters (i.e., GABA, glycine) DOA: <3 hr ROA: (IV, IM, PO) Effect: Mild sedation, muscle relaxation, enhances effect of concurrently used agents Adverse: Excitement in some species (horses, dogs), hepatoxicity has been reported with PO administration in cats Approved: Dog

Drug: Midazolam (Versed; Hypnovel): Class: Benzodiazepine tranquilizer (minor) MOA: Activates CNS benzodiazepine receptors, which increase inhibitory neurotransmittors (i.e., GABA, glycine) DOA: <2 hr (duration is slightly less than diazepam) ROA: (IV, IM, SC) Effect: Mild sedation, muscle relaxation; works well IV or IM Adverse: Excitement in some species, respiratory depression Approved: None

of 25 Drug: Flumazenil (Romazicon) Class: Benzodiazepine receptor antagonist MOA: Competes with benzodiazepines for receptor DOA: 2–3 hr. ROA: (IV) Effect: Specific reversal of benzodiazepine tranquilizers Adverse: Rare Approved: None.

 Alpha2-Adrenergic Agonists

Mode of action: produce CNS depression by stimulating both presynaptic alpha2- adrenoreceptors in the CNS and peripherally. - decreasing nor-epinephrine release centrally and peripherally reducing ascending nociceptive transmission. The net result is a decrease in CNS sympathetic outflow and a decrease in circulating catecholamines and other stress-related substances; the CNS effects of alpha2-agonists can be antagonized by aplha2-receptor antagonists. Example * Xylazine (Rompun) * Detomidine * Medetomidine

Drug: Xylazine (Rompun; Ansed) Class: Alpha2 agonist MOA: Activates CNS alpha2 receptors, which inhibit neurotransmitter release in brain DOA: Dose and species dependent; 15–30 min (analgesia); 1–2 hr (sedation) ROA: (IV, IM, SC) Effect: Sedation, analgesia, muscle relaxation Adverse: Bradycardia, conduction disturbances, hypotension, respiratory depression, hypoxia Approved: Horses (10% formulation); dogs

Drug: Medetomidine (Dormitor) Class: Alpha2 agonist MOA: Activates CNS alpha2 receptors, which inhibit neurotransmitter release in brain DOA: Dose and species dependent; 60–120 min ROA: (IV, IM, SC) Page 8 of 25 Effect: Sedation, analgesia, muscle relaxation Adverse: Bradycardia, conduction disturbances, hypotension, respiratory depression, hypoxia Approved: Dogs.

Drug: Romifidine (Sedivet) Class: Alpha2 agonist MOA: Activates CNS alpha2 receptors, which inhibit neurotransmitter release in brain DOA: Dose dependent; >120 min ROA: (IV, IM, SC) Effect: Sedation, analgesia, muscle relaxation Adverse: Bradycardia, conduction disturbances, hypotension, respiratory depression, hypoxia Approved: Not currently approved in the United States, but studies have been published for dosages in dogs and horses.

Drug: Tolazoline (Tolazine) Class: Alpha1 and alpha2 receptor antagonist MOA: Occupies and antagonizes alpha2 receptors (least specific for the alpha2 receptor) DOA: 2 hr ROA: (IV, IM) Effect: Reverses effects of alpha2 agonists Adverse: Hypotension with rapid injection due to vasodilatory effect, excitement, tremors, salivation, tachypnea Approved: Horses

Drug: Yohimbine (Yobine)

Class: Alpha2 antagonist MOA: Blocks alpha2 receptors; also has antiserotonin activity DOA: <1 hr ROA: (IV, IM) Effect: Reverses effects of alpha2 agonists Adverse: Hypotension with rapid injection due to vasodilatory effect, excitement, tremors, salivation, tachypnea Approved: Dogs

