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• Two main classes of diuretics are used in management of chronic hypertension: thiazides and potassium sparing drugs. 

• Objective: pharmacological alteration of sodium load.

  • A reduction in sodium leads to reduced intravascular volume and a blood pressure reduction.

  • Thiazide diuretics cause an inhibition of NaCl transport in the Distal Convoluted Tubule (DCT)

• Orally active thiazide drugs have historically been a mainstay of antihypertensive treatment.

• Reduction in blood pressure is initially due to a reduction in extracellular volume and cardiac output.

  • Long-term antihypertensive effects of thiazides appear due to reduced vascular resistance. The exact mechanism responsible for the reduction in vascular resistance is not known.

•  Thiazides, due to their inhibition of the Na⁺-Cl^- symport system, increase sodium and chloride excretion.(renal synport diagram)

• By increasing the sodium load at the distal renal tubule, thiazide indirectly increases potassium excretion via the sodium/ potassium exchange mechanism.

Adrenergic nerve blockers

• Adrenergic nerve blockers include: guanethidine (Ismelin), guanadrel (Hylorel) and reserpine.

  • These agents inhibit sympathetic function at the level of the nerve ending.

  • Antihypertensive effects result from the inability of the sympathetic nervous system to produce vasoconstriction.

  • Guanethidine (Ismelin) and guanadrel (Hylorel) act by a similar mechanism: replacement of norepinephrine by an inactive transmitter.

  • Reserpine acts by depleting norepinephrine and dopamine from vesicles.

Adverse Effects 

• Adverse effects of guanethidine (Ismelin) and guanadrel (Hylorel) are related to sympathetic blockade

  • symptomatic hypotension, sexual dysfunction in males, diarrhea

• Side effects of reserpine are typically related to CNS effects, particularly sedation and difficulty in concentration.

• Vasodilators used for chronic treatment include hydralazine (Apresoline) and minoxidil (Loniten).

• These drugs are not typically administered as monotherapy due to:

  • Significant, reflex-mediated cardiac stimulation and water retention.

  • They are combined with sympatholytic drugs (e.g. propranolol (Inderal)) and diuretics.

• Hydralazine (Apresoline)

  • Dilation: effect greater on arterioles, compared to venules

  • Most pronounced dilation:

    • coronary, renal, splanchnic, and cerebral circulation

  • Mechanism of action: vasodilation may be mediated by vascular smooth muscle calcium ion transport inhibition

  • Pharmacokinetics:

    • Extensive hepatic first pass effect

    • Major route metabolism: acetylation

    • Patients categorized as "rapid acetylators": reduce bioavailability (30% bioavailability); "slow acetylators" (50% bioavailability) {oral administration}

  • Cardiovascular Effects:

    • Greater effect on diastolic blood pressure

    • Reduce systemic vascular resistance

    • Increased: (baroreceptor reflex-mediated; some direct cardiac effect also likely)

      • heart rate

      • stroke volume

      • cardiac output

    • Limited orthostatic hypotension --secondary to greater effect on arterioles than veins

    • Renin activity increased -- mediated by reflex activation of sympathetic nervous system activity (increase secretion of renin by renal juxtaglomerular cells)

• Minoxidil:(Loniten)

  • Orally active

  • Direct relaxation arteriolar smooth muscle (limited effect on venous capacitance)

  • When combined with diuretic and sympatholytic (e.g. beta-blocker):

    • Minoxidil can very effective for management of severe hypertension--associated with:

      • renovascular disease

      • transplant rejection

      • renal failure

  • Generally,  usage is now reduced since safer drugs (calcium channel blockers; ACE inhibitors) are available and are as effective

  • Pharmacokinetics:

    • Excellent absorption following oral administration (90%, gastrointestinal)

    • Substantial metabolism (glucuronidation; only 10% excreted unchanged)

  • Cardiovascular Effects:

    • Increased heart rate; cardiac output (secondary to reflex increase in sympathetic nervous system activity)

    • Increased plasma renin, norepinephrine (also water and sodium retention)

    • Minimal orthostatic hypotension

• Nitroprusside (Nipride)

  • Overview: nitroprusside (Nipride)

