Download 1 - كلية الطب البيطري جامعة الكوفة

‫محاضرات م‪.‬م سعديه صالح مهدي الزيني‬
‫كلية الطب البيطري ‪ /‬جامعة الكوفة‬
‫فــرع الفسلجــة واألدويــة‬
‫ماجستير أدوية وسموم‬
Drugs Affecting the Central Nervous System
Most drugs that affect the central nervous system (CNS) act by altering some step
in the neurotransmission process.
Drugs affecting the CNS may act presynaptically by influencing the production,
storage, release, or termination of action of neurotransmitters. Other agents may
activate or block postsynaptic receptors.
Neurotransmission in the CNS
the CNS communicates through the use of more than 10 (and perhaps as many
as 50) different neurotransmitters. In contrast, the autonomic nervous system uses
only two primary neurotransmitters, acetylcholine and norepinephrine.
Synaptic Potentials
In the CNS, receptors at most synapses are coupled to ion channels; that is,
binding of the neurotransmitter to the postsynaptic membrane receptors results in
a rapid but transient opening of ion channels. Open channels allow specific ions
inside and outside the cell membrane to flow down their concentration gradients.
The resulting change in the ionic composition across the membrane of the neuron
alters the postsynaptic potential, producing either depolarization or
hyperpolarization of the postsynaptic membrane, depending on the specific ions
that move and the direction of their movement.
1- Excitatory
Stimulation of excitatory neurons causes a movement
of ions that results in a depolarization of the
Postsynaptic membrane. These excitatory postsynaptic
potentials (EPSP) are generated by the following
1-Stimulation of an excitatory neuron
causes the release of neurotransmitter molecules,
such as glutamate or acetylcholine, which bind to
receptor on the postsynaptic cell membrane.
This causes a transient increase in the Permeability
of sodium (Na+) ions.
2- The influx of Na+ causes a weak depolarization or EPSP
that moves the postsynaptic potential toward its firing threshold.
3- If the number of stimulated excitatory neurons
increases, more excitatory neurotransmitter is
released. This ultimately causes the EPSP
depolarization of the postsynaptic cell to pass a
threshold, thereby generating an all-or-none action
potential.
2- Inhibitory
Stimulation of inhibitory neurons causes movement
of ions that results in hyperpolarization of the
postsynaptic membrane. These inhibitory postsynaptic
potentials (IPSP) are generated by the following:
1- Stimulation of inhibitory neurons releases
neurotransmitter molecules, such as
gama-aminobutyric acid (GABA) or glycine,
which bind to receptors on the postsynaptic
cell membrane. This causes a transient increase
in the permeability of specific ions, such as
potassium (K+) and chloride (Cl-) ions.
2-The influx of Cl- and efflux of K+ cause a weak
hyperpolarization or IPSP that moves the
postsynaptic potential away from its firing threshold.
This diminishes the generation of action potentials.
Combined effects of the EPSP and IPSP
Most neurons in the CNS receive both EPSP and IPSP input. Thus,
several different types of neurotransmitters may act on the same neuron, but each
binds to specific receptor.
Neurodegenerative Diseases
Alzheimer's disease is characterized by the loss of cholinergic neurons
Parkinson's disease is associated with a loss of dopaminergic neurons in the
substantia nigra. Parkinsonism is a progressive neurological disorder of muscle
movement, characterized by tremors, muscular rigidity, bradykinesia Most cases
involve people over the age of 65
Drugs Used in Parkinson's Disease
Currently available drugs offer temporary relief from the symptoms of the disorder,
but they do not arrest or reverse the neuronal degeneration caused by the disease.
