Pharmacology of Sedatives and Anticonvulsants

Central and Peripheral Nervous System Drugs

• These drugs treat conditions affecting the nervous system.

Muscle Relaxants

• Muscle relaxants relieve musculoskeletal pain or spasm and severe musculoskeletal spasticity.
• They are used to treat conditions such as Multiple Sclerosis (MS), cerebral palsy, stroke and spinal cord injuries.
• Two main classes of muscle relaxants are centrally-acting and peripherally-acting.

Centrally-Acting Muscle Relaxants

• These drugs act on the central nervous system to treat acute spasms caused by anxiety, inflammation, pain, or trauma.
• Examples: baclofen, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine.
• Pharmacokinetics: Absorbed in the gastrointestinal tract (GIT), widely distributed, metabolized in the liver and excreted through the kidneys. Onset is typically 30 minutes to 1 hour after oral administration, with duration varying from 4 to 25 hours (longest for cyclobenzaprine).
• Pharmacodynamics: Do not directly relax skeletal muscles, but depress the central nervous system (CNS).
• Pharmacotherapeutics: Treat acute, painful musculoskeletal conditions. Usually prescribed with rest and physical therapy.
• Drug Interactions: Can interact with other CNS depressants, resulting in increased sedation, impaired motor function, and respiratory depression. Cyclobenzaprine interacts with MAOIs, potentially causing high body temperature, excitation, and seizures. Methocarbamol can antagonize the cholinergic effects of anticholinesterase drugs used to treat myasthenia gravis.
• Adverse Reactions: Commonly affect the central nervous system (CNS). Gastrointestinal issues, hypotension, and cardiac arrhythmias are possible. Chlorzoxazone can discolor urine, turning it orange to purplish-red. Tizanidine has been linked to liver toxicity and hypotension.

Peripherally-Acting Muscle Relaxants

• Dantrolene sodium is the most common.
• Primarily affects the muscles.
• High doses are toxic to the liver.
• Pharmacokinetics: Peak is 5 hours after ingestion, absorbed slowly in the GIT, highly plasma bound, metabolized in the liver (half-life 4-8 hours), excreted in the urine (half-life 9 hours, potentially longer in liver dysfunction).
• Pharmacodynamics: Acts on the muscle, interfering with calcium ion release from the sarcoplasmic reticulum, weakening muscle contraction force.
• Pharmacotherapeutics: Primarily used to manage spasticity, especially in patients with cerebral palsy, multiple sclerosis, spinal cord injury, and stroke. Also, used to treat and prevent malignant hyperthermia
• Drug Interactions: Simultaneous use with other CNS depressant medications (such as anxiolytics, sedatives, hypnotics) may increase CNS depression. Co-administration with estrogen may increase liver toxicity risk.

Sedatives, Anxiolytics, and Hypnotic Agents

• Sedatives reduce activity or excitement.
• In high doses become hypnotics.
• 3 main classes of synthetic drugs are benzodiazepines, barbiturates, and nonbenzodiazepine-nonbarbiturate drugs.

Benzodiazepines

• Minor tranquilizers; anxiolytics.
• Therapeutic effects include daytime sedation, sedation before anesthesia, sleep inducement, reducing anxiety and tension, skeletal muscle relaxation, and anticonvulsant activity.
• Examples: estazolam, flurazepam, lorazepam, quazepam, temazepam, triazolam.
• Pharmacokinetics: Well absorbed from the GIT, widely distributed, metabolized in the liver and mostly excreted in the urine.
• Pharmacodynamics: Stimulate GABA receptors in the ascending reticular activating system (RAS) of the brain; low doses decrease anxiety, high doses induce sleep.
• Pharmacotherapeutics: Used for daytime sedation, pre-anesthesia sedation, sleep induction, anxiety reduction, muscle relaxation, and anticonvulsant action. Clinical indications include relaxing patients before surgery, treating anxiety, and treating seizure and insomnia disorders.
• (No information on adverse reactions or drug interactions is present in the notes)

