6.2. Pharmacology exam notes - CNS 2

Principles of Pharmacology - Week 7 Study Notes

Overview of Central Nervous System Medications

  • Medications used for specific CNS conditions include:

    • Depression and mood stabilizers

    • Epilepsy

    • Parkinson's disease

    • Alzheimer's disease

Depressive Disorders

Disorders of Mood

  • Changes in mood and anxiety levels are normal; however, some mental health conditions exhibit excessive, inappropriate, or distorted emotional states causing debilitating anxiety.

  • These disorders of mood are also known as affective disorders.

  • Pharmacological management of depression is typically one component of treatment; it is not always the most effective approach.

  • Drug therapy tends to be more effective when combined with cognitive behavioral therapy (CBT) and counseling.

Biology of Depression

  • Depressive illness is believed to be linked to changes in:

    • Brain Structure

    • Metabolism

    • Neurotransmitter release

  • There is currently no comprehensive understanding of the underlying pathophysiology of depression.

Proposed Synaptic Abnormalities

  • The Monoamine Theory of Mental Depression suggests that mood disorders stem from abnormalities in levels of:

    • Serotonin

    • Noradrenaline

    • Dopamine

  • Depression is characterized by synaptic depletions of:

    • Noradrenaline

    • Serotonin

    • Dopamine

  • Mania is characterized by an increase in neurotransmitter release, particularly noradrenaline.

Drugs that Block Monoamine Uptake

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

  • Locking the reuptake of monoamines is a key mechanism for several groups of antidepressants, including:

    • Serotonin Selective Reuptake Inhibitors (SSRIs)

    • Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

    • Tricyclic Antidepressants (TCAs)

    • Monoamine Oxidase Inhibitors (MAOIs)

Antidepressant Drug Therapy

  • SSRIs:

    • Mechanism: Block serotonin reuptake into the presynaptic terminal, elevating synaptic serotonin levels.

  • SNRIs:

    • Mechanism: Block amine reuptake pump on presynaptic terminals, increasing synaptic levels of noradrenaline and serotonin, with minor dopamine effects.

  • TCAs:

    • Mechanism: Block amine reuptake pump (non-selective).

  • MAOIs:

    • Mechanism: Prevent breakdown of excess neurotransmitters post-release.

Post-Synaptic Mechanisms

  • Antidepressant mechanisms involve complex interactions at the post-synaptic cells and neurotransmitter receptors.

  • Important neurotransmitter pathways include:

    • Adrenergic (Noradrenaline)

    • Serotonergic (Serotonin)

    • Include various classes of antidepressants such as SSRIs, SNRIs, TCAs, and MAOIs affecting neurotransmitter activity.

Specific Antidepressant Medications

  • Tricyclics (e.g., Amitriptyline, Nortriptyline):

    • Block reuptake of noradrenaline and serotonin, well absorbed orally, metabolized in the liver.

    • Can cause sedation, particularly in the elderly, and have potential for adverse interactions with drugs like alcohol.

  • SSRIs (e.g., Fluoxetine, Escitalopram):

    • First SSRI was Prozac; primarily blocks serotonin reuptake pump.

    • Also used for panic disorder, phobias, OCD; generally less toxic than TCAs.

    • Common side effects include nausea, vomiting, and sexual dysfunction.

  • SNRIs (e.g., Venlafaxine, Duloxetine):

    • Block both serotonin and noradrenaline reuptake; used for both depression and anxiety with relatively mild side effects.

  • MAOIs (e.g., Phenelzine, Tranylcypromine):

    • Increase monoamines by obstructing their breakdown with adverse effects associated with various foods (e.g., tyramine).

Patient Guidance on MAOIs

  • Patients on irreversible MAOIs like Tranylcypromine should avoid tyramine-rich foods to prevent hypertensive crises and other complications. Examples include:

    • Aged cheeses

    • Processed or fermented meats

    • Pickled products

Other Antidepressants

  • Alternatives:

    • St. John’s Wort: Interacts with liver enzymes.

    • Ketamine: Fast-acting antidepressant showing promise but lacks long-term efficacy evidence.

    • Psilocybin/MDMA: These substances will be discussed further in the following sessions.

Anticonvulsants

What is a Seizure?

  • Seizures result from sudden, uncontrolled electrical disturbances in the brain, generally originating from a group of hyperexcitable neurons known as the focal point.

