Arterial Vasodilators - Hydralazine is a 2nd/3rd line agent, typically used to treat hypertensive crises. It is also used as first-line therapy

along with Labetalol to treat Preeclampsia (pregnant lady severe HT) o Hydralazine Metabolism: Well absorbed in the GI tract, extensively metabolized in GI mucosa + Liver o Genetic Variation: Acetylation shows distinct genetic contribution. Slow acetylaters may require lower

doses, and fast acetylaters may need higher doses. - Minoxidil is a 3rd/4th line prodrug. It must be activated by hepatic sulfotransferase to

minoxidil N-O-sulfate. Side effect is Hirsutism – so used to treat male pattern baldness o Glucuronidation (Minoxidil N-O-Glucuronide) for excretion

(2/6-8) Schlemmer Recitation: Pharmacology of Antihypertensives How does all this work? Recall, Blood Pressure (BP) = Cardiac Output (CO) • Peripheral Vascular Resistance (PVR)

- CO = Heart Rate (HR) • Stroke Volume (SV) - If you’re going to change BP, you much change one of these other dependent variables.

Diuretic [Sodium Water Balance]: Typically the first pharmacological treatment given for treating Hypertension - Short-term MoA: Decrease blood volume and CO, while decrease Na+ stores. This levels off in 6-8 weeks. - Long-term MoA: Sodium within muscles causes stiffness, rigidity. Long-term Na+ depletion leaves to decreased

PVR and CO normalizes. - Classes: While there are multiple classes of diuretics, only Thiazides and potassium-sparing diuretics are

clinically relevant. Loop, for example, are not as effective in treating HT. - Thiazides

o Most frequently prescribed, effective at treating mild to moderate essential HT. They are less effective in individuals with cardiac or renal comorbidities

o Dosing: Lower doses produce similar antihypertensive action as the higher doses. Use the lower dose!

o MoA: Inhibit NaCl reabsorption in the distal convoluted tubule on the luminal (urine) side. § Blocking Na+/Cl- transporter enhances downstream Ca2+ reabsorption! § Acute effect: COß, PVR~Ý - Reduction in blood volume § Chronic effect (>6-8w): CO Normalizes, PVRß

o AE: Hypokalemia (Kß), Hyperuricemia (Gout!), Hyperglycemia (only worry if you’re diabetic), HLÝ § The major AE to be concerned with is hypokalemia. In cardiac patients, this can be a big deal.

- Potassium-Sparing Diuretics o Avoids K depletion and enhances the natriuretic effect of other diuretics o Aldosterone Antagonists: Block aldosterone receptors in the late distal and

cortical collecting tubules. Normally, aldosterone functions to increase BP. o AE: Hyperkalemia (KÝ), Gynecomastia, Hypochloremic metabolic acidosis

CNS-Acting Sympathoplegic [DSympathetic] Indication: Used to treat moderate HT - MoA: Reduce sympathetic nervous system outflow from the brain. - Class Advantage: These drugs maintain the baroreceptor reflex, meaning, orthostatic

hypotension is low. Falls in the elderly lead to broken hips. The mortality rate of broken hips is 20% - blood clots during recovery.

- Indication: Used to treat moderate HT - Methyldopa: Methyldopa will be converted to a-methyl-NE by endogenous enzymes, a false transmitter

o CNS Activity: BPß. Action related to CO and HR is controversial, though minimally will decrease both. § The Schlemm says: a-methyl-NE stimulates post-synaptic a-adrenoceptors to reduce PVR § But I believe: I propose a-methyl-NE stimulatess pre-synaptic a2 autoreceptors and blocks post-

synaptic a receptors, leading to ßsympathetic outflow and BPß. Schlemmer rejected my thought o Peripheral Activity: While replacing NE as a false transmitter, it does not produce antihypertensive action

- Clonidine: o CNS Activity: BPß, HRß, Parasympathetic ToneÝ, ßSympathetic outflow. Functions as a direct agonist

of a-adrenoceptors in the medulla of the brain o Peripheral Activity: Clonidine is associated with an initial BPÝ, due to the peripheral a-receptors on

arterioles. When administered IV, patient will experience transient vasoconstriction. However, this peripheral action is very brief as they are only partial agonists at peripheral adrenoceptors

o AE: Dry mouth (a-mediated response), Sedation, Sudden withdrawal after chronic use – rebound § It is recommended to taper off the drug when d/c