Barbiturates

• Primary pharmacologic action is reducing overall CNS alertness.
• Examples: amobarbital, aprobarbital, butabarbital sodium, mephobarbital, pentobarbital sodium, phenobarbital, secobarbital sodium.
• Pharmacokinetics: Well absorbed from GIT, distributed widely, metabolized in the liver and excreted in the urine.
• Pharmacodynamics: Depress sensory and motor cortex activity in the brain, causing drowsiness. Higher doses cause respiratory depression and death. Stabilize nerve membranes throughout the CNS by influencing ion channels directly within the cell membrane.
• Pharmacotherapeutics: Used as sedatives and hypnotics in the treatment of insomnia, preoperative sedation, and anesthesia. Also used in relieving anxiety and as anticonvulsants.

Nonbenzodiazepines-Nonbarbiturates

• Act as hypnotics for short-term insomnia treatment.
• Include chloral hydrate, ethchlorvynol, and zolpidem.
• Pharmacokinetics rapidly absorbed from the GIT, metabolized in the liver, excreted in the urine; zolpidem has longer effectiveness (35 days).
• Pharmacodynamics: Mechanism of action (MOA) isn't fully understood, thought to produce depressant effects similar to barbiturates,
• Pharmacotherapeutics: Used for short-term treatment of insomnia, sedation before surgery, and some EEG studies.
• Drug interactions: Can cause additive CNS depression when taken with other CNS depressants, resulting in drowsiness, respiratory depression, stupor, coma, and death.

Antianxiety Drugs

• Also known as anxiolytics, used to treat anxiety disorders.
• Three main types are benzodiazepines, barbiturates, and buspirone.

Buspirone

• First anxiolytic in a class of drugs (azaspirodecanedione derivatives).
• Fewer side effects than benzodiazepines or barbiturates.
• Advantages: Less sedation, no increased CNS depressant effects with alcohol or other CNS depressants; low abuse potential.
• Pharmacokinetics: Rapid absorption, extensive first-pass effect in the liver, eliminated in urine and feces.
• Pharmacodynamics: Unknown exact mechanism of action but produces effects in areas of the midbrain related to serotonin receptor activity.
• Pharmacotherapeutics: Used to treat generalized anxiety; ineffective when quick relief is needed.
• Drug Interactions: Does not interact with alcohol or other CNS depressants, but may cause hypertensive reaction when combined with MAOIs.

Antidepressants

• Treat affective disorders such as depression.
• Include Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), and Selective Serotonin Reuptake Inhibitors (SSRIs).

MAO Inhibitors

• Two classifications based on chemical structure: hydrazines and nonhydrazines.
• Pharmacokinetics: Absorbed rapidly and completely in the GIT, metabolized in the liver to inactive substances, mostly excreted by kidneys.
• Pharmacodynamics: Inhibit monoamine oxidase, making more norepinephrine and serotonin available to receptors, thus relieving depression symptoms.
• Pharmacotherapeutics: Atypical depression treatment, may be used for other conditions resistant to other treatments.
• Drug interactions: Interactions with antidiabetics may enhance hypoglycemic (low blood sugar) effects, and interactions with meperidine may cause excitation, hypertension, severe temperature rise, and coma. Interactions with tyramine-containing foods or sympathomimetic drugs may cause severe reactions.

Tricyclic Antidepressants (TCAs)