Narcotic analgesic

of 25 Narcotic agents (drugs): - a drug that produce state of sleep accompanied by analgesia. Narcotic analgesic Act by reversible combination with one or more specific receptors in the brain and spinal column - Produces a variety of effects  Analgesia  Sedation  Dysphoria  Euphoria  excitement - Act as an agonist or antagonist • Pure agonists stimulate all receptors – morphine, fentanyl and oxymorphone • Mixed agonists/antagonists block one type of receptor and stimulate another • Pure antagonists such as naloxone will reverse the effects of pure and mixed agonists with very little clinical effect on their own Also classified according to their analgesic activity and their addiction potential Pure agonists are more effective for severe pain in order of decreasing potency they are: Fentanyl ; Oxymorphone ;Buprenorphine ; Meperidine ; Pentazocine Commonly used as an analgesic in premedication, as an induction agent or can be used for balanced anesthesia and post-operative pain control. Provides some sedation and may potentiate the action of the sedative that it is given with has a synergistic effect. Fentanyl, sufentanil and oxymorphone are often part of a balanced anesthetic regimen. Fentanyl is available as a transdermal patch in various sizes for long-term analgesia used as neuroleptanalgesia in combination with tranquilizer. Morphine can be injected epidurally or sub-arachnoidally for regional analgesia.

Other narcotic analgesic: Pethidine; Methadone; Etorphine; Fentnyl

of 25 Opioids Agonists Naturally occurring Narcotics Moe of action: Act by reversible combination * Opium with one or more specific receptors (i.e. μ, κ, *Morphine sulphate (Duramorph) δ) in the brain and spinal cord to produce a Synthetic Narcotics variety effects including analgesia, euphoria, * Meperidine (Demerol) dysphoria,, and excitement. * Oxymorphone (Numorphan) * Butorphanol tartrate (Torbutrol, Torbugesic) The opioids are used as preanesthetic or post- * Fentanyl (Sublimaze) anesthetic because of their sedative and * Hydrocodone bitartrate (Hycodan, Tussigon) analgesic properties. * Etorphine (M-99) * Pentazocine (Talwine, Takwin-V) Clinical uses: Opioid agonists are used for * Diphenoxylate (Lomotil) analgesia, sedation, restraint, anesthetics, * Apomorphine treatment of coughing, and treatment of * Methadone (Dolophine) diarrhea. * Codeine *Carfentanil (Wildnil) Adverse side effects: these can include * Buprenorhine (Buprenex) respiratory depression, excitement (cat and horses), nausea, vomiting, diarrhea, defecation, panting, and convulsion, Overdose causes profound respiratory depression Opioid Antagonists They block the effects of Opioids by binding Classified in to: with opiate receptors, displacing narcotic - Pure antagonists molecules already present, and preventing - Partial antagonists (may have some agonist further narcotic binding at the site activity). * Nalaxone (Nalaxone HCl, Naracan) * Nalorphine (Nalline *Note: Opioids: the term opioids is refer to all exogenous and synthetic compounds that bind to specific subpopulation of opioid receptors.

Opioid receptors • Mu found in pain - regulating areas of the brain. Contribute to: • analgesia • Euphoria • Respiratory depression • Physical dependence • Hypothermic action • Kappa found in the cerebral cortex and spinal cord Contribute to: • Analgesia • Analgesia • Sedation • And miosis Page 11 of 25 • Sigma may be responsible for struggling, whining, hallucination and mydriatic effects. • Delta modify Mu receptor activity.

* Note: Sequential analgesia: is term introduced to describe the use of partial agonist subsequent to pure agonists (usually Fentanyl) in an attempt to reverse residual respiratory depression whilst maintaining analgesia.

Drug: Morphine (Duromorph) Class: Opioid agonist MOA: Activates μ opioid receptors in CNS and other organs DOA: 4 hr. ROA: (IM, SC, PO) Effect: Analgesia, sedation, alleviates pulmonary edema by increasing venous capacitance; provides 10–24 hr of analgesia as far forward as the thoracic limbs when administered epidurally. Adverse: Respiratory depression, flatulence, constipation, histamine release with IV administration; excitement possible in horses and cats Approved: None

Note: should be used under strict supervision because of its potential for abuse.

