Drugs Affecting the Central Nervous System

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Drugs Affecting the Central Nervous System

• Pharmacology 49.222
• Bill Diehl-Jones RN, PhD
• Faculty of Nursing and Department of Zoology

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Agenda

• Zen Review
• CNS drugs
• anxiolytics and hypnotics
• stimulants
• Anaesthetics
• Antidepressants

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Anxiolytics and Hypnotics
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Two Classes

• Benzodiazepines
• pam and lam
• Eg clonazepam, midazolam, lorazepam
• Others
• Buspirone
• Barbiturates
• Non-barbiturates

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Benzodiazopines

• Bind adjacent to GABA receptor
• Enhances affinity of receptor for GABA
• Hyperpolarizes neurons, prevents firing

Cl-
Benzodiazipene
GABA
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Benzodiazopines

• Currently, mainstay of anxiolytic therapy
• Whats good about benzodiazepines
• Relatively high therapeutic index (O/D is rare)
• Also useful for treating muscle (diazepam) and
  sleep (lorazepam) disorders, seizures
  (clonazepam)
• Whats bad about benzodiazepines
• Effects potentiated by alcohol

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Buspirone

• Use
• General anxiety disorders
• Mode of action
• Activates 5-HT1a1 receptor (and possibly others)
• Slow onset, less drowsiness, fatigue than most
  benzodiazepines

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Barbiturates

• Examples pentobarbital (als)
• Clinical Use
• Formerly, main anxiolytics
• Now, used for anaesthesia, anticonvulsant
• Mode of action
• Inhibits Na/K transport in portion of RAS
• Whats bad
• Drowsiness, hangover
• Induce P450 enzymes (so what?)

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Non-Barbiturates

• Chloral Hydrate
• Antihistamines
• Eg diphenhydramine
• Alcohol
• Eg Laphroiag Single Malt Scotch
  
  
  
  
  
  
  
  
  
  

NAD
NADH
NAD
NADH
Acetaldehyde
Acetate
Disulfaram
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CNS Stimulants
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Flavours

• Psychomotor Stimulants
• Amphetamine
• Caffeine
• Theophylline
• Nicotine
• Psychotomimetic Drugs
• Lysergic Acid Diethylamide (LSD)
• Phencyclidine (Angel Dust)
• Tetrahydrocannabinol (THC)

Mehylxanthines
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Amphetamines "Faster, faster, until the thrill
of speed overcomes the fear of death."Hunter S.
Thompson

• Clinical Use
• Few, due to side effects
• ADHD and Narcolepsy
• Mode of Action
• Releases intracellular catecholamines
• Blocks MAO
• Stimulates entire CNS and sympathetic branch of
  ANS

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Mechanisms of Action of Amphetamines
Dopa
MAO
-
Dopamine 5-HT NE

Amphetamine
Increased NT
Receptor
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Clinical Effects of Amphetamines

• CNS
• Increased alertness
• longer-lasting than cocaine
• decreased fatigue/appetite
• Irritability, weakness
• amphetamine psychosis
• Arrhythmias, circulatory collapse

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Methylxanthines

• Clinical Uses
• Cardiovascular (caffeine/theo)
• Positive inotrope/chronotrope
• Apnea/bradycardia
• Asthma (theo)
• Why?
• Other effects
• Diuretic
• stimulant

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Methylxanines

• Modes of Action
• Increases Cai
• Increases cAMP, cGMP
• Blocks adenosine receptors

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Methylxanthine Facts

• Caffeine
• Lethal dose is 10 g (100 cups)
• Withdrawal symptoms in people who routinely have
  more than 600 mg/day (6 cups)
• Theophylline
• LOTS in tea

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Nicotine

• Clinical Uses
• None
• Mode of Action
• Low dose
• Ganglionic stimulation
• High dose
• Ganglion blockade

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Nicotine

• Physiological Effects
• CNS
• Crosses blood-brain barrier
• Low dose euphoria, relaxation, arousal
• High dose respiratory effects, hypotension
• Peripheral
• Again, depends on dose

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Psychotomimetic Drugs
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LSD

• Clinical Uses
• ?
• Modes of Action
• 5-HT agonist
• Physiologic Effects
• Sympathetic
• Pupillary dilation, increased BP, piloerection
• CNS
• Altered perceptual states
• True dependence rare

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THC

• Clinical Uses
• ?
• Modes of Action
• THC receptors exist in CNS, but mode unknown
• Physiological effects
• Immediate, peak at 20 min
• Impairs short term memory, produces euphoria,
  increases apetite, increase HR, decrease BP

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PCP

• Clinical Uses
• Anaesthetic (ketamine -research only)
• Mode of Action
• DO, 5-HT, NE reuptake inhibitor
• Physiological Effects
• Dissociative behaviour, coma

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Anaesthetics
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What is Anaesthesia?
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What Factors are Important in Anaesthetic
Selection?
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Preanaesthetics

• Anticholinergics
• Antiemetics
• Antihistamines
• Barbiturates
• Benzodiazepines
• WHY?

