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Beta Blockers - Classification and Therapeutic Uses

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Classification of Beta Blockers

A. Cardioselectivity (β1 vs β2 selectivity)

Cardioselectivity is relative and dose-dependent - at high doses, β1-selective agents also block β2 receptors.

B. Intrinsic Sympathomimetic Activity (ISA / Partial Agonist Activity)

• ISA agents cause less resting bradycardia and are preferred in patients with mild bradycardia.

C. Alpha-blocking Property (Combined α + β blockade)

• Labetalol: blocks α1, β1, β2 - used in hypertensive emergencies, pregnancy-induced hypertension
• Carvedilol: blocks α1, β1, β2 + antioxidant property - used in heart failure

D. Membrane Stabilizing Activity (MSA / Local Anesthetic Effect)

• Propranolol, Acebutolol, Oxprenolol possess MSA (relevant only at high doses)

E. Pharmacokinetic Classification

F. Generation-based (KD Tripathi)

• 1st generation: Non-selective - Propranolol, Nadolol, Timolol
• 2nd generation: Cardioselective - Atenolol, Metoprolol, Bisoprolol
• 3rd generation: Vasodilating β-blockers - Nebivolol (NO mediated), Carvedilol (α-blockade), Celiprolol (β2 agonism)

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Therapeutic Uses of Beta Blockers

1. Cardiovascular Uses

• Reduce cardiac output by decreasing heart rate and contractility
• Inhibit renin release (β1 effect on JG cells)
• Preferred in: young hypertensives, hypertension with tachycardia, post-MI hypertension, hypertension with angina

• Reduce O2 demand by decreasing HR, contractility, systolic BP
• Drug of choice in stable/exertional angina
• Propranolol, Metoprolol, Atenolol commonly used

• Reduce infarct size, prevent ventricular arrhythmias, reduce mortality
• Both acute (IV metoprolol) and long-term prophylaxis

• Carvedilol, Metoprolol succinate, Bisoprolol - proven mortality benefit in chronic stable HF
• Start at low dose, titrate up slowly (initially may worsen HF)

• Class II antiarrhythmic agents
• Useful in: SVT, atrial fibrillation/flutter (rate control), ventricular tachycardia (especially catecholamine-induced), PSVT
• Sotalol: class III + class II properties

• Reduce obstruction by decreasing HR and contractility

• IV Esmolol or labetalol - reduce rate of pressure rise (dP/dt)

2. Non-Cardiovascular Uses

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Organophosphorus (OP) Poisoning - Emergency Management

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Mechanism of Toxicity

1. OP compound binds covalently to the serine hydroxyl group of AChE (phosphorylation of AChE)
2. This prevents breakdown of acetylcholine (ACh) at synapses
3. ACh accumulates at all cholinergic junctions:
   • Muscarinic receptors (parasympathetic effectors + sweat glands)
   • Nicotinic receptors (NMJ + autonomic ganglia)
   • CNS cholinergic synapses
4. "Aging" - with time, the OP-AChE bond becomes permanent (irreversible); once aging occurs, new enzyme must be synthesized (takes weeks)
   • Aging is rapid with some agents (e.g., Soman - minutes), slow with others (Malathion - hours/days)
5. Result: cholinergic crisis = massive overstimulation followed by paralysis

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Clinical Features - The Cholinergic Toxidrome

A. Muscarinic Effects (M-receptor stimulation - parasympathetic)

• Eyes: Miosis (hallmark), blurred vision, lacrimation, conjunctival injection
• Respiratory: Bronchospasm, excessive bronchial secretions, rhinorrhea - this is the main cause of death
• GI: Nausea, vomiting, diarrhea, abdominal cramps, fecal incontinence
• Urinary: Urinary incontinence
• Cardiovascular: Bradycardia, hypotension, heart block
• Glands: Sweating (profuse), salivation, lacrimation

B. Nicotinic Effects (NMJ + ganglionic stimulation)

• NMJ: Muscle fasciculations (early), weakness, paralysis (late)
• Ganglionic (sympathomimetic): Tachycardia, hypertension, mydriasis (can oppose muscarinic miosis), pallor
• Note: Nicotinic effects often oppose muscarinic cardiovascular effects

C. CNS Effects

• Anxiety, restlessness, emotional lability
• Seizures (often refractory)
• Coma
• Respiratory center depression - another major cause of death

Intermediate Syndrome (IMS)

• Occurs 24-96 hours after acute cholinergic crisis resolves
• Proximal limb weakness, neck flexor weakness, cranial nerve palsies, respiratory failure
• No muscarinic features; due to prolonged NMJ dysfunction
• Requires mechanical ventilation

Organophosphate-Induced Delayed Neuropathy (OPIDN)

• Develops 2-3 weeks after exposure
• Distal sensorimotor axonopathy
• Due to inhibition of neuropathy target esterase (NTE)

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Emergency Management

Step 1: Initial Stabilization (ABC Priority)

