Transcript clinical pharmacology of drugs affecting the nervous system

INTRODUCTION AND GENERAL
PROBLEMS OF MODERN
MEDICAL THERAPY. THERAPY
OF DISEASES OF THE
NERVOUS SYSTEM
KINDS OF TREATMENT
• Ethiotropic treatment (antibacterials,
antidotes)
• Pathognomonic treatment
(antihypertensive, antiarrhythmic,
antiinflammatory agents, antidepressants)
• Symptomatic treatment (pain-killers,
antipyretics)
• Substitutional therapy (enzymes, hormonal
medicines, vitamines)
• Preventive treatment (vaccines, antiviral
drugs)
Terminology
• Symptom - any sensation or change in bodily
function that is experienced by a patient and is
associated with a particular disease
• SYNDROME - a pattern of symptoms indicative
of some disease (Reye's syndrome - acquired
brain disorder following acute viral infections
(especially influenza or chicken pox) in young
children )
FACTORS THAT INFLUENCING ON
TREATMENT EFFECTICITY
Exogenic
Chemical structure and
physical&chemical
characteristics of agents, medicinal form, ways of
using, drug dose, dietery, environmental factors
(metheorological, etc.)
Endogenic
Age, sex, menstruation, pregnancy,
pathological stages
combined
MEDICINAL FORM AND WAYS OF USING
• Biofarmaciya is engaged in the study of
influence of medical form on a
pharmacodynamics and pharmacokinetics
of medications.
• Bioavailability of medications –
complex of pharmacokinetic processes
due to which the effective concentration of
medication is created in the area of
specific receptors (part of preparation,
which got in blood, in relation to a that
amount which was applied)
INFLUENCE OF PATIENT’ S SEX ON DRUGS
ACTION
• Morphin, nicotine, strychnin - the
sensitiveness of women is more high
• Changes of metabolism of theophyllin,
methylprednisolon, paracetamol in the
different phases of menstrual cycle
• Pregnancy – absorbtion gets worse,
biotransformation of medications is slowed
• Menstruation - anticoagulants can cause
the massive uterine bleeding
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INFLUENCE OF BIOLOGICAL RHYTHMS
Administration of GKS between 6-8 h. of
morning
At night maximal sensitiveness of bronchial
tubes to histamin and acetilcholin, it is that is
why expedient to appoint the prolonged forms of
theophyllin in the evening
Hypertensive crises more frequent develop
between 16-24 hours
Maximal diuretic action at the reception of
diuretic preparations is observed in the morning
(to 10 h.)
Toxicity of haloperidol for a day long differs in 5
times
INFLUENCE OF PATHOLOGICAL PROCESSES
ON MEDICATIONS ACTION
• Diminishing of tolerance to cardiac glycosides - at
miocarditis
• Cardiac glycosides operate in the conditions of cardiac
insufficiency
• Paracetamol and other antipyretics reduce a
temperature only at hyperpyrexia
• Slowing of metabolism, growth of toxicity of medications
at pathology of liver
• Slowing of leadingout of medications at pathology of
kidneys
• Inhibition of absorbtion of fat-disolved vitamins at
violation of biliation
• At smoking the risk of tromboembolic complications
grows at the reception of anticoagulants, hormonal
contraceptives
BASIC SYMPTOMS AND SYNDROMES OF
DEFEAT OF NERVOUS SYSTEM
• PAIN
• DIZZINESS
• INCREASE OF INTRACRANEAL
PRESSURE AND HYDROCRANIUM
DEMENCIYA
• VIOLATION OF CONSCIOUSNESS
• COMMA
PAIN
Development of sharp pain is related to the
pain irritations of superficial and deep fabrics
and internalss or parafunction smooth
musculature of internalss without the damage of
fabrics. The neurological reasons of sharp pain traumatic, infectious, dismetabolic and other
damages of CNS.
The mechanisms of chronic pain depending
on a prevailing role in its genesis of different
departments of the nervous system divide into
peripheral, central, united peripheral and central,
psycological
Headache
• Headache— one of the most frequent
symptoms of different diseases. It is arisen
up as a result of irritation of nervous
completions of vessels of chairman or
brain-tunics and depending on reason has
the features. Nosotropic types of
headache: it is vascular – headache of
muscular tension ;- liquorodynamic ; neuralgic; - hallucinogenic (psychalgya);
headache of the mixed genesis.
