ALPHA-2_A AGONISTS

 CLONIDINE,GUANFACINE, METHYLDOPA

inhibit sympathetic outflow from cardiovascular control centers of thebrain (the NTS and RVLM) by:

            a) inhibiting presynaptic Ca²⁺ channels -> ↓ NE release

               b) opening postsynaptic K⁺ channels -> K⁺ efflux -> hyperpolarization

                        Net effect: ↓ peripheral resistance, HR and CO with ↑ vagal tone.  The ↑ vagal tone can cause marked bradycardia in some patients.

CLONIDINE (Catapres) ALPHA-2_A AGONISTS

Higher doses stimulate vascular α_2B receptors -> vasoconstriction.  This might explain the loss of therapeutic effect with higher doses and the initial ↑ in BP when clonidine is given IV.  Given orally, drug levels do not rise as rapidly and the central effects override any vasoconstrictionfollowing oral administration.

USES:            - Antihypertensive

                        - Treat autonomic withdrawal symptoms from opiates, EtOH & nicotine

                        -  Epidural (Duraclon) for severe pain in cancer patients who do not respond to opioids.

                        - Tourette's syndrome                                                                        - Anxiety & panic attacks

                        - Attention deficit hyperactivity disorder (ADHD)                       

- Menopausal flushing

CAUTION Discontinue slowly to avoid rebound sympathetic activity that can lead to a  hypertensive crisis, tachycardia or an arrhythmia

MOST COMMON SIDE EFFECTS:                       

a) dry mouth

b) sedation

c) Constipation is common.  Clonidine ↓s Ach release by stimulating α_2A heteroreceptors on myenteric and submucosal cholinergic neurons -> ¯ peristalsis by relaxing intestinal smooth muscles -> ↑ time for Na⁺/H₂O reabsorption.  It also ¯s GI secretions.  This can cause weight gain.  A diuretic can be added to combat any significant Na⁺/H₂O retention.

d) sexual dysfunction in males. 

- more selective than clonidine -> fewer side effects.  Long t ½ permits once  a day dosing.  Give at bedtime to minimize effects of sedation.

            USES: Antihypertensive & to manage withdrawal symptoms from heroin et al.  Extended release form is approved for threating ADHD.

PRODRUG.

            Metabolized to α-methyl-norepinephrine, an α2 agonist that displaces NE in nerve terminals and is released in its stead.

            In  ̴ 20% of patients, chronic use can cause a (+) Coomb’s test for autoantibodies vs the Rhlocus on RBCs.  1-5% of these patients develop hemolytic anemia.

            Methyldopa has been proven safe to use during pregnancy and is a first line drug in this situation.

.  ALPHA ANTAGONISTS

-ZOSIN

PRAZOSIN (Minipress),TERAZOSIN (Hytrin),DOXAZOSIN (Cardura)

↓ BP by inhibiting vasoconstriction, not by causing vasodilation.  The endpoint is the same but the magnitude of effect and how you got there is different.

PRAZOSIN (Minipress)

ALPHA ANTAGONISTS

selectively blocks a1 in arterioles & veins thus decreasing peripheral resistance & venous return. 

It does not cause reflex tachycardia or INCREASE ­ CO.

  LOW BP might cause Na⁺/H₂O retention.  A diuretic can be added.  Short t ½ – dosed 2-3x/day

a₁ selective - T ½ = 9-12 hrs.  Dosed 1-2 x/day.  Generally, no reflex    tachycardia

USES:           

- Antihypertensive

- Benign prostatic hypertrophy (BPH) – might have actions within the prostate as well as on urethral smooth muscle.

.  DOXAZOSIN (Cardura)

ALPHA ANTAGONISTS

- a1 selective.  T ½ = 22 hrs – 1x/day.  Causes slight reflex tachycardia

            USES:            - Antihypertensive            - BPH

** All 3 of these Rxs cause a “1^st Dose Effect” characterized by postural hypotension & syncope.

It occurs:            a) 30-90 minutes after the 1^st dose

                        b) after a rapid ↑ in dose

                        c) after adding another antihypertensive medication to the regimen

            MECHANISM: It has been postulated that this results from delayed baroreflex compensation for the ↓ BP leading to an exaggerated postural hypotension effect & some tachycardia.