• Airway and breathing are the FIRST priority - respiratory failure is the #1 cause of death
• Remove patient from exposure source (decontamination)
• Remove contaminated clothing; wash skin/eyes with soap and water
• Wear protective gloves (organophosphates penetrate latex)
• Suction excessive secretions
• Intubate if respiratory compromise (GCS < 8 or severe bronchospasm)
• IV access, continuous monitoring (SpO2, ECG, BP)

Step 2: Antidote Therapy

A. Atropine (Antimuscarinic - MAINSTAY)

• Adults: 2-4 mg IV immediately, repeated every 5-10 minutes until atropinization
• Severely poisoned patients may need 20-100 mg or more in 24 hours
• Children: 0.02-0.05 mg/kg IV

• Drying of secretions (dry mouth, dry lung fields)
• Heart rate > 80/min
• Dilated pupils
• Flushed dry skin
• NOT pupil dilation alone - secretion drying is the primary endpoint

Atropine does NOT reverse nicotinic effects (muscle weakness, paralysis, fasciculations) - only reverses muscarinic features

B. Pralidoxime (PAM / Oximes) - Cholinesterase Reactivator

• Must be given before aging occurs
• Reverses BOTH muscarinic AND nicotinic effects (especially NMJ paralysis)

• 1-2 g IV over 15-30 minutes (slow infusion to avoid rapid BP drop)
• Followed by infusion: 200-400 mg/hour
• Repeat 1 g after 1-2 hours if weakness persists

C. Benzodiazepines - for Seizures

• Diazepam 10 mg IV (drug of choice for OP-induced seizures)
• Phenytoin is ineffective
• Seizures are due to central cholinergic excess

Step 3: Supportive Care

• Mechanical ventilation if needed
• Correct electrolyte imbalances
• Monitor cholinesterase levels (RBC AChE and plasma pseudocholinesterase)
• Avoid succinylcholine (metabolized by plasma cholinesterase - prolonged paralysis)
• Avoid morphine, aminophylline (increase toxic effects)

Severity Assessment (Peradeniya Scoring):

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Short Note on Atropine

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Source and Chemistry

• Atropine is the prototype anticholinergic (antimuscarinic) drug
• Natural alkaloid from Atropa belladonna (deadly nightshade)
• Racemic mixture (dl-hyoscyamine); the l-isomer is active
• Tertiary amine - crosses blood-brain barrier

Mechanism of Action

• Competitive, reversible antagonist at muscarinic receptors (M1, M2, M3, M4, M5)
• Blocks effects of ACh at:
  • Parasympathetic effector organs
  • Sweat and salivary glands (sympathetic cholinergic)
  • CNS (unlike quaternary antimuscarinics)
• Does NOT block nicotinic receptors (NMJ, ganglia) at therapeutic doses

Pharmacological Effects (Dose-Dependent)

Organ-wise Effects:

• Mydriasis (dilated pupil) - M3 blockade of pupillary constrictor
• Cycloplegia (paralysis of accommodation) - blocks ciliary muscle
• Increased intraocular pressure (contraindicated in narrow-angle glaucoma)

• Low doses: paradoxical bradycardia (blocks presynaptic M1 autoinhibition, increases ACh)
• Higher doses: Tachycardia (blocks M2 on SA node)
• Blocks vagal influence - increases conduction velocity through AV node

• Bronchodilation (blocks M3 on bronchial smooth muscle)
• Reduced bronchial secretions - useful pre-operatively

• Reduces motility, tone, and secretions
• Reduces salivation, gastric acid (partial)
• Constipation

• Urinary retention (relaxes detrusor, increases sphincter tone)
• Contraindicated in BPH

• Stimulation at higher doses: restlessness, excitement, hallucinations
• Depression at toxic doses: coma, respiratory depression
• Reduces tremor in Parkinsonism (block central muscarinic excess)

• Reduced salivation, sweating, lacrimal secretion
• Reduced bronchial secretions

Pharmacokinetics

• Well absorbed orally and parenterally
• Crosses BBB (tertiary amine)
• T½ ~ 2-3 hours
• Partly metabolized in liver, excreted in urine
• Duration of action: 4-6 hours (mydriatic effect lasts 7-10 days for topical)

Therapeutic Uses

1. Preanaesthetic medication - reduces secretions, prevents vagal bradycardia during intubation
2. Organophosphorus/carbamate poisoning - antidote (as detailed above)
3. Bradyarrhythmias - sinus bradycardia, AV block (IV 0.6-1.2 mg)
4. Ophthalmology - cycloplegic refraction, uveitis (mydriasis breaks posterior synechiae)
5. Antispasmodic - renal/biliary colic (though less popular now)
6. Peptic ulcer (now replaced by H2 blockers/PPIs - less selective)
7. Motion sickness - hyoscine (scopolamine) preferred
8. Parkinsonism - reduces central cholinergic excess
9. Cardiopulmonary resuscitation (historically used; less recommended now)

Adverse Effects

• Dry mouth, constipation, urinary retention
• Tachycardia, blurred vision
• CNS: confusion, hallucinations, delirium (especially in elderly - anticholinergic syndrome)
• Hyperthermia (anhidrosis + hot environment)

