Pharmacology I
Antihypertensive Drugs Objectives

Learning Objectives:

Understand the therapeutic goal for treating hypertension
Goals are:

1. BP
2. O₂ demand by the
3. the workload of the
4. amt of remodeling of the and vasculature
5. volume thereby MSAP

HTN can be treated by:

1. diuretic to blood volume
2. b -blocker to SNS activity
3. ACE Inhibitor to remodeling
4. Ca⁺² channel blocker to block inward movement of Ca⁺² by binding to L-type channels and keeping them closed.
5. Direct a ₁ blocker will vasodilate.
6. a ₂ agonist inhibits the release of NE, which then outflow so it depresses a ₁ activity and causes vasodilation.

Treatment strategies:

• As above to lower blood volume, block SNS activity and vasodilate. Recommended 1^st line for HTN are b-blocker/diuretics. Ca⁺² channel blockers are recommended when the 1^st line agents are contraindicated or ineffective.
• Goal is to prevent stroke, MI, CHF and total mortality. Recent data suggests that diuretics are superior to b-blockers in older adults.

1. Diuretic - blood volume which workload of . This O₂ demand. Loop diuretics such as lasix stimulate Na⁺ to stay in the tubules at the ascending loop and thus cause more Na⁺ excretion. These are the most potent diuretics. The problem with them is that they also stimulate Ca⁺² & K⁺ secretion. Thiazide diuretics inhibit the reabsorption of Na⁺ and Cl^- but do stimulate the reabsorption of Ca⁺² (and so these are beginning to be used for osteoporosis.) The K⁺- sparing diuretic comes in 2 classes – spironalactone and amiloride. Spironalactone inhibits aldosterone action so it prevents the Na⁺/K⁺ exchange at the collecting tubule. It is a lousy diuretic but is useful in the sparing of K⁺ and thus is often used in conjunction with another diuretic. Amiloride inhibits the Na⁺/H⁺ and Na⁺/K⁺ exchange at the collecting tubules. Mannitol is the osmotic diuretic. It works by changing the osmolarity of the urine and thus changes the driving force of water so more stays in the urine and less is reabsorbed. Urea is another one but 60% of it is reabsorbed and can then cause pH problems.
2. b -blockers- BP by ing CO. They may also sympathetic outflow from the CNS and inhibit the release of renin from the kidneys thus ing the formation of angiotensin II and thus aldosterone and ADH.

Another view: b -blockers in the b ₁ block will CO which will ¯ BP, in the kidneys b ₁ block will renin release which will AII which will TPR which will ¯ BP and AII also will stimulation of aldosterone and ADH which will Na⁺ and H₂O retention which will Blood volume which will CO. a ₁ in the VSM block will cause vasodilation thus a in TPR. When there is an in SNS stimulation, both a ₁ and b ₁ are mediated by a ₁ stimulation neurally in the carotid sinus (baroreceptors) to the medulla. b -blockers will block the b ₁ response but not the a ₁ response so an in SNS stim will cause an in TPR only without the concurrent in HR and contractility

3 types of b -blockers: nonselective – which doesn’t discriminate btw different subtypes of b -blockers. Propranolol is the prototype. It blocks b ₁ and b ₂ so you would see a in CO and blood volume and possible bronchial vasoconstriction. These drugs are contraindicated in pts with asthma for that reason. They are also contraindicated in pts with Type I DM or who are susceptible to hypoglycemia since there are b ₂ receptors in the liver which are stimulated by hypoglycemia and if blocked will not then mediate the glycogenolysis necessary to bring up the serum glucose level to normal. Selective b ₁ Blocker such as atenolol block b ₁ only and thus only affect the b ₁ receptors in the © and kidneys and don’t affect the b ₂ receptors in the lungs or liver. Partial agonists like pindolol have ISA or intrinsic sympathomimetic activity which means they still will have some sympathomimetic activity of in HR and contractility and an in TPR, although because they are only a partial agonist will not have as great of an effect than the intrinsic agonist of NE or epi. The partial agonist will compete for the sites and can block the response some but these are not recommended or highly utilized drugs. Full Agonists like labetolol will block a ₁ , b ₁, and b ₂ which will then block all the hemodynamic effects.