                        To minimize the risk of injury from hypotension, it is recommended that the 1^st dose betaken at bedtime.

BETA BLOCKERS

-OLOL

PROPRANOLOL,NADOLOL (Corgard),TIMOLOL (generic), PINDOLOL (generic),LABETALOL (Trandate),PENBUTOLOL (Levatol),CARVEDILOL (Coreg)

Blocking β₂ receptors in vasculature can -> unopposed α₁-mediated                                     vasoconstriction and ↑ vascular resistance.  However, the net effect is a ↓ in BP from combined                                                             (-) inotropic effects and inhibition of renin release.

            WHAT IS THE EFFECT ON HR, CONTRACTILITY, CO & MYOCARDIAL O2 DEMAND?

            CAUTION if asthma / COPD / bronchospasms -            WHY?

            CAUTION if DIABETIC –            WHY?  Remember your autonomics!

                        In the sympathetic fight or flight response, glucose is needed for energy.  Sympathetic signals are sent to the adrenal medulla to release catecholamines, namely EPI.

                        One role of EPI is to stimulate glycogenolysis partly through a β₂ mechanism.  By blocking β receptors, you inhibit glycogenolysis -> ↓ blood sugar.

                        In diabetics on β blockers, when the next dose of insulin or oral hypoglycemic is due, blood sugar will ↓ even further and the patient can become hypoglycemic.

                        WHAT IS A CARDINAL CARDIOVASCULAR SIGN OF HYPOGLYCEMIA?

                        WHY DOES THIS OCCUR?

                        WILL YOU SEE IT?                                    WHY?  (Think this through!)

                                                MONITOR BLOOD GLUCOSE CAREFULLY!

            ¯ BP/CO can ¯ renal blood flow causing Na⁺/H₂O retention.  If so, add a diuretic.

            Discontinue slowly to avoid precipitating an arrhythmia, angina attack or sudden death.

1.  BRADYCARDIA

2.  FATIGUE – This is related to a ↓ in muscle K⁺.  β₂ stimulation normally drives K⁺ into tissues.              Therefore, β block can be expected to do the opposite.  However, they generally do not cause                                                                         frank hyperkalemia.

3.  INCREASE­ PLASMA LIPIDS

PROPRANOLOL (Inderal)

BETA BLOCKERS

nonselective, blocks β₁ and β₂ equally.  Therapeutic effects based on blocking β1.  Higher doses have a "quinidine-like" local anesthetic effect.

            USES: hypertension, supraventricular arrhythmias, MI, angina, migraine, block symptoms                                                             associated with hyperthyroidism & pheochromocytoma

NADOLOL (Corgard)

BETA BLOCKERS

TIMOLOL (generic)

BETA BLOCKERS

hypertension, migraine

PINDOLOL (generic)

BETA BLOCKERS

has high intrinsic sympathomimetic activity (ISA).  It therefore does not ¯ BP & HR as much as other β blockers.  This can be useful in hypertensive patients with bradycardia.

            WHAT DOES HAVING ISA MEAN?

LABETALOL (Trandate)

 BETA BLOCKERS

has 4 different isomers each with different activity.

            Some                        a) block α₁ -> vasodilation -> ↓ BP

            Others              b) block β₁ -> ↓ HR & BP

            Still another            c) stimulates β₂ -> vasodilation -> ↓ BP

            Effect c) enhances effect a) whereas effect b) prevents reflex stimulation of HR caused byeffects a) and c).  By blocking α₁, there is no ↑ in peripheral vascular resistance inresponse to ↓ BP.  This is good for the elderly and African-Americans hypertensives who generally do not respond well to β blockers.

            Expect some orthostatic hypotension from the vasodilation.

            NET EFFECT:  ↓ BP with little or no significant ­ in HR

PENBUTOLOL (Levatol)

BETA BLOCKERS

CARVEDILOL (Coreg)

BETA BLOCKERS

– for hypertension.  Racemic mixture – nonselective α & β block

            Approved for CHF - WHAT IS THE RATIONALE?  In CHF, with the ↓ in CO, there is ↓perfusion of carotid baroreceptors that sense a ↓ in BP.  They send reflex sympathetic signals to ↑ HR and vasoconstrict.  This ↑s afterload which further ↓s CO and can furtherdamage the heart.  β block is used to block this ↑ in sympathetic activity from thebaroreceptors.

