Download CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE

CLINICAL PHARMACOLOGY
OF DRUGS AFFECTING THE
NERVOUS SYSTEM
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.
Amphetamine
Levoamphetamine (Benzedrine), dextroamphetamine
(Dexedrine), and methamphetamine (Methedrine)
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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
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.
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.
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.
Tranquilizers
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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.
Effects
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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 lifethreatening with some of the Benzodiazepines. Physical withdrawal
symptoms can include general pain, stomach cramps, diarrhea, flulike 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.
SEDATIVE - HYPNOTIC AGENTS
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Drug Classes of Sedative-Hypnotics
Barbiturates
Benzodiazepines
Alcohols/Imidazopyridine
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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]
• 1. Sites of Action:
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Barbiturates act at multiple levels of the
CNS. Sedative-Hypnotic effect involves, in
particular, the reticular activating system.
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Mechanism of Action:
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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)
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reduce glutamate-induced
depolarization via inhibitory action on AMPA-type
glutamate receptors
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at high doses, reduce the
responsiveness of voltage-dependent Na+
channels and directly active GABAA receptors
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)
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 (1040h)
Triazolam
Short (1-3h)
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
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)
Alcohols/Imidazopyridine:
Duration of Action
- Chloral Hydrate
[pro-drug]
- Zolpidem
hours)
- Zaleplon
Long (6-10h)
Short (several
Short (1-3h)
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
Narcotic Analgesic Drugs