Sedatives

Phenothiazines
1. Mechanism
  1. Dopamine Antagonism
2. CNS
  1. Anxiolytic
    1. Neuroleptic
      1. Tranquiliser
        Antiemetic
    2. Mild sedative, if dose is increased, will just prolong level of sedation & increase side effects
3. NO Analgesic properties
  1. Except Methotrimeprazine (small animal immobilon)
4. Side Effects/ Toxicity
  1. Basal Ganglia
    1. Movement disorders (Chronic use - humans)
  2. Pituitary Gland
    1. Increases Prolactin release (Chronic use - humans)
5. CVS
  1. Blocks alpha 1 - adrenoreceptors
    1. Vasodilation & Hypotension
      1. Can promote hypothermia
      2. Anti-arrhythmic action
6. GIT
  1. Antispasmodic action on gut
7. AntiHistamine (receptor blockade)
  1. AntiMuscarinic (receptor blockade)
    1. 5 - HT blockade
8. Potency of action dependent on the type of side chain attached to the N atom of the Phenothiazide ring
  1. R1 = Propylamine
    1. Increases Sedation
  2. R1 = Piperadine
    1. Anticholinergic activity
  3. R1 = Piperazine
    1. Less Sedative and Less Anticholinergic
9. Drugs
  1. Acepromazine (ACP)
    1. Used extensively (Pre-anaesthetic)
    2. Oral tablet (Dogs & Cats), Injection (Small & Large animals), Gel (Horses)
    3. Absorption
      1. Oral bioavailabilty: 20 - 55%
      2. Onset: IM: 20 min, I/V: 5 min
        Lower end of dose range used I/V
        Combined w/ Opiods (Boxers and small animals w/ CV compromise)
        IM Preferred
        I/V: Given slowly to avoid vasodilaton and hypotension
    4. Metabolism
      1. Liver
    5. Distribution
      1. t 1/2 = 4 - 6hrs
    6. Excretion
      1. Conjugated & Non-conjugated metabolites => Urine
    7. Low dose: Behavior; High dose: sedation
      1. Effective on young, anxious animals
    8. Potentiates action of other drugs
      1. Opiods
        General Anaesthetics (Barbituates)
        Local Anaesthetics
    9. May lower the threshold for epileptiform sezures
      1. Anticonvulsant properties
        Potent Spasmolytic
        Tx of Laminitis in Horses
  2. Propionylpromazine
  3. Chlorpromazine
    1. Less potent, longer duration, unreliable in horses (excitement)
  4. Promazine
    1. Better sedation, fewer side effects than Chlorpromazine
  5. Methotrimeprazine
    1. Small animal Immobilin
      1. Potent Analgesic
  6. Promethazine
    1. Irritant, Deep IM, Potent Antihistamine
Butyrophenoenes
1. CNS
  1. Dopamine Antagonism
    1. Sedative Action
      1. Potent Antiemetic
  2. Side Effects
    1. Hallucinations, Agitation (Humans)
2. CVS
  1. Vasodilation
    1. Hypotension
3. Drugs
  1. Azaperone
    1. Sedate/ modify behavior
      1. Pigs (Licensed)
        Tx of aggression
        Transport stress
        Obsteric conditions
        Premed for local and General Anaesthesia
      2. Potentiates Anaesthetic Agents
      3. Slight fall in BP
    2. Absoprtion
      1. Deep IM injection
        Behind ear (Pigs)
        Leave undisturbed for 20 min
    3. Distribution
      1. t 1/2: 2-3 hrs
  2. Fluanisone
    1. Hypnorm: Used in combination w/ Fentanyl
      1. Neurolept Anaesthesia
        Mice, rats, rabbits & guinea pigs
  3. Droperidol
    1. Potent Neuroleptic
    2. t 1/2: 6 - 8 hrs
      1. Potent Antiemetic
    3. Used in combination w/ Fentanyl
      1. Neuroleptanalgesia
Benzodiazepines
1. Mechanism
  1. Potentiation of GABA mediated Inhibition
2. CNS
  1. Primarily Anxiolytic action
  2. Muscle relaxation
  3. Anticonvulsant
  4. Little sedation in young, healthy animals
3. CVS/ Resp.
  1. Minimal depression
4. Drug interactions
  1. Synergistic effects with other central depressants
    1. Ex. Barbituates, Antihistamines and alcohol
5. Metabolism
  1. Liver => Active metabolites
6. Toxicity (Chronic use)
  1. Cognitive impairment
  2. Tolerance
  3. Dependence
7. Drugs
  1. Diazepam (Valium)
    1. Absorption
      1. Insoluble in H2O
        Dissolved in propylene glycol
      2. IV or Oral
      3. Rapid Onset
      4. Long acting
    2. Metabolism
      1. Liver
        Does not induce hepatic enzyme systems
        Severe hepatic dysfunction, prolonged duration of action possible
    3. Distribution
      1. t 1/2: 20 - 40hrs
      2. 95% Protein bound
    4. Side Effects
      1. Pain on injection
      2. Thrombophlebitis
      3. Cardiac Arrhythmias
    5. Uses
      1. To control status epilepticus
      2. Stimulate appetite
