Transcript CLINICAL PHARM_ THE NERVOUS SYSTEM

CLINICAL PHARMACOLOGY OF
DRUGS AFFECTING THE
NERVOUS SYSTEM
BASIC QUESTIONS
• Clinical pharmacology of CNS stimulants
• Clinical pharmacology of antidepressants
• Clinical pharmacology of
antipsychotic/neuroleptic drugs
• Clinical pharmacology of tranquilizers
• Clinical pharmacology of sedative hypnotic agents
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.
CNS Stimulants (cont’d)
• The methylxanthines include theophylline which
is found in tea; theobromine found in cocoa; and
caffeine. Caffeine, the most widely consumed
stimulant in the world, is found in highest
concentration in coffee, but it is also present in tea,
cola drinks, chocolate candy, and cocoa.
• Nicotine is the active ingredient in tobacco.
Although this drug is not currently used
therapeutically nicotine remains important,
because it is second only to caffeine as the most
widely used CNS stimulant and second only to
alcohol as the most abused drug.
CNS Stimulants (cont’d)
AMPHETAMINE
Levoamphetamine, dextroamphetamine, and
methamphetamine (Methedrine)
• Amphetamine is a noncatecholaminergic
sympathetic amine that shows neurologic
and clinical effects quite similar to those of
cocaine.
CNS Stimulants (cont’d)
AMPHETAMINE
• 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
Depression
• The symptoms of
depression are intense
feelings of sadness,
hopelessness, and despair,
as well as the inability to
experience pleasure in
usual activities, changes in
sleep patterns and
appetite, loss of energy,
and suicidal thoughts.
ANTIDEPRESSANTS
• Selective serotonin reuptake inhibitors
• Serotonin/norepinephrine re-uptake
inhibitors
• Atypical antidepressants
• Tricyclic antidepressants
• Monoamine oxidase inhibitors
• Drugs used to treat mania and bipolar disorder
Tricyclic antidepressants Inhibitors of the reuptake of noradrenaline (norepinephrine)
and serotonin (5-HT) in central monoaminergic neurons
1. Sedative
• Amitriptyline
• Clomipramine
• Dosulepin (dothiepin)
• Doxepin*
• Maprotiline
• Mianserin*
• Trazodone*
• Trimipramine
Tricyclic antidepressants (TCAs )
2. Less sedative
• Amoxapine
• Imipramine
• Lofepramine*
• Nortriptyline
*Drugs with fewer anticholinergic effects (dry
mouth, blurred vision, constipation,
difficulty with micturition)
Selective serotonin reuptake
inhibitors (SSRIs)
• Inhibitors of the reuptake of serotonin (5HT) in central monoaminergic neurons
• Fluoxetine
• Paroxetine
• Fluvoxamine
• Sertraline
• Citalopram
Monoamine oxidase inhibitors (MAOIs)
• Inhibitors of the enzyme monoamine oxidase
• Non-selective MAOIs
– Phenelzine, isocarboxazid, tranylcypromine, iproniazid
• Inhibitor of MAOA
– Moclobemide (reversible)
• Inhibitor of MAOB
– Selegiline
• Note that linezolid(an antibiotic) is also a nonselective, reversible MAOI.
Tricyclic antidepressants. Adverse
effects
• Anticholinergic adverse effects are common.
• Tolerance to these effects develops; it is worth encouraging
patients to persevere with treatment if possible.
• Tricyclic antidepressants are associated with cardiac toxicity,
especially in overdose.
• This is characterized by tachycardia, ventricular arrhythmias,
and heart block; prolongation of the QT interval correlates well
with the severity of toxicity.
• Tricyclic antidepressants lower the seizure threshold.
• Hypotension occurs in up to 20% of patients treated with
tricyclic antidepressants.
• Tricyclic antidepressants can cause the syndrome of
inappropriate ADH secretion, resulting in hyponatraemia with
confusion.
• The elderly are especially likely to develop this adverse effect.
Monoamine oxidase inhibitors
• Second-line treatment of depression (nonselective inhibitors and moclobemide).
• Especially if there are phobic or other
atypical symptoms (e.g. hysteria).
• Treatment of Parkinson's disease
(selegiline).
Monoamine oxidase inhibitors
• Avoid these drugs in patients with cerebrovascular disease;
they are more susceptible to adverse effects.
• Avoid them in patients with established cardiac disease,
hypertension, or arrhythmias.
• They can cause CNS stimulation; avoid them in patients
with a history of psychotic illness.
• The non-selective MAOIs can cause idiosyncratic liver
damage; avoid them in patients with hepatic insufficiency.
• There is little evidence of harm from these drugs during
pregnancy, but use them only when the likely benefits are
compelling.
Monoamine oxidase inhibitors
Adverse effects from these drugs are very
common
• CNS effects include dizziness, over-stimulation, insomnia, agitation, and
anxiety.
• They may also have autonomic effects: dry mouth, postural hypotension,
and blurred vision.
• Gastrointestinal adverse effects include nausea and vomiting.
• They can cause hyponatraemia, resulting in confusion and seizures.
• They are most commonly remembered because they can cause the tyramine
(cheese) reaction.
• Note that selegiline does not cause this adverse effect, and that it is less
common with moclobemide.
• The tyramine reaction is characterized by severe hypertension, headache,
palpitation, sweating, nausea, and vomiting. It can be fatal.
• It occurs as a result of ingestion of tyramine-rich foods or co-administration
of other drugs that potentiate aminergic neurotransmission.
• This reaction makes these drugs potentially hazardous and limits their
clinical use.
