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Table of Contents

Chlorothiazide (Diuril)  

• The thiazides act in the distal tubule to decrease sodium reabsorption (inhibits Na/Cl transporter).

  • As a result of decreased sodium and chloride reabsorption, a hyperosmolar diuresis ensues.

  • Delivery of more sodium to the distal tubule results in potassium loss by an exchange mechanism.

• Thiazides also promote calcium reabsorption, in contrast to loop diuretics.

• The initial decrease in blood volume followed by a longer-termed reduction in vascular resistance appear to account for the hypotensive effects of the thiazides.

 Adverse Effects

• Potassium depletion is a potentially serious side-effect that may require potassium supplementation and/or concurrent use of potassium-sparing diuretics.

•  Hyperuricemia may occur precipitating gout. 

  • The increase in systemic uric acid is due to a decrease in the effectiveness of the organic acid secretory system.

•  Diabetic patient may have difficulty in maintaining proper blood sugar levels.

Furosemide (Lasix), Bumetanide (Bumex),Ethacrynic acid (Edecrin) 

• Furosemide (Lasix), bumetanide (Bumex), and ethacrynic acid (Edecrin) are "high-ceiling" loop diuretics acting primarily at the ascending limb of the loop of Henle.

  • The effectiveness of these agents is related to their site of action because reabsorption of about 30 - 40% of the filtered sodium and chloride load occurs at the ascending loop.

  • Distal sites are not able to compensate completely for this magnitude of reduction of NaCl reabsorption.

• Loop diuretics increase urinary Ca²⁺ in contrast to the action of thiazides.

• Loop diuretics also increase renal blood flow by decreasing renal vascular resistance.

• These drugs are rarely used in the management of hypertension because of their short duration of action and the availability of better drugs.

 Adverse Effects

• Ototoxicity

• Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal excretion of uric acid by competition with renal secretory and biliary secretory systems.Therefore these agents can precipitate gout.

• Potassium depletion.

Clonidine (Catapres) (Sympatholytic)

• Antihypertensive:

  • Clonidine (Catapres) acts in the brain, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

  • Mechanism of action: centrally acting selective α₂ adrenergic agonist.

  • Especially effective in

    • Management of severe hypertension or

    • In renin-dependent hypertension

  • Transdermal clonidine (Catapres) patch: useful for surgical patients unable to take oral formulation

  • Clonidine (Catapres) reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance.

    • Reduction in stoke volume occurs due to increased venous pooling (decreased preload).

  • Clonidine (Catapres) does not interfere with cardiovascular responses to exercise.

  • Renal blood flow and function is maintained during clonidine treatment.

  • Clonidine (Catapres) has minimal or no effect on plasma lipids.

Other Clinical Uses

• Analgesia--

  • Preservative-free clonidine administered into epidural/subarachnoid space (150-450 micrograms)-- dose-dependent analgesia

  • No respiratory depression, nausea, vomiting, delayed gastric emptying or pruritus -- effects associated with opioids

    • Probable Mechanism: activation postsynaptic a₂ receptors in the spinal cord substantia gelatinosa

      •  Clonidine (Catapres) and morphine: no cross-tolerance when used concurrently in neuraxial analgesia

  • Side effects of neuraxial clonidine (Catapres)

    •   Hypotension, sedation, dry mouth

• Preanesthetic Medication:

  • Oral clonidine (Catapres) (preanesthetic medication):

    • Enhances intrathecal morphine + tetracaine (pontocaine) for postoperative analgesia (no increase in morphine-related side effects)

    • Preanesthetic clonidine (Catapres) also:

      • Reduces reflex tachycardia that may be caused by direct laryngoscopy for tracheal intubation

      • Reduces intraoperative blood-pressure and heart rate lability

      • Reduces plasma catecholamines levels

      • Significantly decreases anesthetic requirements for inhaled (MAC) and injected agents.