  • Causes of seizures can include:

    • Epilepsy

    • Infection

    • Medication-induced conditions (e.g., Hyponatremia)

    • Fever

    • Alcohol withdrawal

Classification of Seizures

  • Epilepsy: Characterized by recurrent seizures. Seizures classified into:

    • Partial (focal): Affect limited brain areas (one hemisphere).

    • Generalized: Involve both hemispheres.

  • Status Epilepticus: A serious condition where one seizure follows another without recovery.

Seizure Types

  • Focal Onset: 60% of individuals with epilepsy.

  • Generalized Onset: 30%; Unknown Onset: 10%.

  • Secondary Classification considers awareness with motor/non-motor symptoms at onset.

Symptoms Based on Origin

  • Seizure intensity and symptomatology vary extensively based on the focus's origin in areas such as:

    • Frontal Lobe

    • Parietal Lobe

    • Temporal Lobe

    • Occipital Lobe

Pathophysiology of Seizures

  • Characterized by an imbalance between the excitatory (
    Glutamate) and inhibitory (e.g., GABA) neuronal activities, leading to abnormal neuronal firing patterns.

Pharmacological Treatment

  • Drug treatments primarily aim to prevent or control seizures, utilizing a variety of drugs with different mechanisms of action. Treatments are tailored to the patient's seizure type and individual physiology.

Mechanism of Antiepileptic Drugs

  • Vigabatrin: Enhances synaptic GABA concentration by preventing its degradation.

  • Carbamazepine: Blocks voltage-dependent sodium channels to prevent repetitive neuronal discharges.

  • Midazolam: Binds to GABA-A receptors, enhancing GABA actions (short-term use).

  • Valproate: Blocks sodium channels and increases GABA concentration by preventing its breakdown.

  • Pregabalin: Modulates calcium channels, decreasing neurotransmitter release.

  • Topiramate: Slows recovery from sodium channel inactivation and inhibits glutamate effects, also enhances GABA.

  • Levetiracetam: Binds to synaptic vesicle protein 2A, modulating neurotransmitter release.

Pharmacokinetics and Drug Interactions

  • Drug interactions are critical in combination therapy, involving plasma protein binding, hepatic metabolism alteration (inducers vs. inhibitors), and needing careful monitoring to assess efficacy and toxicity.

Neurodegenerative Disorders

Pharmacotherapy in Neurodegenerative Disorders

  • Broad Overview of drug approaches:

    • Alzheimer’s Disease

    • Characterized by neurofibrillary tangles and neuritic plaques leading to cognitive decline.

    • Current therapies focus on maintaining cognitive functions, utilizing reversible anticholinesterases.

    • Parkinson’s Disease

    • Involves degeneration of dopaminergic pathways in the nigrostriatal area.

    • Treatment strategies for relief without fixing underlying issues.

Current Treatments for Alzheimer’s Disease

  • Cholinesterase Inhibitors:

    • Medications such as Donepezil, Galantamine, Rivastigmine aim to enhance cholinergic signaling to improve memory and cognition.

  • Emerging Therapies:

    • Include agonists targeting muscarinic/nicotinic receptors, and potential lead compounds aiming for amyloid clearance and tau protein stabilization.

Parkinson’s Disease Treatment Approaches

  • Five main approaches:

    • Replace dopamine: Levodopa with Carbidopa,

    • Mimic dopamine: Dopamine receptor agonists (Apomorphine, Bromocriptine),

    • Inhibit dopamine breakdown: MAO-B inhibitors (Selegiline, Rasagiline),

    • Release dopamine: Amantadine,

    • Inhibit ACh: Antimuscarinic drugs (Benzatropine, Toletridone).

Levodopa Considerations

  • Due to dopamine's inability to cross the blood-brain barrier, dopamine replacement therapy utilizes Levodopa, which can cross this barrier.

  • Administered with Carbidopa to prevent conversion to dopamine before entering the CNS. This ensures effective delivery and reduces peripheral side effects.

Observational Concerns During Levodopa Adjustments

  • Monitoring patient reactions for gastrointestinal, liver, and muscle function during dosage changes of donepezil or other acetylcholinesterase inhibitors is critical for assessing efficacy and managing side effects, especially as dosage adjustments can lead to increased cholinergic activity in both the central and peripheral nervous systems.

Summary of Alzheimer's Disease Treatment Side Effects

  • Common effects include:

    • Improved cognition

    • Nausea, vomiting, fatigue

    • Elevated liver enzymes

    • Muscle cramps and other side effects needing careful management.