• 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 flow directed 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.

 Adverse effects

Induced by vasodilation: such as: hypotension palpitation tachycardia angina fluid retention headache  Hydralazine: (Apresoline) Sodium and water retention (unless concurrent diuretic administered) Vertigo, nausea, tachycardia, diaphoresis Angina secondary to increase myocardial oxygen demand, secondary to increased rate Occasional peripheral neuropathy (responsive to pyridoxine) Enhanced defluorination of enflurane Drug-induced lupus erythematosus-like syndrome  Lupus erythematosus-like frequency: 10%-20%  associated with chronic treatment  more likely to occur in slow acetylators  reversible upon drug discontinuation Minoxidil: (Loniten) Common: fluid retention (weight gain/edema); diuretics (loop diuretics) may be required Pulmonary hypertension (secondary probably to fluid retention) Pericardial effusion; cardiac tamponade (secondary to fluid accumulation in serous cavities) A drug-induced hypertrichosis is associated with minoxidil. particular around face, arms common in almost all patients treated for longer than one month  Nitroprusside: (Nipride) Toxicity may result from conversion of nitroprusside to cyanide and thiocyanate. Risk of toxicity due to thiocyanate increases after 24 to 48 hours. Nitroprusside can worsen arterial hypoxemia in patients with obstructive pulmonary airway disease since nitroprusside will interfere with hypoxic pulmonary vasoconstriction. A result is increasing ventilation-perfusion mismatching.  Diazoxide (Hyperstat) is infrequently used unless accurate infusion pumps are unavailable.  The mechanism of action involves activation of ATP-sensitive potassium channels, hyperpolarization of arteriolar smooth muscle, relaxation and dilation. Adverse effects include salt and water retention and hyperglycemia. Diazoxide inhibits insulin release

• Stoelting, R.K., "Antihypertensive Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 302-312;and "Peripheral Vasodilators", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 315-322.

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 hypertension.

  • 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)

Adverse Effects

Angioedema, although rare, may be potentially fatal. Respiratory distress: may be managed by epinephrine injection (0.3-0.5 ml of a 1:1000 dilution subcutaneously) Proteinuria: frequency = 1% (more likely with preexisting renal disease) ACE inhibitors should not be used during pregnancy. Dry cough, rhinorrhea, allergic-like symptoms -- most common side effects Airway responses: enhanced kinin activity (secondary to inhibition of peptidyl dipeptidase activity) In renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the post-glomerular arterioles, an effect mediated by angiotensin II.  Use of ACE inhibitors in patients with renovascular hypertension due to bilateral renal artery stenosis can therefore precipitate a significant reduction in GFR and acute renal failure. Initial dose of an ACE inhibitor may precipitate an excessive hypotensive response

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