            Rx Interactions:            - ¯ digoxin clearance -> digoxin toxicity.  ¯ Dose of digoxin.

                                                - Inhibitors of CYP2C9 (amiodarone, fluconazole et al.) ↑carvedilol levels                                                                                     -> ↑ β block & slowing of HR and conduction.

            CAUTION: Rare, but serious, hypersensitivity reactions (anaphylaxis, angioedema, urticaria)                                                 have occurred.  Do not use if there is a history of Stevens-Johnson syndrome,angioedema or any other serious allergic reaction that can be life-threatening

SELECTIVE b₁ BLOCKERS (best for patients with compromised respiratory function)

1.  ATENOLOL (Tenormin)

2.  METOPROLOL (Lopressor)

3.  BETAXOLOL (generic)

4.  ACEBUTOLOL (Sectral)

5.  BISOPROLOL

6.  NEBIVOLOL (Bystolic) 

 ATENOLOL (Tenormin) 

SELECTIVE b₁ BLOCKERS

METOPROLOL (Lopressor)

SELECTIVE b₁ BLOCKERS

BETAXOLOL (generic)

SELECTIVE b₁ BLOCKERS

ACEBUTOLOL (Sectral)

SELECTIVE b₁ BLOCKERS

BISOPROLOL (Zebeta)

SELECTIVE b₁ BLOCKER

NEBIVOLOL (Bystolic)

SELECTIVE b₁ BLOCKER

for hypertension

Ca²⁺ CHANNEL BLOCKERS (CCBs)

-ipine

VERAPAMIL (Calan), DILTIAZEM (Cardizem), NIFEDIPINe (Procardia),NIMODIPINE (generic), ISRADIPINE (DynacirCR), NICARDIPINE (Cardene),FELODIPINE (generic), NISOLDIPINE (Sular),AMLODIPINE (Norvasc),  CLEVIDIPINE (Cleviprex)

            3 Chemical classes:            a) phenylalkylamines                        Prototype: verapamil

                                                b) benzothiazepines                        Prototype: diltiazem

                                                c) dihydropyridines                        Prototype: nifedipine

            MECHANISM: block L-type Ca²⁺ channels.  On T tubules, this site is sometimes called the DHP                                                                                     receptor (DHP = dihydropyridine)

            Dihydropyridines preferentially interact with vascular smooth muscles b/c vascular smooth                                     muscle remains depolarized longer than the nodes permitting access to the Ca²⁺ channel.

            They all preferentially bind to open or inactivated channels, i.e. those in a depolarized state.

            Those acting mainly on vascular smooth muscle relax arterial, not most venous, smooth muscle.

            WILL THIS DECREASE PRELOAD OR AFTERLOAD?

            WHY ISN’T SKELETAL MUSCLE AFFECTED?

Avoid short acting forms.  They can cause reflex tachycardia & activation of the RAAS which is             associated with ↑ morbidity & mortality in patients with chronic hypertension.  Most of these             products are now available in a long acting, controlled release form that circumvents activation                         of the RAAS.

CAUTIONS FOR Ca²⁺ CHANNEL BLOCKERS:

1. They are extensively metabolized by the liver so any ↓ in hepatic function -> significant ↑ Rx levels

            -> hypotensive episodes from excessive vasodilation or cardiodepressant effects.

2. CCBs are (-) inotropes.  In patients with CHF, the effect is additive.  If you add a vasodilator, the             heart could go into decompensation. Although dihydropyridines have minimal effects on the             heart, the potential is there so be careful!

3. Do not take with grapefruit juice.  This juice contains furanocoumarins that inhibit the metabolism of                                                             CCBs -> ↑ Rx levels and side effects.

RX INTERACTIONS:  b Blockers used with verapamil or diltiazem cause additive (-) inotropy ->                        cardiac decompensation (fatigue, shortness of breath, edema, paroxysmal nocturnal dyspnea)

NON-LABELED USES: Raynaud’s phenomenon

SIDE EFFECTS (mostly dihydropyridines): headache, facial flushing, dizziness & pedal edema

CCBs are often used with a nitrovasodilator to lower BP – WHY?