    • Direct-acting, nonselective peripheral vasodilator

    • Relaxation of arterial and venous vascular smooth muscle

    • Structure:

      • ferrous iron center complex with five cyanide moieties and a nitrosyl group (44% cyanide by weight)

    • Immediate onset of action

    • short duration (requires continuous IV administration to maintain effect)

    • high-potency:

      •  requires careful dosage titration

      •  frequent systemic blood pressure monitoring -- often by intra-arterial catheter

  • Mechanism of Action: nitroprusside

    • Nitroprusside interacts with oxyhemoglobin, forming methemoglobin with cyanide ion and nitric oxide (NO) release

    • NO activates guanylyl cyclase (in vascular smooth muscle);resulting in increased intracellular cGMP

    • cGMP inhibits calcium entry into vascular smooth muscle (may also increase calcium uptake by smooth endoplasmic reticulum): producing vasodilation 

      • {The precise mechanisms by which cGMP relaxes vascular smooth muscle remain to be elucidated. It is known, however,  that  cGMP activates: a cGMP-dependent protein kinase,   K+ channels and  decreases IP3 levels, and inhibits calcium entry into vascular smooth muscle cells}

    • NO: active mediator responsible for direct nitroprusside vasodilating effect.

      • Note that organic nitrates (e.g. nitroglycerin) require thio-containing agents to generate NO

  • Metabolism:nitroprusside

    • The reaction: nitroprusside interacts with oxyhemoglobin, forming  methemoglobin with cyanide ion and nitric oxide (NO) release produces an unstable nitroprusside radical

    • Nitroprusside radicals decomposes releasing five cyanide ions (one cyanide reacts with methemoglobin to form cyanomethemoglobin)

    • Remaining free cyanide ions (following reaction with hepatic & renal rhodanase) are converted to thiocyanate {thiosulfate donor: body sulfur stores are sufficient detoxifying about 50 milligrams nitroprusside})

  • Organ System Effects: nitroprusside

    • Overview: Principal actions are found on these systems and in specific effects:

      •  Cardiovascular system

      •  Cerebral blood flow

      •  Hypoxic pulmonary vasoconstriction

      •  Platelet aggregation

    • Cardiovascular Effects:nitroprusside

      • Direct venous/arterial vasodilation; rapid decrease in systemic blood-pressure

      • Reduced systemic vascular resistance (arterial vasodilation; venous capacitance vessel vasodilation)

      • Positive inotropic & chronotropic responses: reflex-mediated secondary response to hypotensive response

      • Net increase in cardiac output due to:

        •  increase contractility

        •  decreased left ventricular ejection impedance

      • Hypotensive response: associated with reduced renal function; renin release occurs (explains overshoot upon nitroprusside discontinuation {ACE inhibitor-sensitive})

      • Nitroprusside: may worsen myocardial infarction damage due to "coronary steal",blood closed erected away from ischemic areas by arteriolar vasodilation

    • Cerebrovascular Effects:

      • Increased cerebral blood flow, volume.

        • With decreased intracranial compliance  results in increased intracranial pressure --

          • Generally, increases in intracranial pressure are most apparent when systemic mean arterial pressure decreases by less than 30%

          • if systemic mean arterial pressure decreases by > 30%, intracranial pressure decreases below the awake level.

      • Nitroprusside contraindicated in patients with known inadequate cerebral blood flow (e.g. high intracranial pressure; carotid artery stenosis)

    • Hypoxic Pulmonary Vasoconstriction

      • Nitroprusside infusion (and other vasodilators) causes decrease in PaO₂

      • Mechanism: vasodilator-mediated reduction in hypoxic pulmonary vasoconstriction

  • Clinical Uses: -- nitroprusside (Nipride)

    1. Control hypotension during anesthesia and surgery

       • Rapid, predictable vasodilation & decrease in BP allows a nearly bloodless surgical field, required in some operations: spine surgery, neurosurgery -also reduces transfusions

       • With respect to other drugs that might be chosen to produce controlled hypotension, nitroprusside is most likely to ensure adequate cerebral perfusion (mean arterial pressure's of 50-60 mm Hg can be maintained without apparent complications {in healthy patients})

       • The potential for cyanide toxicity can be diminished by:

         1. Use of other cardiovascular depressant drugs which reduce nitroprusside requirements

         2. These drugs include: volatile anesthetics, beta-adrenergic antagonists, calcium channel blockers; note that beta adrenergic antagonists may cause a decreased cardiac output-- a potential problem in patients with diminished the ventricular reserve.