Dizziness
• Dizziness is feeling of loss of orientation of body
in space. Meets at disfunction of the sensory
antihunt systems - vestibular, visile and
somatosensor. Dizzinesses are quite often
accompanied by :
• falling
• nystagmus
• an ataxia in extremities
• visceral violations (paleness, sweating, change
of pulse and AP, nausea, vomitting, diarhea).
Increasing of intracraneal pressure
• The increase of intracraneal pressure can
be conditioned: – by the presence of
intracraneal volume process; – by the
increase of volume of cerebrum (edema of
the brain); – by the increase of level of
cerebrospinal liquid at a hydrocephaly
• – by the increase of volume of blood at
vasodilatation in the conditions of
hypercapnia.
DEMENTIA
Dementia is the state, which arises up as a result of
organic defeat of cerebrum and characterized violation of
intellectual activity, worsening of memory of thought,
understanding, language, cognitive functions.
Dementia meets for old years people (more senior
65 years -10 %, more senior 80 years - 20 %).
Select dementia, associated with degenerative
neurological diseases and those which develop on a
background various neurological and somatic diseases
(intoxications, tumours, craniocerebral trauma, metabolic
violations, epilepsy, neuroinfection, internalss
conditioned illnesses, and by the inherited somatic and
neurological diseases).
CONFUSED CONSCIOUSNESS
Under confusing of consciousness
understand impossibility to think with
sufficient speed and clarity. Patients do
not perceive that surrounds them, can not
estimate a situation and does not control
the function of pelvic organs. Types of
violation of consciousness: stupor, sopor
coma , delirium, twilight state of
consciousness
Stupor - is a partial exception of consciousness
with the maintainance of verbal contact on a background
enhanceable perception of all external irritants decline of
own activity. Sopor - psychical and physical activity
expressed to the minimum, a reaction on linguistic
commands absents and is inadequate. Coma
characterized the protracted oppression and loss of
consciousness with the making progress deepening of
disorders vitally of important organs, up to death of brain.
Death of brain is the state at which the brain is damaged
nonreversible and does not function, and cardiac and
respiratory functions are supported artificially.
COMA
• The comatose states can be conditioned:
— by violations of exchange and
intoxications of endogenous or exogenous
character;
• — by cerebral defeats.
Types of the comatose states
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A diabetic coma
Hypoglycemia coma
Cerebral coma
Uremic coma
Hepatic coma
Coma at Addison illness
Thyroid coma
NERVOUS SYSTEM DISEASES
• Divided on: disease of the central, peripheral and
vegetative nervous system. In dependence on
pathogeny of nervous disease divide into three groups:
Inflammatory diseases (meningitis, encephalitis,
myelities).
• Vascular diseases (ischemic and hemorragic strokes of
cerebrum, migraine, sharp necrotizing hemorragic
stroke).
• Demyelinating (degenerative distrophical) diseases
(disseminated sclerosis, sharp disseminated
encephalomyelitis, syringomyelia, lateral amyotrophic
sclerosis)
MENINGITIS
• Meningitises are sharp infectious diseases
with the overwhelming defeat of
arachnoid and soft shells of cerebral and
(or) spinal brain.
• Meningitises can run across in form
leptomeningitis (inflammation of soft and
arachnoid shells), to the arachnoiditis
(isolated inflammation of arachnoid shell,
meets rarely) and pachymeningitis
(inflammation of hard cerebral shell)
MENINGITIS. CLINICAL SYMPTOMS
• Meningeal syndrome: headache, intoxication, meningeal
symptom, change of composition of neurolymph and immunity.
• Headache- holding apart, mainly in frontal, temporal or cervical
areas.
• Meningeal symptoms: Kernig symptom , Brudzinsky. Kernig
symptom: overhead is rigidity of cervical muscles; lower: initial
position: a patient lies on the back, a leg is arcuated at right angles
in hip and knee joints. At the attempt of straightening there is tension
of muscles of back surface of thigh in a knee-joint.
Brudzinsky symptom: overhead: consists in bending of thigh and
shin at an attempt to incline a chairman lying on the back of patient
forward; lower— in bending of contralateral leg at the attempt of
straightening and raising of other leg.
An important symptom of meningeal syndrome is general
hiperesthesia. Patients painfully react on any external irritants —
bright light, loud sound, touch. Level of lg А, Ig G, Ig М changes in
blood serum
Brudzinsky symptom
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
• 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
• 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.
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 AMPAtype 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