• Adverse Effects: 

  • Dry Mouth (xerostomia))

  • Bradycardia (in patients with SA nodal abnormality

  • Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors)

Stoelting, R.K., "Antihypertensive Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 302-312.

Methyldopa (Aldomet) (Sympatholytic)

• Methyldopa (Aldomet) is a prodrug which is metabolized to the active agent, α-methylnorepinephrine.

  • α-methylnorepinephrine acts in the brain, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

• Methyldopa (Aldomet) produces no change in cardiac output in younger patients, but in older patients a decline in cardiac output results from reduced heart rate and stroke volume.

  • The reduction in stroke volume occurs due to increased venous pooling (decreased preload).

• Since renal blood flow and function is maintained during methyldopa treatment, methyldopa maybe valuable in managing hypertensive patients with renal insufficiency.

Guanabenz (Wytensin) (Sympatholytic)    

• Guanabenz (Wytensin)acts in the brain, inhibiting adrenergic outflow from the brainstem.

  •   Inhibition of sympathetic outflow results in a decrease in blood pressure.

• Guanabenz (Wytensin) reduces cardiac output (by reducing both stroke volume and heart rate) and decreases peripheral resistance.

  •  Reduction in stoke volume occurs due to increased venous pooling (decreased preload).

• Guanabenz (Wytensin) does not interfere with cardiovascular responses to exercise.

• Renal blood flow and function is maintained during guanabenz (Wytensin) treatment.

• Guanabenz (Wytensin) has minimal or no effect on plasma lipids.

Adverse Effects: Guanabenz

• Dry Mouth (xerostomia)

• Bradycardia (in patients with SA nodal abnormality)

• Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors)

Guanethidine (Ismelin)and Guanadrel (Hylorel) 

• Guanethidine (Ismelin) inhibits the function of postganglionic adrenergic neurons, thus inhibiting sympathetic function.

• Guanethidine (Ismelin) uses the norepinephrine (N.E.) re-uptake transporter to reach its site of action, the neurosecretory vesicles.

  • Guanethidine (Ismelin) replaces norepinephrine in the vesicle and is released instead of the normal transmitter.

  • Guanethidine (Ismelin) is an inactive transmitter and the replacement of N.E. by an inactive agent is responsible for its antihypertensive effects (maintenance dosing).

• Adrenergic blockade by guanethidine (Ismelin) results in post-synaptic supersensitivity.

• Sympathetic blockade by guanethidine (Ismelin) produces:

  •  Venodilatation

  •  Reduction in cardiac output due to inhibition of cardiac sympathetic innervation

  •  Blockade of  the sympathetic reflex arteriolar response to the reduction in cardiac output.

Adverse Effects:  Guanethidine (Ismelin)and Guanadrel (Hylorel) 

• Symptomatic hypotension (due to sympathetic reflex blockade)

• Sexual dysfunction (delayed ejaculation)

• Diarrhea

• Guanethidine (Ismelin) effects blocked by N.E. reuptake blockers (tricyclic antidepressants, cocaine, ephedrine, amphetamine, chlorpromazine (Thorazine))

Reserpine (Adrenergic Neuron Blocker) 

• Reserpine inhibits the function of postganglionic adrenergic neurons, thus inhibiting sympathetic function.

• Reserpine binds to noradrenergic storage vesicles in central and peripheral sympathetic nerve terminals.

  • Storage vesicles become nonfunctional as a result of interacting with reserpine and lose the ability to store and concentrate norepinephrine (N.E.) and dopamine.

  • N.E. and dopamine leaking from vesicles are enzymatically destroyed in the cytoplasm and as a consequence little transmitter is released upon nerve ending depolarization.

• Depletion of transmitter in both the central and peripheral nervous system suggest that both sites by be important mediators of the antihypertensive response.

• Chronic adrenergic neuronal blockade by reserpine results in a reduction of cardiac output and peripheral vascular resistance.