Morphine and its substitutes: 1. It has a potent analgesic and sedative action due to depression of the sensory area of cerebral cortex. 2. It has a potent respiratory depression and hypotension action. 3. It stimulate vomiting center and gastrointestinal tract for that it is contraindicated in intestinal obstruction. Contraindications • Previous history of opioid excitement. • Morphine has a higher incidence of producing vomiting so should be avoided in cases of GI obstruction and diaphragmatic hernia. • Morphine has both excitement and depression effect the final effect depend on three factors: 1-Species of animal. 2-Dose. 3- Rate of administration • Excitement occurs if given rapidly IV. • Horse and cat are particularly susceptible to excitatory effects . • Dogs generally show sedation although hypnosis can be seen in higher doses in sick animals.

of 25 • Dogs that are not in pain may show excitement Excitement symptom: - mydriasis, nausea and convulsion. Sedation symptom: - miosis, respiratory depression, bradycardia, hypothermia. • Morphine causes excitement in cat and pig and sheep in horse it may cause sedation and sometime excitement.

Drug: Meperidine (Demerol; Pethidine): Class: Opioid agonist MOA: Activates μ receptors in CNS and other organs DOA: <2 hr ROA: (IM, SC) Effect: Analgesia, sedation, increases venous capacitance Adverse: Respiratory depression, flatulence, constipation, bradycardia, can cause histamine release with rapid IV injection, excitement possible in cats, horses Approved: None

Notes:  It also may be combined with a tranquilizer for use as an anesthetic agent (neuroleptanalgesic).  Naloxone is the preferred antagonist.

Drug: Oxymorphone (Numorphan): Class: Opioid agonist MOA: Activates μ receptors DOA: 2–6 hr ROA: (IV, IM, SC) Effect: Analgesia, sedation Adverse: Respiratory depression, bradycardia, excitement in some species Approved: Dogs, cats.

Notes  It is approximately 10 times more potent analgesic than Morphine.  This drug used primarily in dogs for restraint, for diagnostic procedures, and for minor surgical procedures.  It may be combined with a tranquilizer for use as an anesthetic agent (neuroleptanalgesic.  Naloxone is the antagonist. Drug: Butorphanol (Torbugesic; Torbutrol): Class: Opioid agonist/antagonist MOA: Activates (k) and blocks (μ) opioid receptors in brain and spinal cord Page 13 of 25 DOA: 1–2 hr ROA: (IV, IM, SC, PO) Effect: Analgesia, sedation Adverse: Respiratory depression (less than with pure opioids), bradycardia, flatulence, defecation, hypothermia Approved: Horses, dogs.

Notes:  Torbugesic is approved for treatment of the pain associated with colic in horses.  It is also used in combination with other sedative / tranquilizer in horses, dogs, and cats as a preanesthetic for minor surgical procedure.

Drug: Fentanyl (Sublimaze) Class: Opioid agonist MOA: Activates μ opioid receptors DOA: <1 hr; ROA: used as constant rate infusion (IV) or transdermal patch Effect: Analgesia, sedation, 75–125 times as potent as morphine Adverse: Respiratory depression, bradycardia, excitement in some species Approved: None. Note:  Fentanyl transdermal patches are sometimes used in animals to control sever pain.

Hydrocodone bitartrate (Hycodan, Tussigon): it is an opioid agonist; it is used as antitussive agents in dogs.