Contraindications

• Narrow-angle glaucoma
• Benign prostatic hypertrophy (BPH)
• Paralytic ileus, pyloric stenosis
• Tachyarrhythmias

Atropine Toxicity / Poisoning ("Anticholinergic Syndrome")

• "Mad as a hatter, Blind as a bat, Dry as a bone, Red as a beet, Hot as a hare"
• Treatment: Physostigmine (a cholinesterase inhibitor that crosses BBB) - 1-2 mg IV slowly

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Management of Myasthenia Gravis (MG)

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Pathophysiology (Brief)

• Autoimmune disorder: IgG antibodies against nicotinic ACh receptors (nAChR) at the NMJ
• Antibody binding causes:
  • Receptor internalization and destruction
  • Complement-mediated damage to the post-synaptic membrane
  • Functional blockade of nAChR
• Result: Reduced receptor density → inadequate end-plate potential → fatigable muscle weakness
• ~80-85% have anti-AChR antibodies; ~5-10% have anti-MuSK antibodies
• Associated with thymic hyperplasia (65%) or thymoma (10-15%)

Clinical Features (Relevant to Management)

• Fatigable, fluctuating weakness - worsens with activity, improves with rest
• Ocular: ptosis, diplopia (most common presenting symptoms)
• Bulbar: dysarthria, dysphagia, dysphonia
• Limb: proximal weakness
• Respiratory: respiratory failure (myasthenic crisis)
• Myasthenic crisis = respiratory failure due to inadequate treatment or precipitants (infection, surgery, drugs)
• Cholinergic crisis = respiratory failure from over-treatment with anticholinesterases

Management

1. Symptomatic Treatment - Anticholinesterases

• Dose: 30-60 mg orally every 4-6 hours (up to 600 mg/day in divided doses)
• Reversible inhibitor of AChE → increases ACh at NMJ → improves neuromuscular transmission
• Quaternary ammonium compound - does NOT cross BBB (no CNS effects)
• Onset ~30 minutes, duration 3-6 hours
• Side effects: muscarinic overactivity (diarrhea, abdominal cramps, excessive salivation, bradycardia) - controlled with glycopyrrolate or atropine

• Alternative; shorter duration; mainly parenteral use (IV in crisis)
• 0.5-2 mg IM/IV for acute use
• Oral: 15 mg every 2-4 hours

2. Thymectomy

• Recommended for all patients with thymoma (mandatory)
• Also beneficial for generalized MG in patients < 60 years, especially within 3 years of diagnosis
• Achieves remission in ~35% and improvement in ~50% over years
• Mechanism: Thymus harbors myoid cells expressing AChR - source of antigenic stimulus

3. Immunosuppressive Therapy (for long-term control)

• Prednisolone: Starting dose 10-25 mg/day, increasing to 60-80 mg/day (alternate-day regimen preferred)
• Important: Initial worsening (steroid-induced exacerbation) may occur in first 2 weeks - hospitalize
• Maintain dose until remission, then taper slowly
• Most patients respond within 2-4 weeks

• 2-3 mg/kg/day orally
• Onset of action delayed - 3-12 months
• Monitor for hepatotoxicity, bone marrow suppression
• Often used with steroids for maintenance

• Mycophenolate mofetil - 1-1.5 g twice daily; fewer side effects than azathioprine
• Cyclosporine - used when steroids/azathioprine fail
• Tacrolimus, Cyclophosphamide - severe, refractory cases

• For refractory MG, especially anti-MuSK antibody positive
• B-cell depletion

4. Short-term Immunotherapy (for crisis or pre-operative)

• Removes circulating anti-AChR antibodies
• Dose: 3-5 exchanges over 7-14 days
• Response in 1-2 weeks, lasts 4-8 weeks
• Used for: myasthenic crisis, pre-thymectomy, before starting steroids

• 2 g/kg over 2-5 days
• Similar efficacy to plasmapheresis
• Mechanism: Fc receptor blockade, anti-idiotype antibodies, complement inhibition
• Response in 1-2 weeks, lasts 4-8 weeks

5. Management of Myasthenic Crisis

1. Intubate and ventilate if FVC < 15 mL/kg or inability to handle secretions
2. Identify and treat precipitant (infection - antibiotics; stop offending drugs)
3. Temporarily reduce/stop anticholinesterases (may worsen secretion overload)
4. Plasmapheresis or IVIg - rapid response within days
5. Restart pyridostigmine cautiously once ventilatory status improves
6. Edrophonium test to differentiate:
   • Myasthenic crisis: improves with edrophonium
   • Cholinergic crisis: worsens with edrophonium (atropine is antidote)

6. Drugs to Avoid in MG

7. Newer Targeted Therapies

• Eculizumab (anti-C5 complement inhibitor) - approved for refractory generalized AChR+ MG
• Efgartigimod (FcRn antagonist) - reduces IgG antibody levels including anti-AChR
• Rozanolixizumab - FcRn inhibitor

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Summary Table - Key Drug Doses (KD Tripathi Reference)

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