• Effective and inexpensive drugs for major depression.
• Block reuptake of norepinephrine and serotonin.
• Examples include amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine.
• Pharmacokinetics: Well absorbed orally, undergo first-pass metabolism, distributed widely, metabolized in the liver, excreted slowly with long half-lives.
• Pharmacodynamics: Increase norepinephrine and/or serotonin levels by blocking their reuptake into storage granules within presynaptic nerve endings.
• Pharmacotherapeutics: Used to treat major depression, particularly in cases where it has a slow onset.
• Drug Interactions: Can increase the effects of amphetamines/sympathomimetics leading to hypertension, reduce blood levels of barbiturates, increase anticholinergic effects when given concurrently with other anticholinergic drugs, may cause an extremely elevated body temperature and possibly seizures if taken with MAOIs. Potential interactions with antihypertensive medications (clonidine and guanethidine) exist.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Newer generation antidepressants, developed to have fewer side effects than TCAs and MAOIs.
• Examples: citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.
• Pharmacokinetics: Absorbed almost completely orally; highly protein-bound, metabolized by the liver and excreted in the urine.
• Pharmacodynamics: Inhibit the reuptake of serotonin in the brain.
• Pharmacotherapeutics: Used to treat major depressive episodes, similar effectiveness to TCAs, also used in treatment of obsessive-compulsive disorder (OCD), panic disorders, eating disorders, personality disorders, and premenstrual syndrome.
• Drug interactions: Can cause serious, potentially fatal reactions if combined with MAOIs.

Antiparkinsonian Agents

• Drugs to treat Parkinson's disease.
• Two goals: promote dopamine secretion and inhibit cholinergic effects.

Anticholinergics

• Two categories according to chemical structure: synthetic tertiary amines (e.g., benztropine, biperiden) and antihistamines with anticholinergic activity (diphenhydramine, orphenadrine).
• Pharmacokinetics: Well absorbed from GIT, cross the blood-brain barrier (BBB), metabolized in the liver and excreted mostly as metabolites by the kidneys. Distribution patterns are not fully understood.
• Pharmacodynamics: High acetylcholine levels cause an excitatory effect on the CNS; these drugs inhibit acetylcholine's action on receptor sites in the CNS and autonomic nervous system (ANS), decreasing tremors.
• Pharmacotherapeutics: Used in the early stages of Parkinson's disease when symptoms are mild; beneficial for controlling sialorrhea and akinesia, and somewhat effective at decreasing rigidity.
• Drug Interactions: Antipsychotic drugs can reduce the effectiveness of anticholinergics. Over-the-counter (OTC) cough and cold medications can increase anticholinergic effects.

Dopaminergics

• Include drugs chemically unrelated; promote dopamine secretion indirectly.
• Examples: levodopa, carbidopa-levodopa, amantadine, bromocriptine, pergolide, pramipexole, selegiline.
• Pharmacokinetics: Absorbed from GIT, distributed in body tissues, metabolized (especially levodopa) widely, eliminated through urine, liver or both.
• Pharmacodynamics: Some directly raise dopamine levels in the brain (e.g., levodopa) while others facilitate dopamine receptor stimulation (e.g., agonists).
• Pharmacotherapeutics: Primarily used for Parkinson's disease. Levodopa is typically the first choice in most patients.
• Adverse Reactions: Levodopa may cause nausea, vomiting, orthostatic hypotension, anorexia, and confusion; severe cases involve syndrome called neuroleptic malignant syndrome. Amantadine might cause orthostatic hypotension and/or constipation. Bromocriptine could result in persistent hypotension, tachycardia, and worsening angina.

Antiepileptic Agents

• Also called anticonvulsants, they control seizures and epilepsy.
• Common classes include hydantoins, barbiturates, iminostilbenes, benzodiazepines, and valproic acid.

Hydantoins

• First anticonvulsants to treat seizures.
• Include phenytoin, phenytoin sodium, fosphenytoin, and mephenytoin.
• Pharmacokinetics: Phenytoin absorption is slow after oral or IM administration, while mephenytoin is much faster; phenytoin distributes throughout tissues; fosphenytoin has a broader distribution.
• Pharmacodynamics: Stabilize nerve cells, preventing over-excitement, primarily acting on the motor cortex to halt seizure activity spread.
• Pharmacotherapeutics: Primarily used to control complex partial seizures (psychomotor or temporal lobe), tonic-clonic seizures.
• Adverse effects: Potential liver toxicity, bone marrow suppression, gingival hyperplasia, and possibly serious dermatological reactions.