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Phases of Anaesthesia

• Induction
• Unconsciousness rapidly produced (thiopental)
• Muscle relaxants - vecuronium
• Maintenance
• Vital signs, response to stimuli gauged
• Volatile gases usually used. Why?
• Recovery
• Involves redistribution rather than metabolism

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Depth of Anaesthesia

• Stage I Analgesia
• Loss of pain sensation
• At level of spinothalamic tract
• Stage II Excitement
• Delerium, combative behaviour, BP increase
• Barbiturates used to manage this
• Stage III Surgical Anaesthesia
• Regular respiration, muscle relaxation, eye
  movements cease
• Stage IV Medullary Paralysis
• Depression of vasomotor/respiratory centers
• Implications?

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General Anaesthetics

• Inhaled
• Intravenous
• Local

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Inhaled Anaesthetics

• Primarily used for maintenance
• Concentration can be rapidly altered
• Physiological Effects
• Bronchodilation, decr. ventilation, incr. brain
  perfusion
• Potency a factor of lipid solubility. Why?
• Measured as a function of MAC

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Examples of Inhaled Anaestheticsand Relative MAC
Values
Ether
Halothane
Nitrous Oxide
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HomeworkRefer to Table 11.7 for Characteristics
of Inhalation Anaesthetics
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Intravenous Anaesthetics
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Flavours of Intravenous Anaesthetics

• Barbiturates
• Thiopental
• Benzodiazepines
• Midazolam
• Opioids
• Morphine
• Meuroleptanaesthesia
• Droperidol/fentanyl (INNOVAR)
• Ketamine

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Differences Between Inhalation and Intravenous
Anaesthetics

• Inhalation likely no discrete receptors
• Intravenous specific receptors
• For specific differences, refer to Table 11.9

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Local Anaesthetics

• Applied topically
• All have amino group linked to lipophilic portion
• Block conduction of nerve impulses to CNS
• Generally, these inhibit Na channels
• How would this affect action potentials?
• Examples Procaine, lidocaine

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Antidepressants
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Major Groups

• Tricyclics
• SSRIs
• MAO Inhibitors
• Drugs to treat Mania

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Tricyclics/Polycyclics

• Examples
• Amitriptyline, imipramine
• Mode of Action
• Inhibit NE, 5-HT, DO re-uptake
• Also have muscarinic and adrenergic effects
• How is this manifested in terms of side effects
• Clinical Effects
• Elevate mood, mental alertness, reduces morbid
  preoccupation in 50 70 of patients

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SSRI Inhibitors

• Examples
• Fluoxetine, Zoloft, Paxil
• Mode of Action
• Selectively block 5-HT reuptake
• Clinical Effects
• Effective in treating depression, OCD
• Fewer side effects than TCAs. Why?

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MAO Inhibitors

• Examples
• Phenylzine, isocarboxazide
• Mode of Action
• MAO inactivates excess NE, DO, 5-HT
• Inhibitors increase the amounts of these
  neurotranmitters
• Physiological Effects
• Depression
• problems with this drug

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Lithium Salts

• Mode of Action
• Affects IP3, blocks Na channels
• Clinical Effects
• Tmt of manic/depressive patients
• VERY TOXIC

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Neuroleptics

• Antischizophrenic/Antipsychotic Drugs

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Categories of Neuroleptics

• Phenothiazines
• Eg Chlorpromazine
• Benziosoxazoles
• Eg Respiridone
• Dibenzodiazepines
• Eg Cloazapine
• Butyrophenones
• Eg Haloperidol

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How do They Work?

• DO receptor blockers
• 5-HT receptor blockers

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Clinical Effects

• Affect corticostriatial pathways in brain
• However, also affect Nigrostriatial pathways
• What type of side effects might this cause?
• Often have anti-muscarinic effects
• Again, what types of side effects?