1. Calcium channel blockers and Vasodilators in Hypertension Therapy Dr. Thomas Abraham PHAR 417: Fall 2005

2. Proposed role of calcium channels in hypertension  Calcium channels divided into L-type, N-type, P-type and Receptor- operated type.  Activation of receptors linked to the phosphoinositide system (in vascular smooth muscle) and to the cyclic AMP pathway (cardiac muscle) lead to the opening of plasma membrane calcium channels. Calcium channel blockers

3.  Regulation of SA nodal activity by L-type calcium channels to control heart rate.  Regulation of myocardial contractility by L-type channels  Regulation of smooth muscle contractility by vascular L-type channels. Calcium channel blockers

4.  Extracellular calcium concentration is about 2.5 mM or 5 mEq/l while calcium concentrations in resting cell cytoplasm is less than 100 nM (more than 20,000 times difference!). - due to high affinity calcium-ATPase pumps which maintain the gradient. - opening of selective calcium channels allows rapid movement of calcium down its electrochemical gradient. Calcium channel blockers

5. Ca 2+ Closed Open Inactive Regulation of Voltage-Dependent Calcium Channels Depolarization Repolarization Calcium channel blockers

6.  Calcium channel blockers non-competitively antagonize an agonist’s (epinephrine, norepinephrine, angiotensin II and vasopressin) effect to elevate intracellular calcium and increase cardiac and vascular contraction. Dihydropyridines, benzothiazepines and phenylalkylamines are the three main therapeutic classes of calcium channel blockers or antagonists. Calcium channel blockers

7. Dihydropyridine Calcium Channel Blockers  All the drugs of this class are more properly termed 1,4- dihydropyridines.  High lipid:water partition coefficient (lipophilic). Calcium channel blockers

8.  Have good oral absorption but lower bioavailability (50-65%) due to first- pass metabolism; 90-95% of the drug is bound to plasma proteins.  are more potent than the other two classes as vasodilators.  The high lipid solubility of all DHPs and the inability of quaternary DHPs applied to the inside of cells to block L-type channels, may indicate a membrane mechanism of action of the drugs to decrease calcium flow through the channel. - DHPs appear to bind to L-type channels in the inactive state and prevent their opening following membrane depolarization. - Decreased Ca 2+ -influx due to agonist stimulation results in decreased cytoplasmic calcium for mediating contraction of muscle cells. Calcium channel blockers

9.  The high lipid solubility of all DHPs and the inability of quaternary DHPs applied to the inside of cells to block L-type channels, may indicate a membrane mechanism of action of the drugs to decrease calcium flow through the channel. - DHPs appear to bind to L-type channels in the inactive state and prevent their opening following membrane depolarization. - Decreased Ca 2+ -influx due to agonist stimulation results in decreased cytoplasmic calcium for mediating contraction of muscle cells. Calcium channel blockers

10.  Preferentially dilate arteries and arterioles over veins and blocks vascular L-type channels at lower concentrations than cardiac channels. - decrease in both systolic and diastolic BP in a dose- dependent manner. - Decreased TPR results in reflex sympathetic stimulation to the heart to increase heart rate and force (modestly). Calcium channel blockers

11.  Adverse drug effects (generally due to excessive vasodilation): dizziness, hypotension, headache, flushing, nausea; (less common but more serious) peripheral edema, pulmonary edema, coughing and wheezing. Can aggravate ischemic heart disease due to increased myocardial work.  Contraindications: Short-acting nifedipine should not be used in pts. with myocardial ischemia, angina or are post-MI.  Therapeutic uses: hypertension, angina, Raynaud’s syndrome, subarachnoid hemorrhage (nimodipine). Calcium channel blockers

12.  High lipid:water partition coefficient positively affects activity.  Good oral absorption but reduced bioavailability (30-60%) due to first pass metabolism. Metabolism to less active desacetyldiltiazem. High plasma protein binding.  Has similar mechanism of action as the dihydropyridines to limit calcium ion flow through L-type channels to ultimately decrease smooth muscle and cardiac muscle contractility. Calcium channel blockers Benzothiazepine calcium channel blockers, Diltiazem (Cardizem)

13.  Has similar potencies for vascular and cardiac effects so reflex sympathetic activity and cardiac excitation not usually observed. Direct negative chronotropic and inotropic effect of diltiazem results in decrease in cardiac output when TPR decreases.  Adverse effects include bradycardia, heart block, transient sinus arrest, hypotension, flushing, dizziness, headache and constipation. Calcium channel blockers

14. Phenylalkylamine calcium channel blockers, Verapamil (Calan)  Good oral absorption of verapamil but high first-pass metabolism leads to lower bioavailability (15-30%). High plasma protein binding. Metabolized by N-demethylation to norverapamil (less active).  Verapamil inhibits L-type channels and decreases smooth muscle contractility. - The drug enters the muscle cell and appears to bind to the intracellular pore of the channel to cause decreased Ca 2+ ion movement. Calcium channel blockers

15.  It is more effective in producing negative inotropy and chronotropy than DHPs or diltiazem: Less reflex cardiac stimulation and C.O. in response to decreases in TPR.  Adverse reactions are generally similar to those of diltiazem but more severe in nature.  Drug interactions: enhanced cardiac depression with  -blockers. Verapamil also used in treating arrhythmias and to block the P170 glycoprotein (multidrug-resistance transporter) to improve the efficacy of antineoplastic drugs in cancer pts. Calcium channel blockers Phenylalkylamine calcium channel blockers

16. Arterial Vasodilators Hydralazine (Apresoline ®)  Well absorbed from GI tract but oral bioavailability is low due metabolism (N- acetylation) which occurs in the bowels and liver. Slow acetylators would have bioavailability than fast acetylators.  Hydralazine causes direct relaxation of resistance arteries by an unknown mechanism. Does not affect capacitance arteries or veins. Half-life in plasma about 1h but hypotensive effect can be maintained for up to 12h.  Causes significant reflex sympathetic activity which increases HR and force, plasma renin and fluid retention. Increased sympathetic activity due to reflex baroreceptor mechanism, increased norepinephrine release from sympathetic nerves and direct inotropic effects on cardiac muscle.