VERAPAMIL (Calan)

CCB

CCBs WITH PROMINENT EFFECTS ON THE NODES

– acts on nodes & vascular smooth muscle but used mainly for angina and various arrhythmias. 

DILTIAZEM (Cardizem)

CCB

CCBs WITH PROMINENT EFFECTS ON THE NODES

also acts on nodes & vascular smooth muscle but is generally used for angina & various arrhythmias.  

 NIFEDIPINE (Procardia) can cause excessive vasodilation which can ↑ HR & O₂ demand.

            WHAT CAN YOU DO ABOUT IT?

  NIMODIPINE (generic), ISRADIPINE (Dynacirc CR), NICARDIPINE (Cardene),  FELODIPINE (generic), NISOLDIPINE (Sular), AMLODIPINE (Norvasc),  CLEVIDIPINE (Cleviprex) – an IV product for use when oral therapy is not feasible.

ACE INHIBITORS (ACEIs)

-APRIL

 CAPTOPRIL (Capoten),  LISINOPRIL (Prinivil) – excreted unchanged, TRANDOLAPRIL (Mavik), QUINAPRIL (Accupril),  RAMIPRIL (Altace),FOSINOPRIL (Monopril)

MOEXIPRIL (Univasc),  BENAZEPRIL (Lotensin),ENALAPRIL (Vasotec), PERINDOPRIL (Aceon)

RENIN:            WHERE IS IT SYNTHESIZED?

                                    WHAT STIMULATES ITS RELEASE?

                                    WHAT DOES IT DO?

            WHAT CONVERTS ANG I TO ANG II?                       

            EFFECTS OF ANG II:

            a) ↑s total peripheral resistance by constricting arterioles and to some extent venules.

            b) ↑ aldosterone release from the zona glomerulosa of the adrenal cortex.

                        WHAT DOES ALDOSTERONE DO?

            c) releases ADH.            WHAT DOES ADH DO?

            d) releases NE from sympathetic nerve endings -> potentiation of vasoconstriction by Ang II.

            e) ↑s sympathetic outflow from CNS through effects on circumventricular organs (SFO, OVLT).

            f) causes remodeling (proliferation and hypertrophy of vascular smooth muscle and cardiacmyocytes)

All are used for hypertension.  Some are also used for heart failure / MI / left ventricular dysfunction /                                                                                                 diabetic neuropathy

SIDE EFFECTS common to all:

1.  1^st DOSE EFFECT: similar to that seen with the α₁ blockers (see above)

2.  DRY COUGH – incidence 25+%.  More common in women.  Referred to as the bradykinin cough             b/c ACE also metabolizes bradykinin.  Thus, ACEIs ↑ bradykinin levels.  Bradykinin is a             vasodilator and releases histamine -> fluid accumulation in the lungs.  It has been suggested that                                                                         this contributes to the cough.

3.  HYPERKALEMIA – This is predictable.            WHY?  (Think about what Ang II does!)

            Factors that ­ the risk of hyperkalemia:

            a) renal insufficiency, particularly if CHF

            b) adding a K⁺-sparing diuretic

            c) K⁺ supplements

            d) NSAIDS – This should also be predictable – WHY?

                        NSAIDS inhibit synthesis of PGs that normally dilate renal arteries thus causing             constriction of renal arteries & ↓ renal blood flow -> Na⁺/H₂O retention.  By retaining Na⁺, less             Na⁺ is presented to the distal tubules where it is normally reabsorbed in exchange for K⁺.  By not             reabsorbing as much Na⁺, you are not excreting as much K⁺ -> hyperkalemia.

            e) β blockers – WHY?  Stimulating β₂ receptors normally drives K⁺ into tissues.  Blocking these                                                                         receptors would have the opposite effect -> hyperkalemia.

All are used for hypertension.  Some are also used for heart failure / MI / left ventricular dysfunction /diabetic neuropathy

4.  ANGIOEDEMA – Infrequent but potentially fatal.  Rapid swelling in the nose, throat,             mouth, glottis,             larynx, lips & tongue.  AFRICAN-AMERICANS are at greater risk than Caucasians and Asians.