Drug: Etorphine (M-99) Class: Opioid agonist MOA: Activates μ opioid receptors DOA: <2 hr ROA: (IV, IM) Effect: Sedation, analgesia, immobilization, 80–1,000 times as potent as morphine Adverse: Profound respiratory depression, bradycardia, hypertension Approved: Animal use only: exotic animal immobilization. Notes:  It is an opioid that produces analgesic effects 1000 times those of morphine.  It is restricted to use by veterinarians in zoo or exotic animal practice.

of 25  It is lethal to people accidently inject themselves (it is also can be absorbed through intact skin) if the antagonist (Diprenorphine) is not administered immediately.

Drug: Pentazocine (Talwin) Class: Opioid agonist/antagonist MOA: Activates (k) and blocks (μ) opioid receptors in brain and spinal cord: low potency DOA: <2 hr ROA: (IM, SC) Effect: Analgesia, sedation; 0.1–0.3 times potency of morphine Adverse: Respiratory depression (less than with pure opioids), bradycardia, flatulence, defecation, hypothermia Approved: Horses, dogs.

Diphenoxylate (Lomotil): Synthetic opioid agonist combined with atropine for use as an antidiarrheal agent. Apomorphine - generic Labeling: it is an opioid with the principle effect of inducing vomiting by stimulating the chemoreceptor trigger zone in the brain. This drug is often administered by placing a portion of a tablet in the conjunctival sac for absorption.

Methadone (Dolophine): it is a synthetic opioid that was developed as a treatment for Morphine and Heroin addiction in humans. It is primarily use in veterinary medicine is in the treatment of colic pain in horses.

Codeine - generic labeling or in combination: it is an opioid that is available in humans - label products for use as an antitussive in dogs.

Drug: Carfentanil (Wildnil) (requires DEA special user’s permit) Class : Opioid agonist MOA: Activates opioid μ receptors DOA: Prolonged if not reversed ROA: (IM) Effect: Analgesia, sedation, immobilization Adverse: Hypoventilation, excitement (some species), hypothermia, muscle fasciculations Approved: Animal use only, reserved for use in immobilization of wildlife and exotic species Page 15 of 25 Note:  Carfentanil (Wildnil) is used to induce wildlife anesthesia. It has 10.000 times the potency of Morphine.

Drug: Buprenorphine (Buprenex; Temgesic; Vetergesic) Class: Opioid partial agonist MOA: Activates opioid receptors in brain and spinal cord DOA: 6–12 hr ROA: (IV, IM, SC) Effect: Analgesia; minimal sedation Adverse: Respiratory depression (less than with pure opioid agonists), bradycardia, flatulence, defecation, hypothermia; may be more difficult to reverse due to high receptor affinity Approved: None

Drug: Alfentanil (Alfenta; Rapifen) Class: Opioid agonist MOA: Activates μ opioid receptors DOA: <30 minutes; used as constant rate infusion; ROA :( IV) Effect: Analgesia, sedation Adverse: Respiratory depression, bradycardia, excitement in some species Approved: None; rarely used in veterinary medicine

Drug: Diprenorphine (Revivon, M50-50) Class : Opioid agonist/antagonist MOA: Blocks opioid receptors DOA: Short (renarcotization following reversal of potent opioids has been reported); ROA: (IV, IM). Effect: Used to antagonize etorphine Adverse: Opioid sedation and respiratory depression may persist with overdose Approved: Animal use only, for reversal of etorphine in wildlife and exotic species

Opioid antagonist Are used to antagonize the effect of opioid agonist.

Drug: Naloxone (Narcan) Class: Opioid antagonist Page 16 of 25 MOA: Antagonizes all opioid receptors DOA: 30–45 min ROA: (IV, IM, SC) Effect: Reverses the effects of opioid agonists, including respiratory depression and analgesia; has been used in the treatment of hemorrhagic shock Adverse: Stimulates sympathetic nervous system: potential for cardiac arrhythmias Approved: None

Drug: Nalbuphine (Nubain) Class: Opioid agonist/antagonist MOA: Antagonizes μ receptor, activates kappa receptors DOA: 2–3 hr ROA: (IV, IM, SC) Effect: Analgesia, sedation Adverse: Minimal respiratory depression Approved: None

