Sympathetic Drugs

• Drugs acting on the autonomic nervous system include sympathetic and parasympathetic drugs.

Sympathetic Drugs

• Mimics: Mimetics.
• Include Sympathomimetics/Adrenergics.
• LYSE/Break: Lytics.
• Include Sympatholytics/Sympathoplegics.

Direct Sympathomimetics

• Bind directly to receptors.
• NE, epinephrine, and dopamine are endogenous sympathetic agonists.
• Binds to ɑ1, ɑ2, β1, or β2 adrenergic receptors.
• These “turn on” second messengers.

Indirect Sympathomimetics and Mixed Agents

• ↑ sympathetic response = other means.

Major ɑ and β Direct-Acting Agonists

• Drugs that sound natural are categorized this way.
• Includes Epinephrine (Adrenalin chloride).
  • It offers many uses like anaphylaxis, cardiac resuscitation, mydriatic, etc.
• Includes Norepinephrine (Levophed).
  • It offers a specific use: life-threatening hypotension; used to maintain BP.
• Includes Dopamine (Intropin).
  • Used for septic or cardiogenic shock.

α1-Selective Direct-Acting Agonists

• Starts with "Phenyl -".
• Includes Phenylephrine (Neo-Synephrine).
• Includes Phenylpropanolamine.
• They are used for nasal decongestion.
• Methoxamine (Vasoxyl) is an exception.

β-Receptor Specificity/Affinity

• β-NONselective direct-acting.
• Includes Isoproterenol (Isuprel) – β1, β2.
  • Used for bradycardia & asthma.
• B1-Selective direct-acting.
• Includes Dobutamine (Dobutrex) – B1.
  • Used for acute heart failure.

Direct Sympathomimetics - Catecholamines ("DENIED")

• Includes Dobutamine, Epinephrine, Norepinephrine, Isoproterenol, Dopamine.
• These have a short duration of action.
• Clinically used to treat anaphylaxis, cardiac arrest, heart failure and shock.
• Used as IV.

Direct Sympathomimetics - Non-Catecholamines

• These have longer half-lives.
• Includes Phenylephrine & Methoxamine, which is marketed as nasal and ophthalmic decongestants.
• Includes Metaproterenol, Albuterol, Bitolterol, Terbutaline, Isoetharine, Salmeterol, and Salbutamol
  • These are bronchodilators.
• Ritodrine is:
  • A uterine relaxant.
  • Used Orally.

Beta 2 Agonists Types

• Long Acting (Controllers).
• Includes Formoterol, Salmeterol.
• Short Acting (Relievers).
• Includes Metaproterenol, Ritodrine, Terbutaline, Albuterol/Salbutamol, Theophyline (methylxanthine).

Adrenergic Drugs- Adrenaline

• It is the prototype drug.
• Its clinical uses are:
  • Anaphylactic shock (DOC).
  • Bronchial asthma.
  • Cardiac resuscitation.
  • During local anesthesia combined with lidocaine.

Sympathomimetics Acting at Beta Receptor Systems

• Dopamine and Dobutamine are inotropes and vasopressors.
• Used in congestive heart failure and cardiogenic shock.
• These activate the myocardial beta1 receptor.
• This will increase the force of contraction of the failing heart, resulting in an increase in cardiac output.
• These are reserved for the acute management of heart failure.

Indirect Acting Agonists

• These release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect.
• Includes Amphetamine.
• Includes Methamphetamine.
• Useful in narcolepsy, hyperkinetic syndrome of children, attention deficit disorder (ADHD).

Mixed Sympathomimetics.

• These displace NE from presynaptic terminals and bind to adrenergic receptors.
• Ephedrine: Clinically used to treat narcolepsy.
• Mephentermine & Metaraminol: For the treatment of hypotension caused by anesthetics.
• Phenylpropanolamine: Decongestant in oral OTC drugs that can cause hemorrhagic stroke.

Sympatholytic Drugs

Presynaptic Adrenergic Blockers

• Peripheral Presynaptic anti-adrenergics.
• Guanethidine = ↓ Catecholamine release (reuptake to the vesicles then replace NE).
• Guanadrel.
• Bretylium (no longer used).
• Reserpine (deplete catecholamines).

