5.2: Mechanisms of Action: Respiratory, CNS, & Endocrine Agents

Mechanisms of Action: Respiratory, CNS, & Endocrine Agents

This section details the pharmacology and clinical application of drug classes targeting the respiratory system, central nervous system, and endocrine pathways, in accordance with the Australian Medicines Handbook (AMB) and national guidelines.

Respiratory Agents (Asthma & COPD)

Pharmacological management of obstructive airway diseases involves bronchodilators (relievers and symptom controllers) and anti-inflammatory agents (preventers).

1. Beta-2 Adrenoceptor Agonists

• Short-Acting (SABA: Salbutamol, Terbutaline): Provide rapid bronchodilation (onset <5 minutes, duration 4-6 hours) for acute symptom relief.
• Long-Acting (LABA: Salmeterol, Formoterol): Used for maintenance therapy. Formoterol has a rapid onset of action, allowing its use as both a reliever and controller in Single Inhaler Maintenance and Reliever Therapy (SMART).
• Mechanism of Action: Bind to beta-2 receptors on bronchial smooth muscle, stimulating adenylyl cyclase to increase intracellular cyclic AMP (cAMP). This activates protein kinase A, leading to smooth muscle relaxation and bronchodilation.
• Systemic Side Effects: Tremor (activation of beta-2 receptors in skeletal muscle), tachycardia (direct cardiac beta-2 activation and reflex baroreceptor response), and hypokalaemia (stimulation of the Na+/K+ ATPase pump, driving potassium into cells).

2. Anticholinergics (Muscarinic Antagonists)

• Short-Acting (SAMA: Ipratropium) & Long-Acting (LAMA: Tiotropium, Glycopyrronium): Primarily used in Chronic Obstructive Pulmonary Disease (COPD), though LAMA is also an option in severe asthma.
• Mechanism of Action: Competitively antagonize muscarinic M3 receptors on bronchial smooth muscle, blocking the bronchoconstrictor effects of acetylcholine released from vagal nerve endings.
• Adverse Effects: Dry mouth (most common), urinary retention, constipation, and metallic taste.
• Safety Warning: Avoid eye contact with inhaler aerosol or powder, as it can cause pupillary dilation and precipitate acute narrow-angle glaucoma.

3. Inhaled Corticosteroids (ICS: Fluticasone, Budesonide, Ciclesonide)

• Mechanism of Action: Diffuse into target cells and bind to glucocorticoid receptors. The complex translocates to the nucleus, where it represses pro-inflammatory genes (e.g., cytokines, adhesion molecules) and upregulates anti-inflammatory genes.
• Adverse Effects: Local effects include oral candidiasis (thrush) and dysphonia (hoarseness).
• Counselling: Patients must rinse their mouth with water and spit it out after each use to clear deposited drug. Using a spacer with pressurized metered-dose inhalers (pMDIs) reduces oropharyngeal deposition and increases lung delivery.

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Central Nervous System (CNS) Agents

Antidepressants

Critical Overdose and Interaction Risks:

• TCA Overdose: TCA overdose is life-threatening. Blockade of cardiac fast sodium channels causes QRS widening, ventricular arrhythmias, and refractory hypotension. Treatment requires intravenous sodium bicarbonate.
• MAOI Washout Periods: Irreversible MAOIs (phenelzine, tranylcypromine) inhibit MAO permanently. A 14-day washout period is required when switching to or from other antidepressants to avoid serotonin syndrome or hypertensive crisis. Switching from fluoxetine to an MAOI requires a 5-week washout due to the long half-life of its active metabolite, norfluoxetine.
• Tyramine ('Cheese') Reaction: Irreversible MAOIs prevent intestinal breakdown of dietary tyramine (found in aged cheeses, yeast extracts like Vegemite, and red wine). Tyramine enters systemic circulation and displaces norepinephrine from synaptic vesicles, causing a severe hypertensive crisis.

Benzodiazepines (e.g., Diazepam, Temazepam, Lorazepam)

• Mechanism: Positive allosteric modulators of the GABA_A receptor. They bind to the interface of alpha and gamma subunits, increasing the frequency of chloride channel opening in response to GABA. This results in chloride influx, membrane hyperpolarization, and neuronal inhibition.
• Risks: Sedation, anterograde amnesia, respiratory depression, tolerance, physical dependence, and severe withdrawal symptoms. Flumazenil (a competitive benzodiazepine antagonist) can reverse overdose but can precipitate acute withdrawal seizures in dependent patients.

Anticonvulsants

• Phenytoin: Blocks voltage-gated sodium channels. It displays non-linear (zero-order) pharmacokinetics within the therapeutic range, meaning minor dose increases can produce toxic serum concentrations. Adverse effects include gingival hyperplasia, hirsutism, nystagmus, and ataxia. It is a potent CYP enzyme inducer.
• Carbamazepine: Blocks sodium channels. It is unique in inducing its own metabolism (auto-induction). It is associated with severe cutaneous reactions (SJS/TEN), strongly linked to the HLA-B*1502 allele in patients of Asian descent.
• Sodium Valproate: Increases GABA concentrations, blocks sodium channels, and inhibits T-type calcium channels. It is highly teratogenic, causing neural tube defects and cognitive impairment in offspring. In Australia, it must be avoided in female patients of childbearing potential unless no alternative exists.
• Levetiracetam: Binds to synaptic vesicle protein SV2A, modulating neurotransmitter release. It is renally cleared with minimal CYP interactions, but can cause behavioural side effects ('Keppra rage' - irritability, depression, aggression).

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Endocrine Agents (Antidiabetic Medications)

1. Metformin (Biguanide)

• Mechanism of Action: Activates AMP-activated protein kinase (AMPK), leading to:
  1. Decreased hepatic gluconeogenesis (primary effect).
  2. Increased peripheral insulin sensitivity and glucose uptake.
  3. Delayed intestinal glucose absorption.
• Clinical Safety: Does not cause hypoglycaemia when used as monotherapy. High incidence of transient GI side effects (diarrhoea, cramping). Associated with a rare risk of lactic acidosis. Metformin must be withheld prior to iodinated contrast media procedures in patients with eGFR <60 mL/min or history of heart failure/hepatic impairment, and restarted 48 hours later if renal function is stable.

2. Sulfonylureas (e.g., Gliclazide, Glimepiride)

• Mechanism of Action: Bind to the sulfonylurea receptor 1 (SUR1) on pancreatic beta cells, blocking ATP-sensitive potassium (K_ATP) channels. This depolarizes the cell membrane, opening voltage-gated calcium channels, leading to calcium influx and exocytosis of insulin.
• Adverse Effects: Significant risk of hypoglycaemia (especially in elderly and renally impaired patients) and weight gain.

3. SGLT2 Inhibitors (e.g., Dapagliflozin, Empagliflozin)

• Mechanism of Action: Inhibit the Sodium-Glucose Co-transporter 2 (SGLT2) in the proximal convoluted tubule of the nephron, blocking the reabsorption of filtered glucose and promoting glucosuria.
• Clinical Benefits: Provide significant cardiovascular protection (reduction in heart failure hospitalisations) and slow chronic kidney disease progression.
• Adverse Effects: Mycotic genital infections (thrush), urinary tract infections, volume depletion, and euglycemic diabetic ketoacidosis (DKA).
• Clinical Counselling: SGLT2 inhibitors must be withheld during acute illness ('sick day rules') or 2 to 3 days before major surgery to minimize DKA risk.