Thiazides Non-Thiazides

Chlorthiazide HCTZ

Chlorthalidone

Aldosterone Antagonists

Inhibitors of Na+ Influx

Spironolactone Eplerenone

Triamterene Amiloride

CNS-Acting Sympathoplegics Methyldopa Clonidine Guanabenz Guanfacine

I’d buy you Rogaine… When you start losing all

your hair

Adrenergic Neuron Blockers [DSympathetic] - MoA: Impair sympathetic impulses by disrupting NE release at postganglionic effector sites on blood vessels,

producing vasodilation. However, a disadvantage is that they impair the baroreceptor reflex, increasing the chance of orthostatic hypotension à Falls à broken hips à blood clot à dead

- Indication: Used to treat mild to severe HT. Though they are rarely used anymore. - Guanethidine: Extremely potent antihypertensive used to treat severe HT… albeit has many drug interaX

o MoA: Replaces NE in the neuronal cells, inhibiting further NE release at postganglionic effector sites on blood vessels. Elicits vasodilation

- Reserpine: Used to treat mild to moderate HT, though may cause Parkinsonism due to [DAß] o MoA: Blocks uptake of NE, DA, and 5HT into the presynaptic cells, depleting the stores of NE and

inhibiting the release of NE at postganglionic effector sites on blood vessels. Elicits vasodilation a1-Adrenoceptor Antagonists [DSympathetic] Selective

- MoA: Blockade of a1-adrenoceptors at postganglionic sympathetic effector sites on blood vessels, producing vasodilation and the hypotensive effect. Decreased arterial pressure by the dilation of the resistance and capacitance blood vessels. These compounds have less of a reflex tachycardia than the non-selective a blockers.

- Prazosin (Minipres): Capable of crossing the BBB, this drug is actually used to tx other indications such as nightmares associated with PTCD due to the central a blockade.

a-Adrenoceptor Antagonists [DSympathetic] Non-selective [NO LONGER USED!!!!!] - Phentolamine: Capable of blocking both a1-NE and a2-NE receptors, tachycardia may result. No longer used.

b-Adrenoceptor Antagonists (b-Blockers) [DSympathetic] - MoA: b blockers directly block the AV node, which is responsible for rate-regulation (HR). As a result, they

reduce BP by decreasing the cardiac output. There is additional pharmacologic activity depending on the BB & pt o Kidney: b1-receptors mediate catecholamine-induced stimulation of renin production, \ b-blockers

antagonize renin production and further reduce BP o Periphery/Vessels: b-blockers antagonize presynaptic b-receptors ,vasodilation! o Brain: Most b-blockers get into the brain causing AE. The non-CNS active b-blockers are more potent

anti-hypertensives - Indication: Post-MI, High coronary risk, HF See a b-blocker? Think of these indications. - AE: Bradycardia, decreased contractility/excitability, bronchoconstriction, CNS sedation/depression

o Rebound Sympathetic stimulation upon abrupt withdrawal: Slowly ween pt off. Tachycardia, HT, Anx o BG Mask: BB may mask Sx of Hypoglycemia, such as hypoglycemic mediated tachycardia. While BB

are not contraX in DM, be aware they may exacerbate hypoglycemic episodes. - Non-selective: Propranolol (Inderal) Associated with AE such as depression, fatigue.. - Selective b-1 Blockers: Metoprolol (Lopressor), Atenolol (Tenormin)

o b1 receptors are specifically on the heart, meaning these selective compounds have less AE compared to the non-selective. Special about Atenolol, is that it does not cross the BBB to any appreciable extent.

- Mixed Adrenoceptor Activity: Intrinsic Sympathomimetic Activity (ISA): Pindolol (Visken) o MoA: Anti-HT effect occurs by decreasing PVR. Due to b2 agonism>b2 antagonism, there is less

depression of CO and HR, thereby making them better indicated for pt with Bradyarrythmias+PVD o ContraX: Pt with Angina

- b-blockers with a-NE-Blocking activity: Labetalol (Normodyne) Vasodilators

- Oral: Hydralazine, Minoxidil o Hydralazine: Dilates arterioles only. Generally not used as monotherapy as it can produce Tachyphylaxis.