1- Levodopa and carbidopa
Mechanism of action:
a- Levodopa: Because parkinsonism results from insufficient dopamine in specific
regions of the brain, attempts have been made to replenish the dopamine
deficiency. Dopamine itself does not cross the blood-brain barrier, but its
immediate precursor, levodopa, is actively transported into the CNS and is
converted to dopamine in the brain. Large doses of levodopa are required, because
much of the drug is decarboxylated to dopamine in the periphery, resulting in side
effects that include nausea, vomiting, cardiac arrhythmias, and hypotension.
b- Carbidopa: administering of carbidopa, enhanced the effects of levodopa on
the CNS. Carbidopa diminishes the metabolism of levodopa in the
gastrointestinal tract and peripheral tissues
2-Catechol-O-methyltransferase inhibitors
Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT)
to 3-O-methyldopa is a minor pathway for levodopa metabolism. Inhibition of
COMT by entacapone or tolcapone leads to decreased plasma concentrations of 3O-methyldopa, increased central uptake of levodopa, and greater concentrations of
brain dopamine. Both of these agents have been demonstrated to reduce the
symptoms of wearing-of phenomena
3- Dopamine-receptor agonists
a-Bromocriptine: a derivative of the vasoconstrictive alkaloid, ergotamine,is a
dopamine-receptor agonist.
b-Amantadine
It was accidentally discovered that the antiviral drug and effective in the
treatment of influenza, has an antiparkinsonism action. increasing the release
of dopamine, blockading cholinergic receptors.
Drugs Used in Alzheimer's Disease
-Acetylcholinesterase inhibitors
four reversible AChE inhibitors are approved for the treatment of mild to
moderate Alzheimer's disease. They are donepezil, galantamine, rivastigmine,
and tacrine. Except for galantamine, which is competitive, all are uncompetitive
inhibitors of AChE and appear to have some selectivity for AChE in the CNS as
compared to the periphery.
Anxiolytic (minor tranquilizers) and Hypnotic Drugs
Anxiety is an unpleasant state of tension, apprehension, or uneasiness fear that
seems to arise from a sometimes unknown source. Disorders involving anxiety
are the most common mental disturbances. The physical symptoms of severe
anxiety are similar to those of fear (such as tachycardia, sweating, trembling,
and palpitations)and involve sympathetic activation.
1-Benzodiazepines
Benzodiazepines are the most widely used anxiolytic drugs. They have largely
replaced barbiturates and meprobamate in the treatment of anxiety, because the
benzodiazepines are safer and more effective.
Mechanism of action
Two benzodiazepine receptor subtypes commonly found in the CNS have been
designated as BZ1 and BZ2 receptor depending on whether their composition
includes the alpha-1 subunit or the alpha-2 subunit, respectively.The
benzodiazepine receptor locations in the CNS parallel those of the GABA
neurons. Binding of GABA to its receptor triggers an opening of a chloride
channel, which leads to an increase in chloride conductance. The influx of
chloride ions causes a small hyperpolarization that moves the postsynaptic
potential away from its firing threshold and, thus, inhibits the formation of
action potentials.
Actions
1-Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are
thought to reduce anxiety by selectively enhancing GABAergic transmission in
neurons having the alpha-2 subunit in their GABAA receptors,
2-Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety
have some sedative properties, and some can produce hypnosis (artificially
produced sleep) at higher doses. Their effects have been shown to be mediated by
the alpha-1-GABAA receptors.
3-Anticonvulsant: Several of the benzodiazepines have anticonvulsant activity and
some are used to treat epilepsy (status epilepticus) and other seizure disorders.
This effect is partially, although not completely, mediated by alpha-1-GABAA
receptors.
4- Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of
skeletal muscle . probably by increasing presynaptic inhibition in the spinal cord,
where the alpha-2-GABA A receptors are largely located. Baclofen is a muscle
relaxant that is believed to affect GABAb receptors at the level of the spinal cord.
Therapeutic uses
1- Anxiety disorders:
Benzodiazepines are effective for the treatment of the anxiety symptoms secondary
to panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic
stress disorder, and the extreme anxiety sometimes encountered with specific
phobias and schizophrenia.
2- Muscular disorders:
Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in
muscle strain, and in treating spasticity from degenerative disorders, such as
multiple sclerosis and cerebral palsy.
3- Amnesia:
The shorter-acting agents are often employed as premedication for anxietyprovoking and unpleasant procedures, such as endoscopic, bronchoscopic, and
certain dental procedures as well as angioplasty.
4- Seizures: Clonazepam is occasionally used in the treatment of certain types of
epilepsy, whereas diazepam and lorazepam are the drugs of choice in terminating
grand mal epileptic seizures and status epilepticus.
5- Sleep disorders
Pharmacoki netics
Absorption and distribution: The benzodiazepines are lipophilic, and they are
rapidly and completely absorbed after oral administration and distribute
throughout the body.