Drugs and foods that can precipitate the
tyramine reaction in patients taking MAOIs
(not selegiline or moclobemide)
Drugs
• Other amine drugs
– Ephedrine, pseudoephedrine (note that these are
common components of many decongestant cough and
cold cures)
• Dopamine receptor agonists
– Levodopa, pergolide, ropinirole, cabergoline, lisuride,
apomorphine
• Direct sympathomimetics
– Beware lidocaine with adrenaline
• Indoramin
Drugs and foods that can precipitate the
tyramine reaction in patients taking MAOIs
(not selegiline or moclobemide)
Tyramine-rich foods
• Cheese (especially cheddar)
– Not cottage or cream cheeses
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Meat and yeast extracts
Some red wines
Hung game and poultry
Pickled herring
Broad beans
Alcoholic and dealcoholized beverages
Psychoses and bipolar disorder
Antipsychotic/neuroleptic drugs (1)
Dopamine receptor antagonists
• Phenothiazines
– Chlorpromazine
– Prochlorperazine
– Thioridizine
• Thioxanthenes
– Flupenthixol
– Clopentixol
• Butyrophenones
– Haloperidol
• Atypical antipsychoticdrugs
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Risperidone
Clozapine
Olanzapine
Quetiapine
Sertindole
Antipsychotic/neuroleptic drugs (2)
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Sedative and tranquillizing effects.
Treatment of severe anxiety, acute mania, or
psychosis.
Sedation in acute confusional states.
Premedication before general anaesthesia.
As an adjunct to analgesia in palliative care.
Prochlorperazine for antiemetic actions.
Treatment of chronic schizophrenia.
Occasionally used for treatment of intractable
hiccup.
Antipsychotic/neuroleptic drugs (4)
Acute treatment
• The doses of these drugs are lower when they are given by
intramuscular injection than by mouth. This is particularly
true if patients are very physically active (agitated), as this
will increase the speed of absorption from the muscle.
• Review the dose daily to avoid over-sedation.
• Antipsychotic drugs are more effective for the acute
psychotic symptoms of schizophrenia, rather than chronic
withdrawal symptoms.
• They are a specific treatment for schizophrenia, but not for
any other diagnoses. They can provide a window of time in
which to assess and investigate an acutely unwell patient.
Always consider the underlying cause for the patient's
symptoms and treat that, if it is possible.
• Do not withdraw antipsychotic drugs suddenly.
Antipsychotic/neuroleptic drugs (5)
• Antipsychotic drugs can cause the neuroleptic
malignant syndrome.
• This is characterized by fever, anorexia, rigidity,
lowered level of consciousness, and autonomic
disturbances (tachycardia, hyperthermia), and can
be fatal.
• Stop the drug immediately. There are no
established effective treatments, but cooling,
bromocriptine (a dopamine receptor agonist), and
dantrolene can be helpful.
• The syndrome usually lasts 5-7 days.
Antipsychotic/neuroleptic drugs (7)
• The antidopaminergic actions can also cause prolactin release,
leading to galactorrhoea, gynaecomastia, and menstrual
disturbances.
• The anticholinergic actions can cause dry mouth, blurred vision,
and urinary retention.
• Antipsychotic drugs can cause dizziness, but are also used to treat
acute vertigo (see prochlorperazine, p. 62).
• Hypersensitivity phenomena, such as photosensitive rash, are
common.
• These drugs can cause cardiac arrhythmias, usually by prolonging
the QT interval. The risk is greatest with droperidol, haloperidol,
thioridizine, and sertindole.
• Antipsychotic drugs can cause hypotension, especially in
hypovolaemic patients. Take care postoperatively.
• Antipsychotic drugs can lower body temperature.
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.
SEDATIVE - HYPNOTIC AGENTS
Drug Classes of Sedative-Hypnotics
• Barbiturates
• Benzodiazepines
• Alcohols/Imidazopyridine
Barbiturates:
Duration of Action
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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]
SEDATIVE - HYPNOTIC AGENTS
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.
• 2. 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
SEDATIVE - HYPNOTIC AGENTS
3. CNS effects:
Dose-dependent progression: (lower margin of
safety)
Sedation → ‘Hypnosis’ → Anesthesia →
Coma → Death
Anticonvulsant/antiepileptic effect
- 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
Benzodiazepines (Hypnotics and
anxiolytics )
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Long-acting
Diazepam 5 mg
Lorazepam 0.5 mg
Nitrazepam 5 mg
Chlordiazepoxide 15 mg
Short-acting
Oxazepam 15 mg
Temazepam 10 mg
Lormetazepam 0.5-1.0 mg
Loprazolam 0.5-1.0 mg
Used for epilepsy
Clobazam
Clonazepam
INDICATIONS
• Treatment of anxiety, and
premedication before
operations and procedures.
• Short-term use for night
sedation.
• Sedation for procedures.
• Treatment of seizures.
• Skeletal muscle relaxant to
relieve muscle spasm.
• Adjunct to the treatment of
alcohol withdrawal.
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 halflives, ‘rebound’ insomnia (and/or anxiety),
restlessness and even seizures (severity and frequency
of dependence less than that found for barbiturates)
Alcohols/Imidazopyridine:
- Chloral Hydrate
Long (6-10h)
[pro-drug]
short-acting
• Zaleplon
• Zolpidem
• Zopiclone
Short-term treatment of insomnia.
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
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
Zaleplon, Zolpidem, Zopiclone
• Chronic insomnia is rarely helped by treatment
with hypnotics. They are more effective for:
– Transient insomnia in those who normally sleep well
but are subject to a disrupting event (e.g. an operation
or jet lag). Give 1 or 2 doses.
– Short-term insomnia associated with a specific event
(e.g. illness or bereavement). Keep treatment to less
than 1 week.
• These drugs are not licensed for long-term
treatment.
• Take a single dose at night if unable to sleep.