Basic Pharmacology

MUSCARINIC AGONISTS:

• LOW DOSES: Primary effect is vasodilation due to inhibition of sympathetics. In response you see a reflex tachycardia.
• HIGH DOSES: You see a direct bradycardia.
  • You can see Atrial Fibrillation as a side effect, as the Ventricular refractory period is prolonged and the atrial refractory period is shortened.
• EFFECTS: Cholinergic outflow shows the following symptoms:
  • SLUD: Sweating, Lacrimation, Urination, Defecation
  • Profuse diarrhea, vomiting, nausea.
  • Flushed skin.
• Direct Muscarinic Agonists:
  • Choline Esters
  • Alkaloids
• Indirect Muscarinic Agonists
  • Carbamates: Reversible inhibitors of cholinesterase.
  • Organophosphates: Irreversible inhibitors of cholinesterase.
    
     

ORGANOPHOSPHATE POISONING:

• DEATH by Respiratory Suppression in the CNS is the most common cause. This is not an effect on the diaphragm, but rather is a suppression of the respiratory drive (muscarinic receptors) in the CNS.
• 2-PAM (Pralidoxime): Only effective within the first five minutes of exposure.
  • Acetylcholinesterase is a Serine-Protease. It binds to Acetylcholine by latching onto the NH₃ group with a His residue, and hydrolyzing the ester group with a Ser residue.
  • Organophosphates phosphorylate the cholinesterase, rendering it inactive. Within the first few minutes, this phosphorylation is reversible.
  • 2-PAM is a strong nucleophile, and binds with the organophosphates to reverse the phosphorylation.
  • After the first 5 or 10 minutes, aging occurs and the phosphorylation becomes irreversible. After that, 2-PAM no longer works.
• ATROPINE is the treatment of choice after that.
  
   

ANTI-MUSCARINIC AGENTS:

• SIDE-EFFECTS of Anti-Muscarinics: Inhibit all muscarinic activities
  • Peripheral:
    • Dry mouth (no salivation)
    • Constipation (no anal sphincter relaxation, lost GI motility)
    • Blurred Vision (no accommodation)
    • Urinary retention (lost UG motility, no sphincter relaxation)
    • Increased intraocular pressure (sympathetics increase intraocular pressure and parasympathetics decrease it).
  • Central: Impairment of all things that ACh mediates in the CNS
    • Confusion
    • Memory impairment
    • Hallucinations, delusions
      
       

GANGLIONIC BLOCKERS: Trimethaphan and Hexamethonium.

• They block all autonomic responses.
• RESULTS:
  • Orthostatic Hypotension: block sympathetic reflex control of vasculature.
  • Tachycardia: Block parasympathetic reflex control of the heart.
  • GI / UG: Decreased motility, urinary retention, constipation (lost parasympathetic reflexes)
  • Mouth: Xerostomia
    
     

ADRENERGIC AGONISTS: Catecholamine, catecholamine-like compounds.

• PHARMACOKINETICS: Never administered orally, due to high first-pass effect.
• ADVERSE EFFECTS:
  • Increased cardiac excitability and arrhythmias ------> ventricular fibrillation.
• CONTRAINDICATIONS: MAO Inhibitors, Cocaine, Tri-cyclics. These all potentiate NE, thus don't give catecholamines!
• SHORT-LIVED: Endogenous catecholamines, or catechol-like compounds, have very short half-lives, due to abundance of MAO and COMT.
  
   

beta-AGONISTS:

• beta₂-AGONISTS: They are primarily used as bronchodilators, but in severe heart failure, there is down-regulation of beta₁-receptors. Thus in CHF, beta₂ may have a significant effect on the inotropic state of the heart.
  
   

MAO-INHIBITORS: Mono-Amine Oxidase Inhibitors. MAO has two isozymes.

• MAO-A: More effective in degrading NE and serotonin.
• MAO-B: Less selective for individual amines.
• Older MAO-Inhibitors are non-selective. Newer ones are isozyme-selective.
  
   

alpha-ANTAGONISTS:

• PRINCIPAL EFFECTS:
  • Decreased TPR, decreased blood pressure (primary effect)
  • Tachycardia (reflex)
  • Increased release of renin (reflex)
• SIDE EFFECTS:
  • Miosis
  • Decreased adrenergic sweating
  • Stuffy nose
  • Increased insulin release
  • Impaired ejaculation
    
     

beta-ANTAGONISTS:

• PRINCIPLE EFFECTS:
  • They decrease the inotropic state of the heart ------> decrease oxygen demand of the myocardium. Useful in treating angina pectoris.
  • They decrease blood pressure:
    • They increase TPR and decrease cardiac output, but the net effect is to decrease blood pressure.
    • They decrease renin secretion in the kidney, which also helps to decrease blood pressure.
  • They decrease AV conduction in the heart, and are useful in treating arrhythmias.
• SIDE-EFFECTS:
  • Rebound Tachycardia can result if the drug is withdrawn quickly, due to denervation supersensitivity (i.e. up-regulation of beta₁-receptors after using the drug for a while).
  • Insulin release is blocked in pancreas ------> possible hyperglycemia, which can be a problem with Diabetics.
  • Can also lead to hypercholesterolemia.
  • Local Anesthesia: Membrane-stabilizing effect occurs as the drugs block Na⁺-channels in heart muscle and in neurons. This is not of clinical consequence, except when using as eye drops.
• CONTRAINDICATIONS: ASTHMA is an absolute contraindication, for non-selective beta-blockers. You don't want to block the bronchodilatory effects of beta₂-receptors!
  • You can possibly use beta₁-selective (cardioselective) antagonists with asthmatics, but even these drugs still have some beta₂-activity (even if minimal).