Adverse effects
1- Drowsiness and confusion
2- Precautions: Benzodiazepines should be used cautiously in treating patients with
liver disease. They should be avoided in patients with acute narrow-angle
glaucoma. Alcohol and other CNS depressants enhance the sedative-hypnotic
effects of the benzodiazepines
2-Benzodiazepine Antagonist
Flumazenil is a GABA-receptor antagonist that can rapidly reverse the effects of
benzodiazepines. The drug is available for intravenous administration only.
Onset is rapid but duration is short, with a half-life of about 1 hour.
2- Barbiturates
The barbiturates were formerly the mainstay of treatment to sedate the patient or
to induce and maintain sleep. Today, they have been largely replaced by the
benzodiazepines, because barbiturates induce tolerance, drug-metabolizing
enzymes, Certain barbiturates, such as the very short-acting thiopental, are still
used to induce anesthesia
Mechanism of action:
The sedative-hypnotic action of the barbiturates is due to their interaction with
GABAA receptors, which enhances GABAergic transmission. The binding site
is distinct from that of the benzodiazepines. Barbiturates potentiate GABA
action on chloride entry into the neuron by prolonging the duration of the
chloride channel openings. In addition, barbiturates can block excitatory
glutamate receptors. Anesthetic concentrations of pentobarbital also block highfrequency sodium channels. All of these molecular actions lead to decreased
neuronal activity.
Actions
Barbiturates are classified according to their duration of action. For example,
thiopental which acts within seconds and has a duration of action of about 30
minutes, is used in the intravenous induction of anesthesia. phenobarbital
which has a duration of action 1-2 days, is useful in the treatment of seizures.
1- Depression of CNS:
- At low doses, the barbiturates produce sedation.
- At higher doses, the drugs cause hypnosis anesthesia coma death.
2- Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor
response to CO2, and overdosage is followed by respiratory depression and death.
3- Enzyme induction: Barbiturates induce P450 microsomal enzymes in the liver.
Therefore, chronic barbiturate administration diminishes the action of many drugs
that are dependent on P450 metabolism to reduce their concentration.
Therapeutic uses
1- Anesthesia: thiopental
2- Anticonvulsant: Phenobarbital
3- Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous
tension, and insomnia.
Pharmacokinetics
Barbiturates are absorbed orally and distributed widely throughout the body. All
barbiturates redistribute in the body from the brain to the splanchnic areas, to
skeletal muscle, and finally, to adipose tissue. This movement is important in
causing the short duration of action of thiopental and similar short-acting
derivatives. They readily cross the placenta and can depress the fetus. Barbiturates
are metabolized in the liver, and inactive metabolites are excreted in the urine.
Adverse effects
1-CNS: cause drowsiness,
2- Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness
well after the patient wakes, nausea and dizziness occur.
3- Precautions:
may decrease the duration of action of drugs that are metabolized by these
hepatic enzymes.
4- Physical dependence: tremors, anxiety, weakness, restlessness, nausea and
vomiting, delirium, and cardiac arrest.
5- Poisoning: Barbiturate poisoning has been a leading cause of death resulting
from drug overdoses for many decades. Severe depression of respiration is
coupled with central cardiovascular depression.
3- Other Hypnotic Agents
- Zolpidem and Zaleplon
Zolpidem has no anticonvulsant or muscle-relaxing properties. It is rapidly
absorbed from the gastrointestinal tract, elimination half-life (about 2 to 3 hours).
- Chloral hydrate
is a trichlorinated derivative of acetaldehyde that is converted to the active
metabolite, trichloroethanol, in the body. The drug is an effective sedative and
hypnotic that induces sleep in about 30 minutes and the duration of sleep is about 6
hours. Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric
distress. It synergizes with ethanol.
- Ethanol
Ethanol (ethyl alcohol) has anxiolytic and sedative effects. Ethanol is a CNS
depressant, producing sedation and hypnosis with increasing dosage.
Absorbed orally, metabolized primarily in the liver. Elimination is mostly through
the kidney, but a fraction is excreted through the lungs. Ethanol synergizes with
many other sedative agents and can produce severe CNS depression with
benzodiazepines, antihistamines, or barbiturates.
