CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE NERVOUS SYSTEM

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CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE
NERVOUS SYSTEM
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Central Nervous System Stimulants

• Stimulants are drugs that exert their action
  through excitation of the central nervous system.
  Psychic stimulants include caffeine, cocaine, and
  various amphetamines. These drugs are used to
  enhance mental alertness and reduce drowsiness
  and fatigue.
• Stimulants increase alertness, attention, and
  energy, which are accompanied by increases in
  blood pressure, heart rate, and respiration.

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AmphetamineLevoamphetamine (Benzedrine),
dextroamphetamine (Dexedrine), and
methamphetamine (Methedrine)

• These agents produce a feeling of well being and
  euphoria. Cocaine and amphetamine have a
  significant abuse potential because of these mood
  enhancing effects. Tachyphylaxis or tolerance to
  the stimulating actions of these agents can
  develop. These agents produce an increase in
  systemic arterial blood pressure. Heart rate can
  either decrease or increase depending on the
  levels of the drug. Drug toxicity effects
  multiple organ systems and can result in
  arrhythmias, hypertension, psychosis and
  convulsions. The local anesthetic activity of
  cocaine can also contribute to rhythm
  disturbances.
• Clinical Therapeutics of CNS Stimulants
• 1) Because of its local anesthetic activity,
  cocaine has some limited uses as a oral, nasal
  and ophthalmic local anesthetic.
• 2) Appetite suppression - amphetamine and analogs
• 3) Narcolepsy - methylphenidate, amphetamine
  analogs
• 4) Attention deficient disorder with
  hyperactivity (ADHD) - methylphenidate,
  amphetamine and analogs

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Tolerance and Dependence

• Regular use of amphetamines induces tolerance to
  some effects, which means that more and more of
  the drug is required to produce the desired
  effects. Tolerance does not develop to all
  effects at the same rate, however indeed, there
  may be increased sensitivity to some of them.
• Chronic users may also become psychologically
  dependent on amphetamines. Psychological
  dependence exists when a drug is so central to a
  person's thoughts, emotions, and activities that
  the need to continue its use becomes a craving or
  compulsion. Experiments have shown that animals,
  when given a free choice, will readily operate
  pumps that inject them with cocaine or
  amphetamine. Animals dependent on amphetamines
  will work hard to get more of the drug.
• Physical dependence occurs when the body has
  adapted to the presence of the drug, and
  withdrawal symptoms occur if its use is stopped
  abruptly. The most common symptoms of withdrawal
  among heavy amphetamine users are fatigue, long
  but troubled sleep, irritability, intense hunger,
  and moderate to severe depression, which may lead
  to suicidal behavior. Fits of violence may also
  occur. These disturbances can be temporarily
  reversed if the drug is taken again.

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Antidepressant Drugs

• All are effective in relieving depression, but
  they differ in their adverse effects.
• All must be taken for 2 to 4 weeks before
  depressive symptoms improve.
• They are given orally, absorbed from the small
  bowel, enter the portal circulation, and
  circulate through the liver, where they undergo
  extensive first-pass metabolism before reaching
  the systemic circulation.
• They are metabolized by the cytochrome P450
  enzymes in the liver. Many antidepressants and
  other drugs are metabolized by the 2D6 or 3A4
  subgroup of the enzymes.

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Antidepressant Drugs indications for use

• Antidepressant drug therapy may be indicated if
  depressive symptoms persist at least 2 weeks,
  impair social relationships or work performance,
  and occur independently of life events. In
  addition, antidepressants are increasingly being
  used for treatment of anxiety disorders. TCAs may
  be used in children and adolescents in the
  management of enuresis (bedwetting or involuntary
  urination resulting from a physical or
  psychological disorder). In this setting, a TCA
  may be given after physical causes (eg, urethral
  irritation, excessive intake of fluids) have been
  ruled out. TCAs are also commonly used in the
  treatment of neuropathic pain. MAOIs are
  considered third-line drugs, largely because of
  their potential for serious interactions with
  certain foods and other drugs.

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Tranquilizers

• Tranquilizers are divided into a Major
  Tranquilizer and Minor Tranquilizer group.
• Major Tranquilizers include phenothiazines,
  indoles, thioxanthenes, butyrophenones,
  piperazine compounds, and piperidine compounds.
  Trade names include drugs such as Thorazine,
  Haldol, Clozaril and Risperdal. These drugs are
  referred to as Neuroleptics and are most commonly
  prescribed as anti-psychotics. This type of
  tranquilizer is not widely abused.
• Minor Tranquiliers are the more common of the
  tranquilizers. These include the Benzodiazepines,
  known by trade names such as Valium, Xanax,
  Serax, Ativan, Klonopin, Librium and Tranxene.
  There are also combination drugs such as Librax.
  These drugs are very commonly prescribed as
  anti-anxiety drugs, or anxiolytics. They are
  often referred to as Sedative/Hypnotics. They are
  central nervous system depressants with specific
  sites of action. Slang references to these drugs
  include Libs, Tranks, Benzos, and Vees.
• The primary route of administration for these
  medications is oral, swallowed as a tablet,
  capsule, or liquid. They are also available in
  solution form for intravenous use.