Adverse Effect

• CNS effects predominate, including sedation, inability to concentrate, and depression.

Prazosin (Minipress) (α₁-Arenoceptor Antagonis); Terazosin (Hytrin) (α₁-Adrenoceptor Antagonist)

• Prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura) reduce arteriolar resistance and increase venous capacitance as a consequence of α₁ adrenergic receptor blockade.

  • Normal inhibition of norepinephrine-mediate inhibition through α₂ receptors remain-- prazosin (Minipress) is a selective postsynaptic α₁ adrenergic receptor blocker

  • The short-term increase in heart rate and plasma renin levels do not persist although the vasodilation continues.

  • Prazosin (Minipress) monotherapy --less effective than thiazide diuretics

  • Prazosin (Minipress) in combination with other agents: quite effective in young patients with moderately severe hypertension

  • Good patient compliance

• Cardiovascular Effects:

  • Prazosin (Minipress) reduces systemic vascular resistance without:

    • Causing reflex-mediated tachycardia

    • Causing increases in plasma renin (as seen with minoxidil/hydralazine)

      • Absence of changes in plasma renin reflect continued α₂ receptor function which normally inhibits renin release (recall that prazosin is an α₁ selective antagonist)

  • Prazosin (Minipress) -- greater affinity for venular α receptors compared to arteriolar α receptors; resultant hemodynamics effect (orthostatic hypotension) --an action more similar to nitroglycerin than hydralazine (Apresoline).

• Renal blood flow is maintained.

• Retention of salt and water occurs.

• α₁-adrenergic receptor blockers reduce plasma triglycerides, total and LDL-cholesterol, and increase HDL-cholesterol.

• Other Therapeutic Uses:

  • Congestive heart failure: valuable for reducing afterload

  • Preoperative preparation of patients with pheochromocytoma

  • Treatment of benign prostatic hypertrophy in older males (drug decreases prostate size)

• Adverse Effect

  • Inital-dose marked orthostatic hypotension is seen in about 50% of cases-- (sudden syncope; dosage dependence)

  • Fluid retention, vertigo

  • dry mouth, urinary frequency, lethargy, sexual dysfunction, nasal congestion, nightmares

• Anesthetic Implications:

  • Prazosin (Minipress)-induced α₁ blockade may cause exaggerated hypotension during epidural anesthesia (α receptor--blockade prevents compensatory vasoconstriction)

    • Prazosin (Minipress)-exacerbated hypotension may not be responsive to typical α₁ adrenergic agonists (e.g. phenylephrine) dosage; epinephrine may be required to increase systemic vascular resistance and BP in this setting

    •  The combination of prazosin (Minipress) and a β-blocker could result in nearly refractory hypotension during regional anesthesia (diminished response to both β and α₁ agonists)

Stoelting, R.K., "Antihypertensive Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 302-312

Labetalol (Trandate, Normodyne) 

• Labetalol (Trandate, Normodyne) is a competitive antagonist at both α₁ and ß₁-adrenergic receptors. It also has an intrinsic sympathomimetic effect at ß₂ receptors

• Antihypertensive effects of labetalol results from actions at both α₁ and β-adrenergic receptors.

  •  α₁ receptor blockade results in vasodilatation which is further enhanced by ß₂ receptor activation.

  •  A reduction in heart rate is mediated by β₁ receptor antagonism.

• Labetalol (Trandate, Normodyne) does not alter serum lipids.

 Adverse Effects

• Orthostatic hypotension may occur due to α₁ receptor blockade.

• Urinary retention

• Liver injury has been reported with labetalol (Trandate, Normodyne) usage.

• Bronchospasm -- incidence similar to that observed with metoprolol (Lopressor) or atenolol (Tenormin)

• Labetalol (Trandate, Normodyne) metabolites: false positive for pheochromocytoma

• Paresthesias (scalp tingling)

Stoelting, R.K., "Antihypertensive Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 302-312.