Chronic consumption can lead to severe liver disease, gastritis, and nutritional
deficiencies.
CNS Stimulants
1- Psychomotor Stimulants
A- Methylxanthines
The methylxanthines include:
- theophylline which is found in tea
- theobromine found in cocoa
- 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.
Mechanism of action:
Several mechanisms have been proposed for the actions of methylxanthines,
including translocation of extracellular calcium, increase in cyclic adenosine
monophosphate and cyclic guanosine monophosphate caused by inhibition of
phosphodiesterase, and blockade of adenosine receptors. The latter most likely
accounts for the actions achieved by the usual consumption of caffeine-containing
beverages.
Actions:
a- CNS: The caffeine contained in one to two cups of coffee (100-200 mg) causes a
decrease in fatigue and increased mental alertness as a result of stimulating the
cortex and other areas of the brain. Consumption of 1.5 g of caffeine (12 to 15 cups
of coffee) produces anxiety and tremors. The spinal cord is stimulated only by very
high doses (2-5 g) of caffeine.
b- Cardiovascular system:
A high dose of caffeine has positive inotropic and chronotropic effects on the heart.
Note: Increased contractility can be harmful to patients with angina pectoris. In
others, an accelerated heart rate can trigger premature ventricular contractions.
c- Diuretic action:
Caffeine has a mild diuretic action that increases urinary output of sodium,
chloride, and potassium.
d- Gastric mucosa:
Because all methylxanthines stimulate secretion of hydrochloric acid from the
gastric mucosa, individuals with peptic ulcers should avoid beverages containing
methylxanthines.
Therapeutic uses: Caffeine and its derivatives relax the smooth muscles of the
bronchioles.
Pharmacokinetics: The methylxanthines are well absorbed orally. Caffeine
distributes throughout the body, including the brain. The drugs cross the placenta to
the fetus and is secreted into the mother's milk. All the methylxanthines are
metabolized in the liver, then excreted in the urine.
Adverse effects: Moderate doses of caffeine cause insomnia, anxiety, and agitation.
A high dosage is required for toxicity, which is manifested by emesis and
convulsions.
B-Nicotine
is the active ingredient in tobacco. Although this drug is not currently used
therapeutically (except in smoking cessation therapy). 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.
In combination with the tars and carbon monoxide found in cigarette smoke,
nicotine represents a serious risk factor for lung and cardiovascular disease,
various cancers, as well as other illnesses. Dependency on the drug is not easily
overcome.
Mechanism of action:
In low doses, nicotine causes ganglionic stimulation by depolarization. At high
doses, nicotine causes ganglionic blockade. Nicotine receptors exist at a number of
sites in the CNS, which participate in the stimulant attributes of the drug.
Actions:
- CNS: Nicotine is highly lipid soluble and readily crosses the blood-brain barrier.
Cigarette smoking or administration of low doses of nicotine produces some
degree of euphoria and arousal as well as relaxation. High doses of nicotine result
in central respiratory paralysis and severe hypotension caused by medullary
paralysis. Nicotine is an appetite suppressant.
- Peripheral effects: The peripheral effects of nicotine are complex.
- Stimulation of sympathetic ganglia as well as the adrenal medulla increases
blood pressure and heart rate. Thus, use of tobacco is particularly harmful in
hypertensive patients.
- Stimulation of parasympathetic ganglia also increases motor activity of the
bowel. At higher doses, blood pressure falls, and activity ceases in both the
gastrointestinal tract and bladder musculature.
Pharmacokinetics: Because nicotine is highly lipid soluble, absorption readily
occurs via the oral mucosa, lungs, gastrointestinal mucosa, and skin. Nicotine
crosses the placental membrane and is secreted in the milk of lactating
women.Clearance of nicotine involves metabolism in the lung and the liver and
urinary excretion.
Adverse effects: The CNS effects of nicotine include irritability and tremors.
Nicotine may also cause intestinal cramps, diarrhea, and increased heart rate and
blood pressure. In addition, cigarette smoking increases the rate of metabolism for
a number of drugs.
C- Varenicline
it is useful as an adjunct in the management of smoking cessation in patients
with nicotine withdrawal symptoms.
D-Cocaine
is a widely available and highly addictive drug that is currently abused daily by
more than 3 million people in the United States.