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Effects

• The minor tranquilizers induce a feeling of calm
  and relaxation. Depending on the medication and
  dosage this can range from feelings of mild
  euphoria to states of drowsiness, confusion, and
  lightheadedness. Effects can include hostility,
  blurred vision, hallucinations, lethargy,
  headaches, memory loss, disorganized thinking,
  and irritability. Other common effects include
  impaired motor function, dry mouth, nausea,
  vomiting, and sweating. Certain Benzodiazepines,
  including Valium, can produce toxic reactions
  when combined with alcohol.
• The Benzodiazepines (Minor Tranquilizers) can be
  addictive even at prescribed dosages if the
  medication is administered for long periods of
  time. The withdrawal process can be painful and
  even life-threatening with some of the
  Benzodiazepines. Physical withdrawal symptoms can
  include general pain, stomach cramps, diarrhea,
  flu-like symptoms, and heart palpitations. There
  is also the possibility of seizure with certain
  medications. The withdrawal can also produce
  psychosis, hallucinations, delusions, paranoia,
  and depression.

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SEDATIVE - HYPNOTIC AGENTS

• Drug Classes of Sedative-Hypnotics
• Barbiturates
• Benzodiazepines
• Alcohols/Imidazopyridine
• Barbiturates
• Duration of Action Onset
• - Phenobarbital Long (6-12 h) 20 min
• - Pentobarbital Intermediate (4-6 h) 3 min
• - Secobarbital Short-Intermediate (3-6 h) 2
  min
• - Thiopental/ Short (15- 30 min) few seconds
• Methohexital
• All are derivatives of barbituric acid

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• 1. Sites of Action
• Barbiturates act at multiple levels of the CNS.
  Sedative-Hypnotic effect involves, in
  particular, the reticular activating system.
• 2. Mechanism of Action
• - facilitate the action of GABA at GABAA
  receptors by increasing the duration of channel
  openings (bind at a distinct site from that bound
  by benzodiazepines)
• - reduce glutamate-induced depolarization via
  inhibitory action on AMPA-type glutamate
  receptors
• - at high doses, reduce the responsiveness of
  voltage-dependent Na channels and directly
  active GABAA receptors

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• 3. CNS effects
• Dose-dependent progression (lower margin of
  safety)
• Sedation ? Hypnosis ? Anesthesia ? Coma
  ? Death
• Anticonvulsant/antiepileptic
• - all barbiturates stop convulsions in progress
  if given IV at high enough dosage
• - some can prevent seizures (eg. phenobarbital),
  but are not drugs of first choice owing to
  sedative effect (except for children) used to
  maintain control of status epilepticus
• For animal surgery, methohexital may be used as
  an induction agent only. Pentobarbital
  (Nembutal) used, but has a very low margin of
  safety in rodents and guinea pigs (consequently,
  often agent of choice for rapid, humane
  euthanasia)

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• Adverse effects
• - respiratory depression via action on
  respiratory center in the medulla is the usual
  cause of death with overdose depression occurs
  at supra-hypnotic doses
• - generalized CNS depression impaired motor and
  cognitive skills
• - uncommon rash, dermatitis, decreased red
  blood cells and platelet
• - physiological and psychological dependency
  significant incidence of abuse

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• Benzodiazepines Duration of Action
• - Flurazepam Long (30-100h) pro-drug
• - Diazepam active metabolites
• - Temazepam Intermediate (10-40h)
• - Triazolam Short (1-3h)

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• Effects and uses
• - drugs of choice for sedation and hypnosis
  (higher margin of safety)
• flurazepam long-acting pro-drug
• temazepam slowly absorbed, intermediate acting
  drug with no active metabolites most highly
  prescribed hypnotic
• triazolam rapid but short-acting drug
• diazepam (Valium) long-acting drug may be
  useful as adjunct in animal surgery
• - at sedative doses may cause euphoria and
  disinhibition
• - anticonvulsant (primary drug for initial
  treatment of status epilepticus)
• - anxiolytic
• - muscle relaxation (used in spasticity largely
  via effect in spinal cord)
• - ethanol withdrawal

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• Adverse reactions
• - hangover (esp. with benzodiazepines with
  long half-lives diazepam)
• - early morning awakening for benzodiazepines
  with short half-lives triazolam
• - impaired motor and cognitive skills
• - anterograde amnesia
• - chronic use/dependence more intense
  withdrawal symptoms with benzodiazepines having
  short half-lives rebound insomnia (and/or
  anxiety), restlessness and even seizures
  (severity and frequency of dependence less than
  that found for barbiturates)

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Alcohols/Imidazopyridine

• Duration of Action
• - Chloral Hydrate Long (6-10h) pro-drug
• - Zolpidem Short (several hours)
• - Zaleplon Short (1-3h)

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• 1. Chloral hydrate rapidly metabolized in liver
  to triethanolamine - pharmacologically active
  (also metabolized to trichloroacetic acid, which
  is toxic and may accumulate) mechanism of action
  is not known
• - oft-used sedative-hypnotic for animals
  undergoing surgery
• - institutional use
• 2. Zolpidem non-benzodiazepine that acts via
  subtype of GABAA receptor
• - an effective, short-acting hypnotic agent
  (most highly prescribed hypnotic)
• - much lower risk of tolerance and dependency
  but some mild cognitive impairment during onset
• - little anticonvulsant or muscle relaxant
  effects
• 3. Zaleplon an alternative non-benzodiazepine
  that also acts via the GABAA receptor
• - similar to Zolpidem, but without effects on
  cognitive function

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Narcotic Analgesic Drugs
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