5.  FETAL TOXICITY – Pregnancy category D: (+) evidence of human fetal risk but benefits might                                     outweigh risks in life-threatening situations or diseases for which safer Rxs cannot beused or are ineffective

            Continuous administration during the 2^nd-3^rd trimesters can -> oligohydramnios, fetal calvarial &                                                 pulmonary hypoplasia, growth retardation & death.

            Several ACEIs have been detected in breast milk.  Be careful if nursing.  These Rxs can causeanuria and death in the neonate.

Rx INTERACTION: NSAIDS -> Na⁺/H₂O retention.  Certain PGs inhibit ADH.  Inhibiting synthesis of             these PGs -> ↑ ADH -> H₂O retention.  This interferes with the actions of             antihypertensive Rxs                                                 & can -> weight gain.  See 3d) above to explain Na⁺ retention.

** ACEIs tend to be less effective in African-Americans than they are in other races.

ACEIs

ACTIVE (not proRxs):

1.  CAPTOPRIL (Capoten) – food ¯s absorption – give 1 hr before meals.

2.  LISINOPRIL (Prinivil) – excreted unchanged

used for hypertension.  Some are also used for heart failure / MI / left ventricular dysfunction /diabetic neuropathy

ACEIs

PRO-RXS

 TRANDOLAPRIL (Mavik),  QUINAPRIL (Accupril),RAMIPRIL (Altace), FOSINOPRIL (Monopril), MOEXIPRIL (Univasc),BENAZEPRIL (Lotensin),ENALAPRIL (Vasotec),PERINDOPRIL (Aceon)

            The suffix "lat" denotes the active form of the Rx.  Ex: ramiprilat, enalaprilat, fosinoprilat

All are used for hypertension.  Some are also used for heart failure / MI / left ventricular dysfunction /diabetic neuropathy

ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)

-ARTAN

CANDESARTAN (Atacand), EPROSARTAN (Teveten),

IRBESARTAN (Avapro), LOSARTAN (Cozaar), OLMESARTAN (Benicar), VALSARTAN (Diovan), TELMISARTAN (Micardis), AZILSARTAN (Edarbi)

Blocking AT-1 receptors will have similarbenefits as the ACEIs.

Theoretically, they should be more effective that ACEIs b/c Ang II can be synthesized from                                     angiotensinogen by other enzymes such as chymase in connective tissues and mast cells and by trypsin. These other enzymes are not inhibited by ACEIs.

            They are in pregnancy category D but they do not cause angioedema and the incidence of coughis less b/c they do not interfere with the metabolism of bradykinin.

            Hyperkalemia is common if decreased renal function or if taking K⁺ sparing diuretics.

CANDESARTAN (Atacand)

ANGIOTENSIN II RECEPTOR BLOCKER (ARB)

is a prodrug activated by ester hydrolysis on absorption.

            OTHER USE:  prophylaxis against migraine RX INTERACTION:  ­s Li+ levels

IRBESARTAN (Avapro)

ANGIOTENSIN II RECEPTOR BLOCKER (ARB)

 LOSARTAN (Cozaar)

ANGIOTENSIN II RECEPTOR BLOCKER (ARB)

Parent & metabolite are active giving it a long t ½ thus 1x/day dosing.  It is less effective in African-Americans but this does not apply to all ARBs. 

Also approved for  diabetic nephropathy.

            FOOD INTERACTION: Avoid grapefruit juice - delays conversion to its active metabolite.

TELMISARTAN (Micardis)

ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)

HYDRALAZINE (generic)

MISCELLANEOUS VASODILATORS

Relaxes arteriolar smooth muscle by

            a) ↓ IP₃-mediated release of Ca²⁺ from the SR

            b) opens ATP-dependent K⁺ channels (K⁺_ATP) -> hyperpolarization

            This causes a dramatic ­ in sympathetic activity resulting in:

            a) ↑ HR & contractility                        WHAT CAN YOU DO ABOUT IT?

            b) ↑ plasma renin                                    WHAT CAN YOU DO ABOUT IT?

            c) fluid retention from ↑ renin                        WHAT CAN YOU DO ABOUT IT?