Mechanism of action:
The primary mechanism of action underlying the central
and peripheral effects of cocaine is blockade of reuptake
of the monoamines(norepinephrine, serotonin, and dopamine)
into thepresynaptic terminals from which these neurotransmitters
are released . This blockade is caused by cocaine binding to the
monoaminergic reuptake transportersand,thus, potentiates and
prolongs the CNS and peripheral actions of these monoamines.
Actions:
CNS:Cocaine acutely increases mental awareness and produces a feeling of well-being
and euphoria. Cocaine increases motor activity, and at high doses, it causes tremors
Sympathetic nervous system:
Peripherally, cocaine potentiates the action of norepinephrine, and it produces the
fight or flight syndrome characteristic of adrenergic stimulation. This is
associated with tachycardia, hypertension, pupillary dilation, and peripheral
vasoconstriction.
Hyperthermia: from the drug's propensity to cause hyperthermia.
Therapeutic uses:
cocaine is applied topically as a local anesthetic (causes vasoconstriction) during
eye, ear, nose, and throat surgery. Whereas the local anesthetic action of cocaine
is due to a block of voltage-activated sodium channels, an interaction with
potassium channels
Pharmacokinetics:
Cocaine is often self-administered by chewing, intranasal snorting, smoking, or
intravenous (IV) injection. The peak effect occurs at 15 to 20 minutes after
intranasal intake of cocaine powder, and the high disappears in 1 to 1.5 hours.
Adverse effects:
- Anxiety: The toxic response to acute cocaine ingestion can precipitate an
anxiety reaction that includes hypertension, tachycardia, sweating, and paranoia.
Because of the irritability, many users take cocaine with alcohol.
- Depression: stimulation of the CNS is followed by a period of mental
depression.
Anesthetics
General anesthesia is essential to surgical practice, because it renders patients analgesic,
amnesic, and unconscious, and provides muscle relaxation and suppression of
undesirable reflexes. general anesthetics are delivered via inhalation or intravenous
injection.
Factors in selection of anesthesia
a- Status of organ systems
1- Liver and kidney: Of particular concern is that the release of fluoride, bromide,
and other metabolic products of the halogenated hydrocarbons can affect these
organs, especially if the metabolites accumulate with repeated anesthetic
administration over a short period of time.
2- Respiratory system: For example, asthma and ventilation or perfusion
abnormalities complicate control of an inhalation anesthetic. All inhaled anesthetics
depress the respiratory system.
3- Pregnancy: There has been at least one report that transient use of nitrous oxide
can cause aplastic anemia in the unborn child. Oral clefts have occurred in the
fetuses of women who have received benzodiazepines.
b- Concomitant use of drugs
Commonly, surgical patients receive one or more of the following preanesthetic
medications:
- benzodiazepines, such as midazolam or diazepam, to allay anxiety and facilitate
amnesia;
-barbiturates, such as pentobarbital, for sedation;
- antihistamines, such as diphenhydramine, for prevention of allergic reactions,
- ranitidine, to reduce gastric acidity
- antiemetics, such as ondansetron, to prevent the possible aspiration of stomach
contents;
- opioids, such as fentanyl, for analgesia
- anticholinergics, such as scopolamine, for their amnesic effect and to prevent
bradycardia and secretion of fluids into the respiratory tract.
Anesthesia can be divided into three stages:
1- Induction is defined as the period of time from the onset of administration of the
anesthetic to the development of effective surgical anesthesia.
2- Maintenance provides a sustained surgical anesthesia
3- Recovery is the time from discontinuation of administration of the anesthesia until
consciousness and protective physiologic reflexes are regained.
Depth of anesthesia
The depth of anesthesia has been divided into four stages. Each stage is characterized
by increased central nervous system (CNS) depression, which is caused by
accumulation of the anesthetic drug in the brain. These stages were discerned and
defined with ether, which produces a slow onset of anesthesia and with halothane
and other commonly used anesthetics, the stages are difficult to characterize clearly
because of the rapid onset of anesthesia.
1- Stage I Analgesia: Loss of pain sensation results from interference with sensory
transmission in the spinothalamic tract. The patient is conscious and conversational.