Better used in combination therapy for HT. o Minoxidil: Dilates arterioles only. Operates by opening K+ channels in arteriole muscle membranes to

suppress contraction. Topically used for hair regrowth due to Hirsutism AE - Parenteral: Na+Nitroprusside (Members of this class cause tachycardia and provoke angina

o Na+Nitroprusside: Potent vasodilator (arterioles+veins) used in HT emergencies, do not use it for a long period of time because it causes the accumulation of Cyanide. Cyanide is not good.

o Fenolopam: Dilates arterioles only. It is a D1 agonist, thereby promoting natriuresis. Watch out though causes increases in intraocular pressure, do not use it in Glaucoma pt

- Calcium Channel Antagonists o MoA: Anti-HT: Inhibition of Ca2+ into the smooth muscle of arterioles, reducing PVR and \ BP

§ Reduction in PVR is the mechanism by which edema occurs – blood pooling o Indication: Used as anti-arrythmics, Anti-anginals, anti-hypertensives o Non-DHP: Verapamil, Diltiazem

§ MoA: Decrease the conduction through the AV node, producing a negative inotropic effect. These drugs are potent vasodilators, decrease the HR, \ COß, BPß

§ Indication: Safer for pt with Hx MI, Less risk of Tachycardia, but far more DDI o DHP: Nifedipine, Amlodipine

§ MoA: Potent vasodilators, just less cardiac depressant activity compared to the Non-DHP § AE: Risk of Tachycardia. Potential for COÝ. MI Risk (increased with SA-Nifedipine, use LA)

• Verapamil is pretty god damn constipating, fill their bottle with some Colace Inhibitors of Angiotensin

- So you’re a prescriber eh? ACE then ARB. Ok? Nice. - Angiotensin-Converting Enzyme Inhibitors (ACE-I) Captopril

o MoA: Inhibits the synthesis of AngII (a potent vasoconstrictor) from AngI. Additionally, they block the breakdown of bradykinin (which is a vasodilator), which can accumulate and produce a dry cough

- Angiotensin Receptor Blockers (ARBs) Losartan o They block AngII Type 1 Receptors. So they are AT1 Antagonists.

(2/7) Jun Lecture: Pathophysiology and Pharmacotherapy of Hypertension II Screening for HT

- Normal Frequency: Patients with normal BP for their age need only be screened annually for HT - Elevated/Risk Frequency: Patients with risk factors or elevated (120-129) readings require semiannual screenings - Primary HT Screening: Recognizable by slow rise in BP associated with negative lifestyle factors - Secondary HT Screening: Relevant to cases of abrupt HT onset, check for TOD, labs (K), and causes

Official HT Diagnosis - Guidelines stress Dx to be based on ³ 2 BP readings at each of ³ 2 visits following initial screening - Recommendations: Use a home BP monitoring (ABPM/HBPM) device, to help eliminate white coat syndrome

o HT = At home monitor daytime average ³ 130/80 o ABPM takes BP q15-20m during the day and q30-60m during sleep. Gold Standard, it is the better

predictor of future CV events, though is facing resistance in terms of reimbursement opportunities Decision to Treat: The thresholds at which ‘treatment’ and medications are initiated is sub-stratified by the risks •••Higher Risk: Treat these individuals when Average Blood Pressure ³ 130/80 AND have one of these factors:

- Risk Factor: Clinical CVD – Treatment is a secondary prevention - Risk Factor: 10-year atherosclerotic CVD risk ³10% -- Tx is a primary prevention

o This is calculated by age, race, cholesterol, PMHx, ASA, Smoking, BP meds - à Tx: Lifestyle Mod + BP Meds and Reassess in 1 month

•••Lower Risk: Treat these individuals when Average Blood Pressure ³140/90. Boom. - The 10year ASCVD risk for these patients is <10% and is not too big of a concern. Tx is a primary prevention - à Tx (1): Lifestyle Modifications for 3-6 months, do some ABPM. If unsuccessful and BP ³ 140/90…. - à Tx (2): Add a BP medication with a goal of <130/80

•••No Risk/Chill Risk - Normal BP (<120/80): Promote healthy living, follow-up in 1 year. - Elevated BP (120-129/<80): Lifestyle Modification, reassess in 3-6 months

Precision Medicine: Individualizing Therapy with BP Goals - The overall goal is to reduce morbidity and mortality from CV events. Target BP goals may need to be adjusted

based on adverse effects or specific pulse pressure anomalies. Non-Pharmacologic Intervention

- All patients are recommended to participate in these interventions to promote a heart-healthy life - Activity: Weight Loss, Increase Exercise (150min/week), Stop Boozing

o Each kg of weight loss correlates to 1 mmHgß - Intake: Heart healthy diet (DASH), ßNa+ intake, ÝK+ intake (from dietary sources, if no ContraX)

o Na+ Restriction: Sodium restriction is associated with reductions in BP. § Salt-Sensitive: More common in AA, Geriatrics, and comorbidities (DM, CKD, MetabSynd)