α2-Selective Direct Acting Agonists

• Are Centrally Acting Antiadrenergics and can cause sedation.
• Clonidine (Catapres): Used to manage High Blood Pressure & ADHD.
• Guanfacine: Used to manage High Blood Pressure & ADHD.
• Methyldopa (Aldomet): Used to manage High Blood Pressure.
• Guanabenz: Used to manage High Blood Pressure.

α₁ - Adrenergic Selective, Reversible

• All drugs that ends in "- ZOSIN”.
• Includes Prazosin (Minipres).
• Includes Doxazosin (Cardura).
• Includes Terazosin (Hytrin).
• Effects:
  • ↓ BP without ↑ HR.
  • It can cause first-dose syncope.
• Indication:
  • Hypertension.
  • Treats urinary retention due to BPH.

ɑ1,ɑ2 – Nonselective Blocker

• Drugs that start with "Phen-”.
• Irreversible = Longest.
  • Phenoxybenzamine (Dibenzyline): Used before operation for Pheochromocytoma.
• Reversible = Shortest.
  • Phentolamine (Regitine): Used to manage paroxysmal HTN due to Pheochromocytoma.

α2 – Selective Blocker, Reversible

• Yohimbine: Used for erectile dysfunction.

Βeta Adrenergic Receptor Blockers

• These drugs are competitive antagonists of the beta adrenergic receptors.
• Beta blockers are either selective for the beta1 receptor or nonselective beta₁ and beta2 antagonists.
• Propranolol is a prototype drug.

Beta-Blocker Main Contraindications/Cautions "ABCDE"

• Asthma.
• Block (heart block)/Bradycardia.
• COPD.
• Diabetes mellitus.
• Electrolyte imbalance (hyperkalemia).

Nonselective Beta Blockers "NSTP"

• Nadolol.
• Sotalol.
• Timolol.
• Propranolol/Pindolol.

Cardioselective Beta Blockers "CaN BEAM"

• Celiprolol.
• Nebivolol (most selective): Can cause dyslipidemia.
• Bisoprolol, Betaxolol.
• Esmolol.
• Atenolol, Acebutolol.
• Metoprolol.

Beta Blockers with ISA

• These contain partial agonistic activity.
• Includes Celiprolol, Oxprenolol which can minimize risk for Bradycardia.
• Includes Pindolol, Penbutolol which are nonselective blockers.
• Includes Alprenolol, Acebutolol (B1 selective) which have no effect on lipid levels.

Adverse Effects

• Hypotension.
• Bradycardia.
• Fatigue.
• Drowsiness.
• Bronchoconstriction and sexual dysfunction is commonly observed with propranolol.

Beta Blockers with a1 Blocking Activity

• Labetalol Alol = α: Does not cause Dyslipidemia but has added vasodilating effects.
• Carvedilol lol = 1

Beta 2 Blockers

• Butaxamine has no clinical use and is used in experiments.

Cholinergic Drugs

Cholinergic Agents

• Includes Cholinomimetics /Cholinergic Agonists.
• Includes Anticholinergics.

Cholinomimetics

• Direct-Acting Cholinergic Agonists.
• Indirect-Acting Agents (Cholinesterase Inhibitors).

Cholinergic Agonists "ABC MNOP"

• Acetylcholine.
• Bethanechol.
• Carbachol.
• Methacholine.
• Nicotine.
• Pilocarpine.

Types of Cholinergic Agonists

• Acetylcholine is for miosis in cataract surgery.
• Choline derivatives
  • Carbachol: used in glaucoma and miosis for surgery.
  • Methacholine: diagnosis of bronchial airway hyperreactivity.
  • Bethanecol: induce evacuation of non-obstructed bladder.
• Alkaloids:
  • Arecoline.
  • Pilocarpine is for glaucoma and xerostomia.
  • Muscarine.
  • Nicotine is a smoking cessation aid.