Amnesia and a reduced awareness of pain occur as Stage II is approached.
2- Stage II Excitement: The patient experiences delirium and possibly violent,
combative behavior. There is a rise and irregularity in blood pressure. The
respiratory rate may increase. To avoid this stage of anesthesia, a short-acting
barbiturate, such as thiopental, is given intravenously before inhalation anesthesia is
administered.
3- Stage III Surgical anesthesia: Regular respiration and relaxation of the skeletal
muscles occur in this stage. Eye reflexes decrease progressively, until the eye
movements cease and the pupil is fixed. Surgery may proceed during this stage.
4- Stage IV Medullary paralysis: Severe depression of the respiratory and vasomotor
centers occur during this stage. Death can rapidly ensue unless measures are taken to
maintain circulation and respiration.
Inhalation Anesthetics
Inhaled gases are the mainstay of anesthesia and are used primarily for the
maintenance of anesthesia after administration of an intravenous agent, that include
the gas nitrous oxide as well as a number of volatile liquid, eg; ether, diethylether,
chlorophome, halogenated hydrocarbons. The movement of these agents from the
lungs to the different body compartments depends upon their solubility in blood and
tissues as well as on blood flow. These factors play a role not only in induction but
also in recovery.
Potency
The potency of inhaled anesthetics is defined quantitatively as the Minimal
alveolar anesthetic concentration (MAC). Numerically, MAC is small for potent
anesthetics, such as halothane, and large for less potent agents, such as nitrous
oxide. MAC values are useful in comparing pharmacologic effects of different
anesthetics. The more lipid soluble an anesthetic, the lower the concentration of
anesthetic needed to produce anesthesia and, thus, the higher the potency of the
anesthetic.
Solubility in the blood: This is determined by a physical property of the anesthetic
molecule called the blood/gas partition coefficient, which is the ratio of the total
amount of gas in the blood relative to the gas equilibrium
phase. Drugs with low solubility in blood
differ in their speed of induction of anesthesia, such
as nitrous oxide.
In contrast, an anesthetic gas with high blood solubility,
such as halothane, dissolves more completely in the blood.
halothane > enflurane > isoflurane > sevoflurane >
desflurane > nitrous oxide.
Mechanism of action
interactions of the inhaled anesthetics with proteins
comprising ion channels. In addition, the inhalation
anesthetics block the excitatory postsynaptic current
of the nicotinic receptors.
Intravenous Anesthetics
Intravenous anesthetics are often used for the rapid induction of anesthesia, which is
then maintained with an appropriate inhalation agent. They rapidly induce
anesthesia and must therefore be injected slowly. Recovery from intravenous
anesthetics is due to redistribution from sites in the CNS.
a-Barbiturates
Thiopental is a potent anesthetic but a weak analgesic. It is an ultrashort-acting
barbiturate and has a high lipid solubility. When agents such as thiopental and
methohexital are administered intravenously, they quickly enter the CNS and
depress function, often in less than 1 minute.
These drugs may remain in the body for relatively long periods of time after their
administration, because only about 15 percent of the dose of barbiturates entering
the circulation is metabolized by the liver per hour.
The barbiturates are not significantly analgesic and, therefore, require some type of
supplementary analgesic administration during anesthesia to avoid objectionable
changes in blood pressure and autonomic function. All barbiturates can cause
apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm.
b. Benzodiazepines
The benzodiazepines are used in conjunction with anesthetics to sedate the patient.
The most commonly employed is midazolam, which is available in many
formulations, including oral. Diazepam and lorazepam are alternatives. All three
facilitate amnesia while causing sedation.
c. Opioids
Because of their analgesic property, opioids are frequently used together with
anesthetics; for example, the combination of morphine and nitrous oxide provides
good anesthesia for cardiac surgery.
d. Ketamine
Ketamine a short-acting, nonbarbiturate anesthetic, induces a dissociated state in
which the patient is unconscious but appears to be awake and does not feel pain.
This dissociative anesthesia provides sedation, amnesia, and immobility. It is
metabolized in the liver, but small amounts can be excreted unchanged. It is not
widely used, because it increases cerebral blood flow and induces postoperative
hallucinations.