            Hydralazine is metabolized by acetylation.  WHAT IS THE SIGNIFICANCE OF THIS?

            Most common side effects:  Hypotension, tachycardia, headache.  Strong baroreflex can cause                                                                         myocardial ischemia which could precipitate an angina attack.

            Most serious side effects:

                        a) Lupus syndrome – 4x more often in women & more common in Caucasians.                                                              Generally with chronic use.  Incidence related to dose and acetylator phenotype.

                        b) Symptoms resembling serum sickness

            BIDIL – hydralazine + isosorbide: Promoted for African-Americans who don’t respond well to                                                                                                 β blockers, ACEIs or ARBs.

NITROPRUSSIDE (Nitropress)

MISCELLANEOUS VASODILATORS

metabolized to nitric oxide in vascular smooth muscle or liberates             nitric oxide through a non-enzymatic mechanism.  Dilates arteries and veins.  Given by IV                                                 infusion.  Light sensitive - the IV bag and line must be wrapped in foil.

            Onset within 30 seconds.  Hypotensive effects disappear within 3 minutes of discontinuation.

            Nitric oxide is metabolized to cyanide which in turn is metabolized to thiocyanate for excretion. Chronic infusion or ↓ renal function can cause accumulation of cyanide or thiocyanate ->  toxicity (thiocyanate: nausea, disorientation, spasms, convulsions, psychosis).

            USES: hypertensive emergencies / controlled hypotension to ¯ bleeding during surgery / acute   CHF to elicit a reflex ­ CO

FENOLDOPAM (Corlopam)

MISCELLANEOUS VASODILATORS

IV for hypertensive emergencies.  MECHANISM:  Stimulates DA D₁    receptors in coronary, renal & mesenteric arteries

            CAUTION if:    a) using with a b blocker -> ­­ hypotension

                                                b) glaucoma -> ­ intraocular pressure

                                                c) allergic to sulfas.  Contains sulfite

MINOXIDIL (generic)

MISCELLANEOUS VASODILATORS

ProRx.  Activates K⁺ channels -> K⁺ efflux -> hyperpolarization ->             relaxation of vascular smooth muscle.  It dilates arteriolar resistance vessels with no significant             effect on venous capacitance.  It elicits a strong baroreflex ­ in CO, stimulates renin release &             causes fluid retention.            WHAT CAN YOU DO ABOUT THIS?

            It can flatten & invert T-waves & cause pericardial effusions -> tamponade.  It is generally used                                     with a diuretic for severe hypertension that is unresponsive to diuretics alone.

            Chronic use can cause hypertrichosis.             WHAT ELSE IS THIS RX IS USED FOR?

RX TREATMENT FOR PULMONARY ARTERIAL HYPERTENSION (PAH)

Pulmonary arterial constriction, hypertrophy & fibrosis -> right ventricular overload & failure.

EPOPROSTENOL (Flolan), TREPROSTINIL (Remodulin), ILOPROST (Ventavis), BOSENTAN (Tracleer),AMBRISENTAN (Letairis)

EPOPROSTENOL (Flolan)

PAH Rx

TREPROSTINIL (Remodulin)

PAH Rx

– a PGI₂ analog with actions similar to epoprostenol.

ILOPROST (Ventavis)

PAH Rx

BOSENTAN (Tracleer)

PAH Rx

- MECHANISM:  Antagonist at endothelin-1 (ET-1) receptors ET_A & ET_B.

            ET-1 is a powerful vasoconstrictor whose levels in the pulmonary artery are elevated in PAH.

            ET_A mediates vasoconstriction & cell proliferation.  ET_B mediates vasodilation, anti-proliferation                                                                         & clearance of ET-1

            CAUTION:            a) potential liver toxicity. Liver transaminases may be elevated 3x the upper limit                                                                                                 of normal.

                                    b) teratogenic in animals so be careful if pregnant.

                                    c) potential to ↓ sperm count.

            Metabolized by & induces CYP3A4 & CYP2C9.  It can induce its own metabolism.

            Bosentan must be obtained from the manufacturer through a limited access program.

AMBRISENTAN (Letairis)

PAH Rx