Anticholinesterase Drugs "POP CORN"

• Physostigmine: Antidote for atropine or scopolamine poisoning.
• Organophosphates: Mainly used for myasthenia gravis.
• Pyridostigmine: Mainly used for myasthenia gravis.
• Carbamates: Treats confusion (dementia) related to Alzheimer’s and Parkinson’s.
• Rivastigmine: Treats confusion (dementia) related to Alzheimer’s and Parkinson’s.
• Neostigmine: Reversal agent for non-depolarizing NMB.

Cholinesterase Inhibitors

• Edrophonium Com: Used in Tensilon Test for diagnosis of MG.
• Carbamates Compete with Ach for the active site of the enzyme.
  • Physostigmine, Demecarium, Neostigmine, Ambenomium, and Pyridostigmine.
• Organophosphates have very high affinity for the active site of the enzyme.
  • Echothiopate is for glaucoma.
  • Parathion and Malathion are pesticides.

Cholinergic Response

• Diarrhea.
• Urination.
• Miosis.
• Bradycardia.
• Bronchoconstriction.
• Emesis.
• Lacrimation.
• Salivation.
• Sweating.

Cholinesterase Inhibitors Treat

• Glaucoma: a group of eye diseases characterized by abnormally high intraocular fluid pressure and damaged optic disk which can lead to irreversible blindness by damaging the optic nerve.
• Myasthenia gravis: a neuromuscular disease leading to fluctuating muscle weakness and fatiguability that is caused by an autoimmune disorder in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction.

Myasthenia Gravis

• Symptom: Ptosis of the left eye (drooping eyelids).
• Treated medically with:
  • Cholinesterase Inhibitors.
  • Immunosuppressants.
  • Thymectomy in selected cases.

Cholinergic Antagonists

• Includes Muscarinic Blockers.
• Includes Ganglionic Blockers.
• Includes Neuromuscular Blockers.
• They are all competitive antagonists which can be overcome by adequate concentrations of cholinergic agonist.

Muscarinic Antagonist

• Atropine is the prototype agent.
• Actions are dose-dependent.
  • Decreased salivary and bronchial secretions.
  • Decreased sweating.
  • Pupil dilation and tachycardia.
  • Inhibition of voiding.
  • Decreases GI motility.
  • Decreased gastric secretions.

Common Antimuscarinic

• Think: "Inhibits Parasympathetic And Sweat”.
• Includes Ipratropium, Pirenzepine, Atropine, Scopolamine.

Uses of Muscarinic Antagonists

• EYE-atropine, homotropine, tropicamide (Mydriatic).
• CNS- benztropine, scopolamine (Antiparkinson agent).
• RESPIRATORY- ipratropium (For motion sickness).
• GU- oxybutynin (For asthma, and inhibits voiding).
• GI- pirenzepine, glycopyrrolate, propantheline (For peptic ulcer).
• Nicotinic - Hexamethonium (Treats IBS, Enuresis, Hyperhidrosis, HTN Crisis).

Ganglionic Blockers

• Ng antagonists are occasionally used to treat hypertensive crisis.
• Block nicotinic receptors in both the sympathetic and parasympathetic ganglia.
• Seldom used clinically because of the complex and unpredictable actions.
  • Includes Hexamethonium, Mecamylamine, Trimethephan.

Clinical Uses for Cholinergic Antagonists

• Preanesthetic medication to prevent secretions.
• Prevention of motion sickness.
• For peptic ulcer.
• For irritable bowel syndrome.
• Mydriasis and cycloplegia.
• Adjunct treatment for Parkinsonism.
• Antispasmodic.
• Relieve bladder spasm, enuresis, and diarrhea.

Side Effects of Cholinergic Antagonists

• Classic anticholinergic/antimuscarinic side effects are:
  • Dry mouth, constipation, and tachycardia.
• Severe antimuscarinic effects:
  • Restlessness, headache, rapid and weak pulse, blurred vision, hallucinations, ataxia, “burning" skin, and possibly coma.
• Some antipsychotics, antihistamines, antidepressants, and opioids have anticholinergic effects.