Barbiturates

• Long-acting, but less commonly used due to adverse effects compared to their older counterparts.
• Includes phenobarbital.
• Pharmacokinetics: Slow absorption, significant metabolism in the liver, some excretion unchanged in urine.
• Pharmacodynamics: Inhibits impulse conduction in CNS structures like ascending RAS, cerebral cortex, and cerebellum; stabilizes nerve membranes directly.
• Pharmacotherapeutics: Used in treating partial, tonic-clonic, and febrile seizures.
• Adverse effects: High potential for CNS depression including sedation, hypnosis, and deep coma; physical dependence and withdrawal potential.

Iminostilbenes

• Includes carbamazepine.
• Pharmacokinetics: Slow and erratic absorption, rapid distribution, significant metabolism, mostly excreted in urine after metabolism in the liver.
• Pharmacodynamics: Inhibit neural transmission, stopping the spread of seizure activity.
• Pharmacotherapeutics: Considered a first choice for both generalized tonic-clonic seizures and partial seizures (complex and simple).

Benzodiazepines

• Used for treating different types of seizures and other conditions.
• Include diazepam, clonazepam, and clorazepate.
• Pharmacokinetics: Absorbed quickly, distributed widely, high protein binding, metabolized in the liver, and excreted in the urine.
• Pharmacodynamics: They potentiate (increase) GABA effects, stabilize nerve membranes (reducing excitability), generally acting as anticonvulsants, anxiolytics, sedatives, hypnotics and muscle relaxants.
• Pharmacotherapeutics: Helpful in treating absence, atonic, and myoclonic seizures.

Valproic Acid

• Unrelated to other anticonvulsants chemically.
• Includes valproate and divalproex.
• Pharmacokinetics: Converted quickly to valproic acid in the stomach or GIT; widely distributed; high protein binding, metabolized in the liver, excreted in urine.
• Pharmacodynamics: Unknown precise mechanism but thought to boost GABA levels.
• Pharmacotherapeutics: Used in long-term management of absence, myoclonic, and tonic-clonic seizures.

Antipsychotic Agents

• Control psychotic symptoms like delusions and hallucinations in schizophrenia, mania, and other psychoses.
• Two main groups: typical and atypical.

Typical Antipsychotics

• Three main chemical categories of phenothiazines include aliphatic, piperidine and piperazine according to various adverse reaction patterns observed.
• Pharmacokinetics involve primarily liver metabolism, largely excreted in urine. Highly lipid-soluble, distributed widely, and highly concentrated in the brain.
• Pharmacodynamics: Work by blocking postsynaptic dopaminergic receptors. Phenothiazines stimulate the extrapyramidal system.
• Pharmacotherapeutics: Treat schizophrenia, calm anxious or agitated patients, help alleviate delusions & hallucinations.
• Drug interactions: Increase CNS depression potential with other CNS depressant drugs, elevated risk of hypertensive reaction with MAOIs, reduce levodopa effectiveness, lower seizure threshold with other seizure medications, can decrease anticholinergic effects when taken with anticholinergics.

Atypical Antipsychotics

• Less side effects, especially weight gain.
• More effective in treating negative symptoms of psychosis.
• Less likely to cause extrapyramidal side effects (EPS), like Parkinsonism.
• Examples: clozapine, olanzapine, risperidone.
• Pharmacokinetics: Absorbed after oral administration, largely metabolized/bound, excreted in urine with some in feces.
• Pharmacodynamics: Dopamine receptor blockers (but not as effective compared to typical antipsychotics). Also block serotonin receptors.
• Pharmacotherapeutics: Used in schizophrenics unresponsive to typical antipsychotics.
• Pharmacodynamics: Alter function of the P-450 enzyme system, impacting metabolism of atypical antipsychotics and/or potentially negating effects of levodopa or other dopamine agonists.

Test your knowledge on the pharmacological actions and characteristics of various sedative and anticonvulsant medications. This quiz covers drug classifications, therapeutic effects, as well as potential risks and side effects. Perfect for students studying pharmacology or related fields.