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Medical Pharmacology Lectures:  Cardiovascular Pharmacology, Antihypertensive Agents Slide 5

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Diuretics

Thiazides

  • Hydrochlorothiazide (HydroDIURIL)

  • Chlorthalidone (Hygroton)

  • Chlorothiazide (Diuril)

  • Indapamide (Lozol)

  • Metolazone (Zaroxolyn)

Potassium Sparing

  • Amiloride (Midamor)

  • Spironolactone (Aldactone)

  • Triamterene (Dyrenium)

Loop Diuretics

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

  • Torsemide (Demadex)

 

 

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.

 

Antihypertensive Drug List

Centrally Active

  • Clonidine (Catapres)

  • Methyldopa (Aldomet)

  • Guanabenz (Wytensin)

  • Guanfacine (Tenex)

 

Adrenergic Neuron Blocker

  • Guanadrel (Hylorel), Guanethidine (Ismelin)

  • Reserpine

 

Adrenoceptor Antagonists

  • Prazosin (Minipress) (α), Terazosin (Hytrin) (α)

  • Labetalol (Trandate, Normodyne) (α and beta)

 

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.

Adverse Effects

  • Dry Mouth

  • Parkinsonian signs

  • Reduced libido

  • Hyperprolactinemia (gynecomastia, galactorrhea)

  • Bradycardia (in patients with SA nodal abnormality)

  • Hepatoxicity (avoid in patients with hepatic disease)

  • Positive Coombs' test (20%)

    • 1-5% of those with positive Coombs' develop hemolytic anemia (requiring immediate discontinuation of the drug)

 

 

 

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 1-adrenergic receptors. It also has an intrinsic sympathomimetic effect at 2 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 2 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.

 

 
 
 
 
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