      3. + Ketamine (Horses and Small animals): Induce and Maintain Anaesthesia
      4. + Hypnorm (small mammals): Anaesthesia w/ muscle relaxation
  2. Midazolam
    1. Does NOT cause Thrmbophlebitis
    2. Absorption
      1. H2O soluble
      2. IV, IM, Oral
    3. Distribution
      1. Short duration
        t 1/2: Cats: 2 hr
  3. Climazolam
    1. Horses: Maintain Anaesthesia + Ketamine
  4. Tolezepam
    1. + Tiletamine (Dissociative Anaesthetic
8. Benzodiazepine Antagonists
  1. No intrinsic efficacy; Competetive Anatagonist
  2. Flumazenil
    1. Humans
    2. Dogs, Cattle, Sheep: Antagonism of Diazepam/Midazolam sedation
    3. Has some Inverse Agonist Activity
  3. Sarmazenil
    1. Antagonize Midazolam, when used in combination w/ Ketamine to maintain Anaesthesia in Horses
  4. Inverse Agonists
    1. Act @ GABA receptor
      1. CLOSE the Cl- channel
        Causes the neuron to become vulnerable to excitation
        May promote convulsions
Alpha 2 - Agonists
1. Vary in Selectivity for Alpha 1 and Alpha 2 receptors
  1. Some also bind Nonadrenergic Imidazoline receptors
    1. Stimulation = Hypotension and Anti-arrhythmic action
    2. Imidazoles
      1. Detomidine
        Really expensive
        Really potent
        Equipotent in Horses and Cattle
        Absorption
        IV or IM
        Distribution
        Longer duration
        t 1/2: 1 - 2 hrs (Horses)
        Urogenital
        Slows uterine electrical activity
        Better for pregnant cows
      2. Romifidine
        Distribution
        Longer duration
        t 1/2: up to 3 hrs
        CNS
        Causes less ataxia in horses
      3. Medetomidine
        Dogs, Cats, Exotics & Horses
        Absorption
        IM, IV or S/C
        Distribution
        t 1/2: 3 hrs
        Very potent & very selective for Aplha 2 receptors
        Profound ANaesthetic sparing effect
        Max effect on BP w/ low doses
        Equal mixtture of 2 enantiomers
        Dexmedetomidine
        Levomedetomidine
        Pharmacologically inactive
      4. Dexmedetomidine (Dogs)
        Very potent
        Greater slectivity for Alpha 2 receptors than Alpha 1
        CVS
        Antiarrhythmic
        Depresses HR
        Hypotension
        Pale/ blue tinged mucous membranes
        Distribution
        Highly protein bound: 94%
        Doses based on body surface area
        Anaesthetic sparing
        Reduce dose of induction by 30-60%
        Should only be used for procedures < 20 min
      5. Clodine
    3. Oxazolines
      1. Rilmenidine
    4. (DO NOT BIND to imidazoline receptors) Phenylethylamines
      1. Xylazine
        Absorption
        IM or IV
        Cows, Horses: 24 hr rule (before 2nd dose)
        Distribution
        t 1/2: Species, Route and Dose dependent
        Metabolism
        Metabolised to multiple products that are excreted in urine
        Low selectivity for Alpha 2 receptors
        Used in Small and Large animals
        CNS
        Species differences in sensitivity
        Ruminant > Horse/Dog > Pig
        CVS
        Arrhythmogenic
        Unlike modern drugs
        Urogenital
        Contraction of Uterine smooth muscle
        Not licensed for Cows in 3rd trimester => Abortion
2. CNS
  1. Sedation (Pre-synaptic)
  2. Analgesia
    1. Muscle Relaxation
      1. + Ketamine
    2. Given intrathecally or Extradurally
3. CVS
  1. Vasoconstriction
  2. Hypertension
    1. Bradycardia
      1. Due to Vagal reflex (feeback mechansims)
4. Works well w/ Opiods
  1. Anaesthetic sparing effects (50-95%)
5. RESP.
  1. Respiratory depression
    1. Reduction in airway resistance
    2. Xylozene (Sheep)
6. GIT
  1. Vomiting (Some species)
  2. GI motility depressed
7. Endocrine
  1. Inhibition of ADH
    1. Diuresis
  2. Inhibition of Insulin release
    1. Hyperglycemia
8. Urogenital
  1. Uterine contraction (Cows)
9. Alpha 2 - Anatagonists
  1. Atipamezole (Antisedan)
    1. "Reversal"
  2. Yohimbine
  3. Tolazoline
  4. Sedation induced by Alpha 2 - Agonists may be reversed by specific Alpha 2 - Antagonists
    1. Going to reverse Analgesic properties too!
  5. Absorption
    1. IM

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Phenothiazine_Ring (image/png)

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Sedatives

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	Erstellt von melian.yates vor etwa 11 Jahre