Principles of Pharmacology - Week 7 Seminar Notes

Topic = Central Nervous System 2

Overview of CNS Medications

• Focus Areas:

  • Medications for specific CNS conditions, including:

  • Depression and mood stabilizers

  • Epilepsy

  • Parkinson’s Disease

  • Alzheimer’s Disease

Depressive Disorders

Disorders of Mood

• General Characteristics:

  • Changes in mood and anxiety are normal in daily life.

  • Mental health conditions may involve distorted emotional states, leading to disabilities.

• Terminology:

  • Also referred to as affective disorders.

• Treatment Approaches:

  • Pharmacological management is often one part of treatment.

  • Combination with cognitive behavioral therapy and counseling is usually more effective.

Biology of Depression

• Pathophysiology:

  • Associated with changes in brain:

  • Structure

  • Metabolism

  • Neurotransmitter release

• Current Understanding:

  • No comprehensive understanding of the underlying pathophysiology of depression.

Synaptic Abnormalities in Mood Disorders

• Key Conditions:

  • Depression

  • Mania

• Monoamine Theory:

  • Mood disorders stem from abnormalities in neurotransmitter levels:

  • Serotonin

  • Noradrenaline

  • Dopamine

  • Depression: Synaptic depletion of noradrenaline and serotonin.

  • Mania: Increased neurotransmitter release, especially noradrenaline.

Evidence for Monoamine Theory

• Supporting Evidence:

  • Reduction of monoamine levels in depressed individuals.

  • Monoamine oxidase levels are higher in depression.

  • Certain drugs lowering monoamines induce depressive symptoms.

  • Drugs increasing monoamine levels often have antidepressant effects.

• Inconsistent Evidence:

  • Rapid increase of monoamines does not ensure immediate clinical improvement.

  • Not all drugs raising monoamine levels exhibit antidepressant activity.

• Conclusion:

  • Antidepressants remain effective despite debate; modern treatment should be holistic, combining lifestyle changes and therapy rather than a singular focus on neurochemicals.

Drug Mechanisms in Depression

Monoamine Uptake Blockers

• Mechanism:

  • Transmitters are cleared from synapses via active transport into nerve endings.

  • Drugs that block monoamine reuptake include:

  • SSRIs (Serotonin Selective Reuptake Inhibitors)

  • SNRIs (Serotonin-Noradrenaline Reuptake Inhibitors)

  • TCAs (Tricyclic Antidepressants)

  • MAOIs (Monoamine Oxidase Inhibitors)

Types of Antidepressant Drugs

• SSRIs:

  • Example: fluoxetine, escitalopram, citalopram.

  • Action: Block serotonin uptake, increasing synaptic levels.

  • Uses: Effective in anxiety disorders.

  • Adverse Effects: Nausea, sexual dysfunction, risk of serotonin syndrome.

• SNRIs:

  • Example: venlafaxine, duloxetine.

  • Action: Block both serotonin and noradrenaline reuptake.

  • Adverse Effects: Nausea, sexual dysfunction, insomnia.

• TCAs:

  • Example: amitriptyline, nortriptyline.

  • History: Among the oldest antidepressants.

  • Adverse Effects: Sedation, antimuscarinic effects, cardiac arrhythmias.

• MAOIs:

  • Example: phenelzine, tranylcypromine.

  • Action: Prevent breakdown of neurotransmitters.

  • Adverse Effects: Interaction with tyramine-containing foods leading to hypertensive crises.

Common Antidepressants Table

• Class | Mechanism of Action | Therapeutic Effects | Common Side Effects

• SSRIs (Fluoxetine, Sertraline) | Block SERT → ↑ serotonin | First-line for depression, anxiety | Nausea, sexual dysfunction

• SNRIs (Venlafaxine) | Block SERT & NET → ↑ serotonin & norepinephrine | Effective in severe depression | Nausea, hypertension

• TCAs (Amitriptyline) | Non-selective reuptake inhibitor | Effective but side effects limit use | Sedation, dry mouth

• MAOIs (Phenelzine) | Inhibit MAO-A & B → ↑ monoamines | Treatment-resistant depression | Hypertensive crisis with tyramine

Lifestyle and Dietary Considerations with Medications

• MAOIs and Tyramine:

  • Tyramine triggers norepinephrine release and is usually degraded by MAO.

