Gen-Pharm_Neuromuscular-Disorders-4

Neuromuscular Disorders Overview

• Lecture Title: Neuromuscular Disorders

• Presented by: Patricia Angeles-Jorgensen, RN, MD, Occupational Health Physician

Parkinsonism

Definition and Symptoms

• Chronic neurologic disorder affecting extrapyramidal motor tract, which is responsible for posture, balance, and locomotion.

• Syndrome manifesting in several symptoms:

  • Bradykinesia: Slow movement and tremors.

  • Rigidity: Increased muscle tone, leading to stiffness.

  • Emotional flatness: Lack of facial expressions.

  • Involuntary tremors: Commonly in head and neck.

  • Pill rolling movement: Specific hand movement where fingers roll as if manipulating a pill.

• Typical onset: Between 50-70 years of age.

Pathophysiology

• Neurotransmitter imbalance: Between dopamine (DA) and acetylcholine (ACh).

• Neuronal degeneration: Primarily affects neurons in the substantia nigra of the midbrain, projecting to basal ganglia.

• Cause: Unknown, with a focus on neurotransmitter dynamics.

Neurotransmitters Involved

• Dopamine (DA):

  • Inhibitory neurotransmitter released from dopaminergic neurons.

  • Controls ACh levels, inhibiting excitatory responses.

• Acetylcholine (ACh):

  • Excitatory neurotransmitter released from cholinergic neurons.

• Consequences: As DA neurons degenerate, ACh levels dominate, causing overstimulation of neurons and movement disorders (e.g., tremors).

• Dopamine depletion: Around 80% of dopamine is depleted by the time symptoms are visible.

Medications for Parkinsonism

Symptomatic Treatment

• Aim: To reduce symptoms rather than cure the disease.

• Medication Types:

  • Anticholinergics: Block ACh receptors.

  • Dopaminergics: Stimulate dopamine receptors.

• Therapeutic strategy: Start with small doses and gradually increase as the disease progresses.

Anticholinergic Medications

• Examples:

  • Benztropine mesylate (Cogentin)

  • Trihexyphenidyl (Artane)

  • Ethopropazine (Parsidol)

  • Orphenadrine (Norflex)

• Indications: To decrease ACh levels; helps symptoms like rigidity, sweating, drooling, and tremors.

• Side effects: Include dry mouth, urinary retention, constipation, and blurred vision.

Carbidopa/Levodopa Therapy

• Drug Name: Carbidopa/Levodopa (Sinemet)

• Mechanism of Action:

  • Replaces deficient dopamine in the brain, aiming to restore balance with ACh.

  • Levodopa is converted to dopamine by the enzyme dopa decarboxylase, aided by Carbidopa that prevents premature conversion.

  • Results in lower required doses to achieve therapeutic effects.

• Possible Side Effects: Nausea, vomiting, involuntary dystonic movements, psychotic behavior.

Selegiline HCl (Eldepryl) - MAO-B Inhibitor

• Function: May selectively inhibit MAO-B and dopamine metabolism, extending dopamine's action period.

• Role: Used as adjunct therapy with levodopa to reduce dosage.

• Prognosis: Early administration may slow disease progression.

• Precautions: Avoid tyramine-rich foods due to potential hypertensive crises.

• Drug interactions: Risky with various tricyclic antidepressants and selective serotonin reuptake inhibitors.

Myasthenia Gravis

Overview

• Nature: An autoimmune disease where the body produces antibodies against ACh receptors, leading to receptor degradation.

• Consequences: Results in weakness and fatigue of skeletal muscles, impairing respiratory function.

• Medicinal Approach: Use of AChE inhibitors to enhance ACh levels at the neuromuscular junction to promote muscle contraction.

Medications for Myasthenia Gravis

• Examples:

  • Neostigmine

  • Pyridostigmine bromide

  • Ambenonium

• Dosage requirements: Medications must be given on a strict schedule to prevent muscle weakness.

• Caution: Overdosing can result in cholinergic crisis; antidote atropine sulfate should be available.

• Diagnosis Tool: Edrophonium chloride (Tensilon) used for diagnostic purposes can relieve ptosis shortly after administration.

Central Nervous System (CNS) Fundamentals

Functions of the CNS

• Components: Brain and spinal cord regulate essential body functions.

• Signal Processing: Linked through afferent nerves (sensory signals) and efferent nerves (responses to stimuli).

• CNS Stimulation: Can either enhance or inhibit neuron activity.

Blood-Brain Barrier (BBB)

• Structure: Protects the brain; tight junctions affect drug entry.

• Crossing Mechanisms: Lipid-soluble agents or drugs with specific transport mechanisms can pass the BBB.

• Clinical Relevance: Presents challenges in treating CNS infections while guarding the brain from toxins.

CNS Neurotransmitters

• Variety and Complexity: CNS has a plethora of neurotransmitters with unknown precise roles, making medication effects difficult to predict.

• Adaptation and Dependence: Chronic use alters drug effects; tolerance and physical dependence may develop (tolerance reduces effect, while dependence leads to withdrawal symptoms upon cessation).

CNS Stimulants

Major Stimulants

• Types: Amphetamines and caffeine stimulate cerebral cortex.

• Specific Actions: Analeptics focus on brainstem and medulla to stimulate respiration; anorexiants suppress appetite.

• Indications: Treatment for narcolepsy, ADHD, appetite suppression, respiration stimulation, and migraines.

Sedative-Hypnotics

Importance of Sleep

• Stages of Sleep:

  • Stage I & II: Light sleep, easily aroused.

  • Stage III: Transition to deeper sleep.

  • Stage IV: Deep, dreamless sleep promoting physical restoration.

  • REM Sleep: Involves dreaming and resets psychic equilibrium.

Insomnia and Drug Usage

• Prevalence: Insomnia is a common sleep disorder requiring treatment for underlying physical or emotional distress.

• Desired Effects of Medications: Quick sleep onset, minimal daytime drowsiness, refreshed awakening, and no hangover.

• Problems: Falling asleep, staying asleep, and early awakenings.

Types of Sedative-Hypnotics

• Distinction:

  • Hypnotics: Induce natural sleep.

  • Sedatives: Calm responses without altering consciousness. Increased doses may lead to sleep induction.

Barbiturates vs. Benzodiazepines

• Barbiturates: Less commonly used due to side effects and abuse potential; used for inducing sleep and sedation, with long-acting forms (e.g., phenobarbital for seizures).

• Benzodiazepines: Considered safer, effective for sleep disorders but should not exceed 3-4 weeks for hypnotic use.

Specific Benzodiazepines

• Examples:

  • Flurazepam (Dalmane): Long-acting, for insomnia.

  • Triazolam (Halcion): Short-acting hypnotic with potential memory loss.

  • Temazepam (Restoril): For insomnia and to reduce nocturnal awakenings.