17.  Adverse effects include: headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness and angina (due to significant vasodilatation); a systemic lupus-like autoimmune response which can involve hemolytic anemia, vasculitis and glomerulonephritis.  Primarily used in hypertensive crisis in pregnant or younger patients, may precipitate MI in older pts. Generally decreases resistance in cerebral, coronary and renal vessels with less effect on arteries of skin and muscles Arterial Vasodilators Hydralazine (Apresoline ®)

18. Minoxidil (Loniten®)  Minoxidil is a basic drug that has to be converted to the active sulfate form by the actions of hepatic sulfotransferases.  Well absorbed from GI tract but peak hypotensive effects lag behind peak blood levels. Mostly metabolized to inactive compound by glucuronide conjugation at the N – O position of pyrimidine ring. Arterial Vasodilators

19.  The sulfate conjugation product at the N – O position produces a drug that is able to cause activation of ATP-dependent K + channels. This leads to cell hyperpolarization that eventually causes smooth muscle cell relaxation.  Minoxidil dilates arteries of the skin, skeletal muscle, heart, and GI tract to decrease TPR. Improves renal blood flow in hypertensives and causes renin release.  Adverse effects include: increased renal tubular reabsorption of sodium and fluid retention; increased heart rate, contractility and oxygen consumption; increased pulmonary artery pressure and pulmonary edema; significant body hair growth. Minoxidil (Loniten®) Arterial Vasodilators

20. Centrally-Acting Sympatholytic Agents Methyldopa (Aldomet®)   -methyldopa has to be converted to (1R,2S) isomer of  - methylnorepinephrine by the same enzymes involved in catecholamine biosynthesis.   -methyldopa would exist as a zwitterion at pH 7.4, having both positive and negative charges.   -methyldopa is absorbed from GI tract by an amino acid transporter and taken into the CNS by similar transporter. Excreted mainly as sulfate conjugated or parent drug in urine.

21.  In the CNS  -methyldopa is converted to  -methylnorepinephrine in the adrenergic neurons and released by these neurons to activate  2 - adrenergic receptors. Stimulation of central  2 -adrenergic receptors result in decreased sympathetic drive from the CNS which decreases vascular constriction and decreased TPR.  In older pts.  -methyldopa may cause decreased cardiac output (decreased SV and heart rate) via venodilation and reduction of preload. Centrally-Acting Sympatholytic Agents Methyldopa (Aldomet®)

22.  Even though blood levels of  -methyldopa peak within 3 hours, peak hypotensive effect is not seen for 6-8hours and can be maintained up to 24hours.  Adverse effects are sedation, dry mouth, decreased libido, Parkinson’s-like movement and bradycardia/sinus arrest. More rare effects are hepatitis-like condition and hemolytic anemia. Centrally-Acting Sympatholytic Agents Methyldopa (Aldomet®)

23. Clonidine (Catapress®)  Produces hypotensive effect at low doses by acting on  2 -adrenergic receptors in the medulla to decrease sympathetic output from the CNS. Clonidine causes lowering of TPR and cardiac output to decrease systemic blood pressure.  The hydrophobic halogenated- benzene moiety aids in crossing blood-brain barrier while the drug forms a protonated resonance structure at physiological pH which is probably the active conformation. Centrally-Acting Sympatholytic Agents

24. Clonidine (Catapress®)  Adverse effects to clonidine include sedation, impotence, nausea, dizziness, dry mouth, sleep disturbance, bradycardia and sinus arrest. Sudden discontinuation of clonidine will cause syndrome of headaches, apprehension, tremors, abdominal pain, sweating tachycardia and hypertension. Centrally-Acting Sympatholytic Agents

25. Endothelin Receptor Antagonists Pulmonary Arterial Hypertension  Primary pulmonary hypertension: of unknown cause but may have a genetic component.  Often associated with elevated plasma levels of endothelin, a polypeptide produced by endothelial cells.  Drug-induced PAH: fenfluramine, methamphetamine, cocaine.  Other causes of PAH: HIV, portal vein obstruction, pulmonary embolism  Symptoms: dyspnea, chronic fatigue, dizziness, fainting, edema, chest pains

26. Endothelin Receptor Antagonists Endothelin  Released by endothelial cells to activate endothelin receptors ET A and ET B on vascular smooth muscle.  Activation of ET receptors results in smooth muscle contraction and increased pulmonary artery pressure.  ET-1 levels are elevated in CHF, systemic and pulmonary hypertension, acute MI, cardiogenic shock, myocardial ischemia.

27. Endothelin Receptor Antagonists Bosentan (Tracleer®)  Non-selective ET receptor antagonist  Results in pulmonary vasodilation and decreased PAH to alleviate symptoms  Decreases pulmonary vascular muscle hypertrophy and right ventricular hypertrophy.  Adverse effects: Cholestatic liver damage (~11%), fetal malformations, decreased hematocrit levels.  Drug interactions: cyclosporine A, glyburide may have additive hepatotoxicity