Local Anesthetics
Local anesthetics are generally applied locally and block nerve conduction of
sensory impulses from the periphery to the CNS. Local anesthetics abolish
sensation (and, in higher concentrations, motor activity) in a limited area of the body
without producing unconsciousness (for example, during spinal anesthesia). The
most widely used of these compounds are lidocaine, mepivacaine, procaine,
ropivacaine, and tetracaine . Of these, lidocaine is the most frequently employed.
At physiologic pH, these compounds are charged; it is this ionized form that interacts
with the protein receptor of the Na+ channel to inhibit its function and, thereby,
achieve local anesthesia. The local anesthetics differ pharmacokinetically as to onset
and duration of action. Adverse effects result from systemic absorption of toxic
amounts of the locally applied anesthetic.
Major tranquilizers (Neuroleptics)
also called antipsychotic drugs, are used primarily schizophrenia. All currently
available antipsychotic drugs that alleviate symptoms of schizophrenia decrease
dopaminergic and/or serotonergic neurotransmission.
The traditionalor typical neuroleptic drugs or (first- generation antipsychotics) and
atypical (or second-generation antipsychotics) are competitive inhibitors at a variety
of receptors (competitive blocking of dopamine) receptors.
Mechanism of action
1- Dopamine receptor blocking activity in the brain: All of the older and most of the
newer neuroleptic drugs block dopamine receptors in the brain and the periphery.
The neuroleptic drugs bind to these receptors to varying degrees (clozapine,
chlorpromazine, and haloperidol.) antagonized example, levodopa.
2- Serotonin receptor blocking activity in the brain: Most of the newer atypical
agents appear inhibition of serotonin receptors (5-HT). Thus, clozapine has high
affinity for dopamine receptor, 5-HT2, muscarinic, and alpha-adrenergic receptors,
but antagonist Risperidone blocks 5-HT receptors.
Therapeutic uses
1- Treatment of schizophrenia:
2- Prevention of severe nausea and vomiting: The older neuroleptics (most
commonly prochlorperazine are useful in the treatment of drug-induced nausea.
3- Other uses: The neuroleptic drugs can be used as tranquilizers to manage agitated.
Neuroleptics are used in combination with narcotic analgesics for treatment of
chronic pain with severe anxiety.
Opioids
Management of pain is one of clinical medicine's greatest challenges. Pain is
defined as an unpleasant sensation that can be either acute or chronic and that is a
consequence of complex neurochemical processes in the peripheral and central
nervous system (CNS). Opioids are natural or synthetic compounds that produce
morphine-like effects. The term opiate is reserved for drugs, such as morphine and
codeine, obtained from the juice of the opium poppy.
All drugs act by binding to specific opioid receptors in the CNS to produce effects
that mimic the action of endogenous peptide neurotransmitters (for example,
endorphins, enkephalins, and dynorphins).
Strong Agonists :(Morphine, Meperidine, Methadone, Oxycodone)
Morphine:
Mechanism of action: Opioids exert their major effects by interacting with opioid
receptors in the CNS and in other anatomic structures, such as the gastrointestinal
tract and the urinary bladder. Opioids cause hyperpolarization of nerve cells,
inhibition of nerve firing, and presynaptic inhibition of transmitter release.
Morphine also appears to inhibit the release of many excitatory transmitters from
nerve terminals
Actions:
A-Analgesia: Opioids relieve pain both by raising the pain threshold at the spinal
cord level and, more importantly, by altering the brain's perception of pain.
B-Euphoria: Morphine produces a powerful sense of contentment and well-being.
Euphoria may be caused by disinhibition of the ventral tegmentum.
C-Respiration: Morphine causes respiratory depression by reduction of the
sensitivity of respiratory center neurons to carbon dioxide. Respiratory depression is
the most common cause of death in acute opioid overdose.
D-Depression of cough reflex: Both morphine and codeine have antitussive
properties.
E-Gastrointestinal tract: Morphine relieves diarrhea and dysentery by decreasing
the motility and increasing the tone of the intestinal circular smooth muscle.
F- Cardiovascular: Morphine has no major effects on the blood pressure or heart rate
except at large doses, when hypotension and bradycardia may occur.
G- Histamine release: Morphine releases histamine from mast cells, causing urticaria,
sweating, and vasodilation. Because it can cause bronchoconstriction, asthmatics
should not receive the drug.