3. ACE Inhibitors lower BP by reducing peripheral vascular resistance without increasing CO, rate or contractility. These drugs block the angiotensin converting enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. These inhibitors also diminish the rate of bradykinin inactivation. Vasodilation occurs as a result of the combined efforts of lower vasoconstriction caused by diminished levels of AII and the potent vasodilator effects of increased bradykinin. AII also affects aldosterone by ing it and thus a in sodium and water retention, which will increase urine output.
4. Ca⁺² channel blockers- intracellular [Ca⁺²] plays an important role in maintaining the tone of smooth muscle and in the myocardium. Ca⁺² channel blockers block the inward movement of Ca⁺² by binding to L-type channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax dilating mainly arterioles. Thereby ing BP. Ca⁺² channel blockers also have a natriuretic effect thereby increasing urine secretion.
5. Direct a ₁ blocker like prozasin have minimal effects on the . They do affect the VSM though and promote vasodilation by inhibiting vasoconstriction and therefore TPR and will CO as the pumps against a TPR. There are some a ₁ receptors on the so there would be a slight in contractility but not significantly enough to CO.
6. a ₂ agonist are pre-synaptic inhibitors of adrenergic release. Clonidine is the prototype and inhibits the neurotransmitters dopa and NE. It is a centrally acting response so inhibits sympathetic outflow. a -methyl dopa is another drug in this category but it is a false NT, which gets in to the presynaptic terminal and goes down the pathway for NE synthesis and gets in to the pre-synaptic vessicles like NE but is less efficacious than NE.

1. Diuretic – Loop = hypokalemia, electrolyte imbalance. Loop – block the reabsorption of salts so stimulate the loss of calcium by stimulating secretion. Another problem is that the kidneys now sense the high Na⁺ in the collecting tubules so will try to reabsorb some of it which then exchanges K⁺ for the Na⁺ so you get hypokalemia. The thiazides also can cause hypokalemia and hyperuricemia. The K⁺- sparing ones are too ineffective to be used alone. Mannitol can have a rebound effect. Caution should be used with all diuretics not to deplete the blood volume too low and cause hypotension!

2. b -blockers- cause hypotension, may decrease libido and cause impotence drug-induced sexual dysfunction which can pt compliance with taking the meds. Abrupt withdrawal may cause rebound HTN probably as a result of upregulation of b receptors. May also produce bradycardia, CHF, brochospasm.

3. ACE Inhibitors – adverse effects are hypotension in hypovolemic states and hyperkalemia. Angioedema is a rare but potentially life threatening reaction. Because of the risk of angioedema and 1^st dose syncope, ACE inhibitors are administered in the MD’s office with close observation. Reversible renal failure can occur in pts with severe renal artery stenosis. ACE inhibitors are fetotoxic and should not be used in pregnant women.

4. Ca⁺² channel blockers – have infrequent side effects which include constipation, dizziness, h/a, fatigue by way of a decrease in BP. Verapamil should be avoided in treating pts with CHF due to the negative inotropic effects.

5. Direct a ₁ blocker- this will block the typical SNS response from postural changes so postural hypotension is a huge concern since the baroreceptor response is blocked by the a ₁ mediated SNS response.

6. a ₂ agonist- sedation is a side effect but no effect of respiratory depression, can also block the normal SNS induced tachycardia and ­ TPR from low BP associated with anesthetic use!

Know which class of drugs may have significant interactions with anesthetics and what are the potential toxicities. For example, know the clinical uses, mechanisms of action, toxicities and ways of minimizing toxicities of nitroprusside.
SNP had the toxicity of cyanide poisoning. It is a 6-coordinate iron salt which when broken down binds to the RBC as cyano-met-Hgb and cyanide in its free form (Cn^-) which is toxic. It is metabolized in the liver then excreted in the kidney. Cyanide concentrations may precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis. SNP is used because when it is metabolized you free up a nitric oxide molecule, which is a potent vasodilator. Cn^- is released however when the NO is freed. Treatment for cyanide poisoning is the following:

• 100% O₂, NaBicarb due to the metabolic acidosis, stop the infusion of SNP, infuse Na Nitrate since this will compete with the formation of cyanomet – Hgb so prevents formation of free cyanide, and vitamin B₁₂ which binds directly to Cn^-.

Other toxicities:

• Lidocaine – effects of succinylcholine may be enhanced
• Nifedipine – the use of fentanyl may increase hypotension
• Nimodipine – the use of this with fentanyl may increase hypotension.
• Atenolol - By decreasing the clearance of continuous infusion, if may increase the effect of perioperative agents such as fentanyl, propafol, sufentanil, ketamine, and etomidate. It may increase the effect/toxicity of haloperidol.
• Loop diuretic- with the use of nondepolarizing agents will have a prolonged duration.
• Verapamil with fentanyl may increase hypotension.
• Amiodarone – used with general anesthesia may result in hypotension.
• Enalapril used with anesthetic agents will increase hypotension effects.
• Dobutamine with general anesthesia have resulted in arrhythmias –ventricular in animals.
• Metoprolol – given in the OR by IV can increase the effect of propafol, ketamine, fentanyl, sufentanil, and etomidate.

Last updated 04/10/00 12:26 PM
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