  • Advice for Patients on MAOIs:

  • Avoid aged foods: cured meats, fermented products, and certain sauces to prevent hypertensive crises.

Anticonvulsants

Understanding Seizures

• Definition:

  • Seizures are caused by uncontrolled electrical disturbances in the brain, originating from hyperexcitable neurons.

• Causes:

  • Conditions leading to seizures include:

  • Epilepsy

  • Infections

  • Electrolyte imbalances

  • Drug use and withdrawal.

Epilepsy and Seizure Classification

• Epilepsy: Characterized by recurrent seizures.

• Classification of Seizures:

  • Partial (Focal): Limited to one hemisphere.

  • Generalized: Involves both hemispheres.

  • Status Epilepticus: Continuous seizures without recovery. Potentially life-threatening.

Pathophysiology of Seizures

• Mechanism:

  • Imbalance between excitatory (increase in Glutamate) and inhibitory (decrease in GABA) nerve activity, leading to irregular neuronal firing.

Pharmacological Treatment of Seizures

• General Approach:

  • Most drugs target the abnormal neuronal discharge rather than the root causes.

  • Toxicity is a common concern with several antiepileptic medications.

Mechanism of Action of Antiepileptic Drugs

1. Vigabatrin: Inhibits degradation of GABA, increasing its levels.

2. Carbamazepine: Blocks sodium channels, preventing repetitive neuronal discharges.

3. Midazolam: Increases GABA action at GABAA receptors.

4. Valproate: Blocks voltage-gated sodium channels and increases GABA effects.

5. Pregabalin: Reduces calcium influx at presynaptic neurons, decreasing neurotransmitter release.

6. Topiramate: Slows sodium channel recovery, inhibits glutamate action and enhances GABA action.

7. Levetiracetam: Modulates excitatory neurotransmission through synaptic vesicle interactions.

Pharmacokinetic Considerations

• Drug interactions: Impacted by protein binding and changes in plasma proteins.

• Monitoring: Essential due to long half-lives and gradual dosing requirements.

Neurodegenerative Disorders

Overview of Alzheimer’s and Parkinson’s Diseases

Alzheimer’s Disease

• Definition: A form of dementia with loss of cortical neurons, leading to brain atrophy and histological changes (neurofibrillary tangles and plaques).

Parkinson’s Disease

• Pathophysiology: Involves degeneration of the nigrostriatal pathway, affecting voluntary motor control due to lack of dopamine.

Symptoms of Parkinson’s Disease

• Motor Symptoms:

  • Bradykinesia

  • Rigidity

  • Tremors

  • Gait difficulties.

• Non-Motor Symptoms:

  • Depression

  • Cognitive impairment

  • Other systemic symptoms.

Pharmacological Treatment of Parkinson's Disease

• Dopaminergic Replacement: Levodopa (with carbidopa) as primary treatment.

• Dopamine Receptor Agonists: Apomorphine, bromocriptine.

• MAO-B Inhibitors: Selegiline, rasagiline for inhibiting dopamine breakdown.

• Dopamine Release Triggers: Amantadine.

• Anticholinergics: Caution advised due to side effects.

Levodopa Details

• Mechanism: Precursor to dopamine, must be administered with inhibitors to prevent premature conversion to dopamine outside the brain.

• Combination: Can be used alongside other drugs like Carbidopa and Entacapone to improve efficacy and reduce side effects.

Pharmacological Management Challenges

• Monitoring Adverse Effects: Increased administration may lead to side effects affecting the gastrointestinal system, liver function, and muscle control.

Summary of Alzheimer’s Disease Pharmacotherapy

• Main Focus: Current treatments enhance cholinergic pathways to improve cognition and manage symptoms; no definitive cure exists.

• Current Therapies Include:

  • Reversible anticholinesterases (e.g., donepezil, rivastigmine).

  • Emerging therapies targeting tau and amyloid pathology.

  • Monitoring is essential for dosage adjustments to mitigate peripheral and CNS effects.