    2. Treatment of hypertensive emergencies

    3. Acute & chronic heart failure

       • Reduction of afterload may be important for patients with CHF, mitral or aortic regurgitation, acute myocardial infarction with left ventricular failure

       • Role of nitroprusside in chronic, congestive heart failure -- advantageous because:

         1. Reduced ventricular ejection impedance (injection at lower end-diastolic volumes

         2. Preload reduction (secondary to blood pooling in venous capacitance vessels -- reflected in decreased ventricular and-diastolic volume)

    4. Surgical indications:

       • Aortic surgery

         • Reduction of proximal hypertension associated with aortic cross-clamping (thoracic aortic aneurysm,dissections, coarctations)

         • Distal hypotension may occur (relative to clamp location)

       • Cardiac surgery necessitating cardiopulmonary bypass

         •  Activation of renin-angiotensin system may cause systemic hypertension during cardiac surgery

           •  Nitroprusside is effective in reducing such increases in BP

         •  Following cardiopulmonary bypass {re-warming phase}, nitroprusside-mediated vasodilation facilitates heat delivery to tissues {reduces nasopharyngeal temperature decline after bypass}

         •  Nitroprusside is effective in managing pulmonary hypertension after valve replacement

       • Pheochromocytoma resection

Hypertensive Crisis

• Vasodilators used for acute management of hypertensive crisis or malignant hypertension include sodium nitroprusside and diazoxide.

  • Nitroprusside sodium (Nipride) is the agent of choice-- advantages

    1. Rapid onset

    2. Effect diminishes rapidly upon drug discontinuation

    3. May also be used (rapid injection) to reduce systemic blood-pressure associated with direct laryngoscopic tracheal intubation

  • Administered by a continuously variable rate i.v. infusion pump, precise blood pressure control can be obtained.

  • Nitroprusside sodium (Nipride), a nitrovasodilator, is metabolized by smooth muscle cells to nitric oxide which dilates both arterioles and venules.

Calcium Channel Blockers

• Calcium channel blockers are effective in treating hypertension because they reduce peripheral resistance.
• Arteriolar vascular tone depends on free intracellular Ca²⁺ concentration.
  • Calcium channel blockers reduce transmembrane movement of Ca²⁺ , reduce the amount reaching intracellular sites and therefore reduce vascular smooth muscle tone.
• All calcium channel blocks appear similarly effective for management of mild to moderate hypotension.
• For low-renin hypertensive patients (elderly and African-American groups), Ca²⁺ channel blockers appear good choices for monotherapy (single drug) control.
• Interactions with Anesthetics:
  • In anesthetized patients with preexisting left ventricular dysfunction--
    •  verapamil (Isoptin, Calan) administration results in:
      1. myocardial depression
      2. reduced cardiac output
  • In patients with depressed left ventricular function, anesthetized with a volatile anesthetic,and undergoing open-chest surgery:
    •  IV verapamil (Isoptin, Calan) or diltiazem (Cardiazem) further decreases ventricular function
  • In patients with preoperative cardiac conduction anomalies, who are being treated with combined calcium channel blockers and beta-adrenergic receptor blockers: The underlying condition does not appear associated with perioperative cardiac conduction abnormalities.
• Interactions with neuromuscular-blocking drugs:
  • Calcium channel blockers potentiate depolarizing and nondepolarizing neuromuscular-blocking drug effects.
  • Similar to effects produced by "mycin" antibiotics in the presence of neuromuscular-blocking drugs
    • Note that verapamil (Isoptin, Calan) possesses local anesthetic properties -- due to sodium channel blockade -- in effect which contributes to neuromuscular-blocking drug effect potentiation
    • Neuromuscular effects of verapamil (Isoptin, Calan): more likely to be evidenced in patients with reduced neuromuscular transmission margin of safety.
  • Neuromuscular-blockade antagonism: possibly impaired by reduced acetylcholine presynaptic release in the presence of a calcium channel blocker (presynaptic calcium influx is typically required for neurotransmitter release)
• Local Anesthetics:
  • Verapamil (Isoptin, Calan): -- potent local anesthetic activity
  • Increased risk of local anesthetic toxicity in regional anesthesia -- when administered to a patient receiving verapamil (Isoptin, Calan).