H- Labor: Morphine may prolong the second stage of labor by transiently decreasing
the strength, duration, and frequency of uterine contractions.
Pharmacokinetics: Absorption of morphine from the gastrointestinal tract is slow. It is
well absorbed when given by mouth. metabolism of morphine occurs in the liver.
Morphine rapidly enters all body tissues, including the fetuses of pregnant women,
Adverse effects: Severe respiratory depression occurs and can result in death from
acute opioid poisoning. Other effects include vomiting, dysphoria, and allergyenhanced hypotensive effects, may cause acute urinary retention. Morphine should
be used with cautiously in patients with bronchial asthma or liver failure.
Moderate Agonists
Codeine
The analgesic actions of codeine are due to its conversion to morphine, whereas the
drug's antitussive effects are due to codeine itself. Thus, codeine is a much less
potent analgesic than morphine, but it has a higher oral effectiveness. Codeine is
often used in combination with aspirin or acetaminophen.
Mixed Agonist-Antagonists and Partial Agonists
Drugs that stimulate one receptor but block another are termed mixed agonistantagonists.
A. Pentazocine
Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is
used to relieve moderate pain. It may be administered either orally or parenterally.
Pentazocine produces less euphoria compared to morphine. In higher doses, the drug
causes respiratory depression and decreases the activity of the gastrointestinal tract
and increase blood pressure and can cause hallucinations, nightmares, dysphoria,
tachycardia, and dizziness.
B. Buprenorphine
Buprenorphine is classified as a partial agonist.
Other Analgesics
Tramadol
Tramadol is a centrally acting analgesic that binds to the opioid receptor. In addition,
it weakly inhibits reuptake of norepinephrine and serotonin. It is used to manage
moderate to severe pain. Its respiratory-depressant activity is less than that of
morphine.
Antagonists
The opioid antagonists bind with high affinity to opioid receptors but fail to activate
the receptor-mediated response. Administration of opioid antagonists produces no
profound effects in normal individuals.
A. Naloxone
Naloxone is used to reverse the coma and respiratory depression of opioid overdose.
It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to
reverse the effect of a heroin overdose. Within 30 seconds of IV injection of
naloxone, the respiratory depression and coma characteristic of high doses of heroin
are reversed, causing the patient to be revived and alert.
B. Naltrexone
Naltrexone has actions similar to those of naloxone. It has a longer duration of
action than naloxone, and a single oral dose of naltrexone blocks the effect of
injected heroin for up to 48 hours.
C. Nalmefene
Nalmefene is a parenteral opioid antagonist with actions similar to that of naloxone
and naltrexone. It can be administered IV, intramuscularly, or subcutaneously. Its
half-life of 8 to10 hours is significantly longer than that of naloxone and several
opioid agonists.
Epilepsy
population will have at least one seizure in their lifetime. Globally epilepsy is the
third most common neurologic disorder after cerebrovascular and Alzheimer's
disease. Epilepsy is not a single entity but, instead, an assortment of
different seizure types and syndromes originating from several mechanisms that
have in common the sudden,
Mechanism of action of antiepileptic drugs
Drugs that are effective in seizure reduction accomplish this by a variety of
mechanisms, including blockade of voltage-gated channels (Na+ or Ca2+),
enhancement of inhibitory GABAergic impulses, or interference with excitatory
glutamate transmission. Some antiepileptic drugs appear to have multiple targets
within the CNS, whereas the mechanism of action for some agents is poorly defined.
The antiepilepsy drugs suppress seizures but do not cure or prevent epilepsy.
Primary Antiepileptic Drugs
A. Benzodiazepines: Benzodiazepines bind to GABA inhibitory receptors to reduce
firing rate. Diazepam, and lorazepam are most often used as an adjunctive therapy
for myoclonic as well as for partial and generalized tonic-clonic seizures.
B. Carbamazepine
Carbamazepine reduces the propagation of abnormal impulses in the brain by
blocking sodium channels, thereby inhibiting the generation of repetitive
action potentials in the epileptic focus and preventing their spread.
Vagal Nerve Stimulation
Vagal nerve stimulation requires surgical implant of a small pulse generator
with a battery and a lead wire for stimulus.