Drug: Nalmefene (Revex) Class: Opioid antagonist MOA: Antagonizes all opioid receptors DOA: Longer acting than naloxone ROA: (IV, IM, SC) Effect: Reverses effects of opioid agonists, including respiratory depression and analgesia Adverse: Stimulates sympathetic nervous system; potential for cardiac arrhythmias Approved: None

Drug: Naltrexone (Trexonil) Class: Opioid antagonist MOA: Antagonizes all opioid receptors DOA: Longer acting than naloxone ROA: (IV, IM,SC) Effect: Reverses the effects of opioid agonists, including respiratory depression and analgesia; available as an oral preparation for humans. Adverse: Stimulates sympathetic nervous system: potential for cardiac arrhythmias Approved: Used for reversal of carfentanil in exotic species.

Sedative drugs and adrenergic agonist. Sedative is defined as a drug, which relieves anxiety and as a result tends to make it easier for the patient to rest or sleep – in fact, they are usually associated Page 17 of 25 with drowsiness. Many drugs fall into the sedative and the hypnotic categories, the differentiation usually being related to dose. They are best considered as one group, exemplified by chloral hydrate or xylazine where low doses cause drowsiness and higher doses cause sleep. So sedation mean calming due to mild degree of depression of central nervous system and most sedative cause drowsiness.

So sedative and anxiolytic premedication decrease anxiety, fear and stimulation of CNS, so it is useful to decrease the dose of anesthetic agents they include: 1-Phenothiazine (Aceprmazine) (Proponylpromazine) (Promethazine) (Chlorpromazine). 2- Butyrophenones (Tranquilizers, anti-emetic). 3- Azaperon (in horses). 4- Benzodiazepines

5- α2 adrenoreceptor agonists: Xylazine, Clonidine, Detomidine, Medetomine and romifidine.

Neuroleptanalgesics Any combination of an analgesic and a tranquilizer (i.e. oxymorphone and acepromazine) ( Acepromazine + Fentanyl) (Droperidol + fentanyl) Or combination between Sedative + Narcotic analgesic Like (Xylazine + Morphine) (Xylazine + Butorphenol)

So: 1- Fentanyl and Droperidol (Innovar - vet): the only commercially available Neuroleptanalgesic 2- Acepromazine and Morphine Acepromazine and Oxymorphone may be prepared by a clinician Acepromazine and Butorphanol Clinical uses: They are used for:  Sedation :Heavier sedation (depending on dose) for short procedures (i.e. wound suturing, porcupine quill removal)  Cardiac or shock cases  Restraint

of 25  And to produce anesthesia.

Adverse side effects: these can include:  Panting (May hyperventilate, or pant a lot )  Flatulence  Animal may defecate or vomit  Personality changes  Increased sound sensitivity (Animal may become hyperactive to auditory stimuli)  And bradycardia  Over dose may cause severe depression of CNS, Respiratory system and cardiovascular system.

of 25 Adjunct to anesthesia: Muscle Relaxants

Muscle relaxant: The drugs which causes relaxation of voluntary muscles by acting on the neuromuscular junction or spinal cord. Indication: - 1. To produce good muscle relaxation during surgical operation i.e. orthopedics or deep abdominal surgery. 2. To facilitate end tracheal intubations. 3. To facilitate ventilation in thoracic surgery. 4. To facilitate correction of dislocated joint. 5. To decrease the doses of general anesthesia. Contraindication: - 1. In animal with respiratory, liver or kidney diseases. 2. In animals suffering from glaucoma. 3. In animals, being recently (30 days) treated with any antibiotics the name which ends in mycin or with organophosphorus compound because these drugs increase the intensity of paralysis and prolong the recovery period. 4. Muscle relaxant drug should not be used without general anesthesia.