Adverse Effects 

• SA nodal inhibition may lead to bradycardia or SA nodal arrest.
  • This effect is more prominent if beta adrenergic antagonists are concurrently administered .
• GI reflux may also occur
• Negative inotropic are augmented if beta-adrenergic receptor antagonists are concurrently administered.
• Calcium channel blockers should not be administered if the patient has SA or AV nodal abnormalities or in patients with significant congestive heart failure.
• A case control study has found that hypertensive patients taking short-acting nifedipine (Procardia, Adalat), diltiazem (Cardiazem) or verapamil (Isoptin, Calan) were 1.6 times more likely to have a myocardial infarction compared to patients taking other antihypertensive drugs.
  • Until this issue is completely resolved, it has been recommended that short-acting calcium channel blockers, particularly nifedipine (Procardia, Adalat), should not be used for treatment of hypertension [The Medical Letter, vol. 39 (issue 994). February 14, 1997]

Stoelting, R.K., "Calcium Channel Blockers", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 352-353.

Angiotensin Converting Enzyme Inhibitors

• Angiotensin II, a potent vasoconstrictor, is produced by the action of angiotensin converting enzyme (ACE) on the substrate angiotensin I.
• Angiotensin II activity
  • rapid pressor response
  • a slow pressor response
  • vascular and cardiac hypertrophy-remodeling.

• Antihypertensive effects of ACE inhibitors are due to the reduction in the amount of angiotensin II produced.
• ACE inhibitors: first line treatment patients with:
  • systemic hypertension
  • congestive heart failure
  • mitral regurgitation
• ACE inhibitors effectively manage hypertension and have a favorable side effect profile.
• ACE inhibitor are advantageous in management of diabetic patients by reducing the development of diabetic neuropathy and glomerulosclerosis.
  • may be safer than other antihypertensive agents in diabetics
• ACE inhibitor are probably the antihypertensive drug of choice in treatment of hypertensive patient who have hypertrophic left ventricles.
  • ACE inhibitor treatment may cause regression of left ventricular hypertrophy
• Hypertensive patients who have ischemic heart disease with impaired left ventricular function also benefit from ACE inhibitor treatment.
• ACE inhibitors reduce the normal aldosterone response to sodium loss (normally aldosterone opposes diuretic-induced sodium loss).
  • Therefore, the use of ACE inhibitors enhance the efficacy of diuretic treatment, allowing the use of lower diuretic dosages and improving control of hypertension.
•  If diuretics are administered at higher dosages in combination with ACE inhibitors significant and undesirable hypotensive reactions ca occur with attendant excessive sodium loss.
• Reduction in aldosterone production by ACE inhibitors also affects potassium levels.
  • The tendency is for potassium retention, which may be serious in patients with renal disease or if the patient is also taking potassium sparing diuretics, nonsteroidal anti-inflammatory agents or potassium supplements.
• Perioperative Issues: ACE inhibitor treatment
  • Consensus: continue drugs until surgery; reinitiate treatment as soon as possible postoperatively
  • Concern: Perioperative hemodynamic instability & hypotension in patients receiving ACE inhibitors.
    •  If ACE inhibitor therapy was maintained the morning of surgery: increased likelihood of prolonged hypotension in patients undergoing general anesthesia.
    • Surgical procedures that are likely to cause major body fluid shifts are more likely associated with: increased likelihood of hypotensive reactions in patients receiving ACE inhibitors:
      •  In these patients -- are reasonable option:
        1. discontinue ACE inhibitor treatment
        2. use shorter-acting IV antihypertensive agents if required
    • Excessive hypotensive reactions probably caused by continued ACE inhibitor treatment perioperatively-- responsive to:
      •  crystalloid fluid infusion
      •  sympathomimetic administration (e.g., ephedrine or phenylephrine)

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