. مهدي صالح سعديه م م محاضراتالزيني

الكوفة / جامعة البيطري الطب كليةواألدويــة الفسلجــة فــرع

وسموم أدوية ماجستير

Drugs Affecting the Central Nervous SystemMost 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 PotentialsIn 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 following1-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 carbidopaMechanism 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 3-O-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 agonistsa-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.

Actions1-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 uses1- 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 anxiety-

provoking 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 neticsAbsorption and distribution: The benzodiazepines are lipophilic, and they are

rapidly and completely absorbed after oral administration and distribute throughout the body.

Adverse effects1- Drowsiness and confusion2- 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 AntagonistFlumazenil 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 high-frequency 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 uses1- Anesthesia: thiopental2- 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 effects1-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.- EthanolEthanol (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 StimulantsA- 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 anesthesiaa- 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 action1- 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 allergy-enhanced hypotensive effects, may cause acute urinary retention. Morphine should be used with cautiously in patients with bronchial asthma or liver failure.

Moderate AgonistsCodeine 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 agonist-

antagonists. 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.