Release of acetylcholine from neurons at the neuromuscular junction

of 25 Mechanism of skeletal muscle relaxation evoked by interference with normal peripheral neuromuscular function: 1. At presynaptic sites A. Inhibition of ACh synthesis (e.g hemicholinium blocks choline uptake) B. Inhibition of Ach release 1. CA++ deficiency, Mg++ increases 2. Procaine 3. Tetracycline and aminoglycoside antibiotics. 4. Some ᵦ - blockers. 5. Botulinum toxin 2. At posynaptic sites A. Persistent depolarization with an agonist that has a longer duration of action than ACh (e.g., succinylcholine chloride). B. Competitive block of ACh receptors causing non-depolarizing blockade (e.g., curare, pancuronium). Types of neuromuscular blocks I. Phase I block: depolarizing block (succinylcholine). II. Phase II block: nondepolarizing block (pancuronium) III. Mixed block: any combination of II and I. IV. Dual block: excessive amounts of depolarizing agents producing phase II block. V. Nonacetylcholine block (procaine, botulinum, decreased Ca++, increased Mg++, decreased K+).

Sequence of muscle of muscle relaxation 1- Oculomotor m. Palpebral m. Fascial m. Tongue and pharynx jaw and tail limbs pelvic m. Caudal abdominal m. Cranial abdominal m. Intercostal m. Larynx diaphragm A. The sequence of motor blockade is highly variable in clinical patients. B. Motor activity to the limbs may appear to return (twitching, jerking) before the diaphragm is fully functional. 2. Intercostal and diaphragmatic muscles are thought to be affected last. 3. Recovery is generally in the reverse order of paralysis. 4. It is possible but difficult to titrate the specific neuromuscular blocking drugs (NMBDs) to paralyze the muscles of the eye while maintaining diaphragmatic function.

of 25 Specific neuromuscular blocking drugs (NMBDs) I. Depolarizing drug act like ACh A. Succinylcholine chloride (Sucostrin, Anectine, Quillicine, suxamethonium) II. Nondepolarizing drugs; competitive blocking drugs A. D-Tubocurarine chloride (curare, Metubine) B. Gallamine triethiodide (Flaxedil) C. Pancuronium bromide (Pavulon) D. Vecuronium bromide (Norcuron) E. Atracurium besylate (Tracrium) F. Mivacurium chloride (Mivacron) G. Doxacurium chloride (Nuromax) H. Pipecuronium (Arduran).

Drug: Guaifenesin (Guailaxin; Glycerol guaiacolate) Class : Central-acting muscle relaxant MOA: Depresses internuncial neuron transmission; central-acting muscle relaxant DOA: Dose dependent; 30 min ROA: (IV) Effect: Muscle relaxation, sedation Adverse: Very safe although overdose can occur, which manifests as forelimb rigidity followed by respiratory paralysis Approved: Horses Note:  Internuncial neuron: a connecting neuron in a neural pathway, usually serving as a link between two other neurons.

Drug: Succinylcholine (Anectine; Sucostrin; Scoline) Class: Depolarizing noncompetitive neuromuscular blocker MOA: Depolarizes nicotinic receptors on muscle motor end plate and prevents neuromuscular transmission. DOA: <15 min; ROA: (IV) Effect: Nonreversible (short-duration) skeletal muscle paralysis Adverse: Respiratory paralysis (necessary equipment to provide mechanical ventilation should be available if this drug is used); prolonged effect with hepatic compromising diseases due to dependency on metabolism by the liver-derived enzyme, pseudocholinesterase; muscle fasciculations; hyperkalemia; known trigger of malignant hyperthermia Approved: None

of 25 Drug: Tubocurarine (Curare) Class: Competitive nondepolarizing neuromuscular blocker MOA: Competitive blockade of acetylcholine receptors of neuromuscular junction DOA: <30 min ROA: (IV) Effect: Reversible skeletal muscle relaxation Adverse: Respiratory paralysis (must control respiration), causes histamine release that results in hypotension and bronchoconstriction Approved: None

Drug: Gallamine (Flaxedil): currently not available commercially Class: Nondepolarizing neuromuscular blocker MOA: Competitive blockade of acetylcholine receptors of neuromuscular junction; prevents muscle contraction DOA: <30 min ROA: (IV) Effect: Reversible skeletal muscle relaxation Adverse: Respiratory paralysis, tachycardia, hypertension Approved: None (has been used in reptiles for immobilization)

Drug: Pancuronium (Pavulon) Class: Competitive nondepolarizing neuromuscular blocker DOA: 30–45 min ROA: (IV) MOA: Competitive blockade of acetylcholine receptors of neuromuscular junction Effect: Reversible skeletal muscle paralysis Adverse: Respiratory paralysis (must control ventilation), minimal cardiovascular effects although may cause transient tachycardia; prolonged effect in renal- and hepatic-compromised patients Approved: None

Drug: Vecuronium (Norcuron) Class: Competitive nondepolarizing neuromuscular blocker MOA: Competitive blockade of acetylcholine receptors of neuromuscular junction DOA: <30 min ROA: (IV) Effect: Reversible skeletal muscle relaxation Adverse: Respiratory paralysis (must control respiration), minimal cardiovascular effects; significant hepatic dysfunction will prolong effect Approved: None

of 25 Drug: Atracurium (Tracrium**) Class: Competitive nondepolarizing neuromuscular blocking agent MOA: Competitive blockade of acetylcholine receptors at neuromuscular junction DOA: <30 minutes (undergoes Hofmann elimination: spontaneous nonenzymatic degradation at body pH; also metabolized by esterases) ROA: (IV) Effect: Reversible skeletal muscle relaxation Adverse: Respiratory paralysis (must support respiration), minimal cardiovascular effects, may cause histamine release Approved: None

Drug: cis-Atracurium (Nimbex) Class: Competitive nondepolarizing neuromuscular blocking agent MOA: Competitive blockade of acetylcholine receptors of neuromuscular junction DOA: <20–30 min (undergoes Hofmann elimination: spontaneous nonenzymatic degradation at body pH) ROA: (IV) Effect: Reversible skeletal muscle relaxation Adverse: Respiratory paralysis (must control respiration), minimal cardiovascular effects Approved: None

Drug: Neostigmine (Prostigmine; Stiglyn) Class: Acetylcholinesterase inhibitor MOA: Inhibits acetylcholinesterase and allows accumulation of ACh, enhances ACh release, induces repetitive firing of the motor nerve terminal DOA: Onset of action is 7–10 min; duration of action is relatively short ROA: (IV) Effect: Antagonize nondepolarizing neuromuscular blockers to restore neuromuscular transmission, onset of action is rapid Adverse: Parasympathetic stimulation including bradycardia, airway constriction, increased secretions Approved: None

Drug: Pyridostigmine (Regonol) Class: Acetylcholinesterase inhibitor MOA: Inhibit acetylcholinesterase and allow accumulation of ACh, enhance ACh release, induce repetitive firing of the motor nerve terminal DOA: Onset of action is 12–16 min and duration 40% longer than neostigmine and Page 24 of 25 Edrophonium ROA: (IV) Effect: Antagonize nondepolarizing neuromuscular blockers to restore neuromuscular transmission Adverse: Parasympathetic stimulation, including bradycardia, airway constriction, increased secretions Approved: None

Drug: Edrophonium (Tensilon) Class: Acetylcholinesterase inhibitor MOA: Inhibits acetylcholinesterase and allows accumulation of ACh, enhances ACh release, induces repetitive firing of the motor nerve terminal DOA: Onset of action is rapid (1–2 min); duration relatively short ROA: (IV) Effect: Antagonize nondepolarizing neuromuscular blockers to restore neuromuscular transmission Adverse: Parasympathetic stimulation: bradycardia, airway constriction, increased secretions Approved: None