- 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)

§ Goal: Small decreases in sodium intake. Otherwise severe restrictions have AE o Dash: Has the greatest impact on HT BP reduction.

Pharmacologic Interventions Class: Diuretics

- Thiazide/Thiazide-like Diuretics (HCTZ < Chlorthalidone, Indapamide, Metolazone) o Place in Therapy: Cornerstone 1st line drugs! Low doses are optimal – Chlorthalidone 12.5-25mg o MoA: Block Na+ reabsorption at the distal tubule, causing volume loss mostly in week 1 (Short-term)

§ Over time, volume loss and CO return to baseline, which is when the long-term vasodilatory effects kick in. Decreased SVR via vasodilation is the long-term dosing effect.

o ADR: Dose-related electrolyte disturbances. ßNa+, ßMg2+, ßK+, ÝCa2+, Hyperuricemia (Gout ppt!) o Monitor: Electrolytes. à Advocate for lower dose thiazides, because the AE increase faster than the BP

benefit. CrCl <30? Swtich em to loops - Loop Diureitcs (Bumetanide, Furosemide, Torsemide)

o Place in Therapy: Rarely used for primary HT. Used as a diuretic when CrCl < 30 or CKD stage 4-5. o ADR: ßCa2+, and overall similar electrolyte distances to HCTZ

- Postassium-Sparing Diuretics (Amiloride, Triamterene) o Place in Therapy: Not used alone. Requires a working kidney, beware of KÝ o Anti-aldosterone Antagonists: (Eplerenone, Spironolactone)

§ Place in therapy: Indicated for primary aldosteronism and resistant HT. § Risk of ÝK – try to avoid K supplements. Spironolactone – grow man-boobs

Class: RAAS - ACE-Inhibitors (ACE-I) (Lisinopril, Enalapril, Captopril, Benazepril, Ramipril)

o Place in Therapy: Cornerstone 1st line drugs! Though more commonly used as add-on therapy for patients with DM, proteinuria, CHF, or CAD.

o MoA: Blocks conversion of AngI-AngII, promoting vasodilation and reduced activation of aldosterone § Blockade of ACE reduces Bradykinin metabolism. Bradykinin also leads to vasodilation which is

great, but the bradykinin accumulates in the lungs and causes a dry cough. ARB time!!!! o ADR: ÝK+, Dry Cough, Angioedema, Nephrotoxicity, Pancreatitis

§ à In volume depleted patients, this can severely decrease Kidney perfusion, causing toxic rises in creatinine.

- Angiotensin Receptor Blockers (ARBs) (Losartan, Valsartan, Irbesartan, Candesartan) o Place in Therapy: 1st line therapy, but usually reserved for ACE-I intolerant individuals o MoA: Blocks AT receptors, causing vasodilation and reduced aldosterone synthesis o ADR: KÝ, Nephrotoxicity

- Renin Inhibitors (Aliskiren) o Place in Therapy: 2nd line/add-on therapy. There are better drugs with less AE. o MoA: Inhibit Angiotensinogen, so less AngI and AngII o ContraX: With ACE/ARB in DM pts. Big risk of Kidney dysfunction, KÝ, Hypotension

Class: Calcium Channel Blockers - Dihydropyridines (DHP) (Amlodipine, Nifedipine, Felodipine, Nicardipine)

o Place in Therapy: Cornerstone 1st line agents, without ‘compelling’ indications. Lol what? o MoA: Vasodilation of the vascular smooth muscle via calcium antagonism. +contractility stuff o ADR: HA, Peripheral Edema (legs/ankles), gingival hyperplasia, light headedness

§ Peripheral Edema occurs due to DHP-induced capillary leakage – capillaries more permeable § Combating Peripheral Edema: Dose ß, Switch Tx, or add ACE-I or ARB

- Non-DHP (Diltiazem, Verapamil) o Place in Therapy: Add-on therapy. They play a dominant role in patients with comorbid AFib or CAD o MoA: Reduce Cardiac Output by decrease the HR and Contractility via AV Node blockade. Blockade is

accomplished by inhibiting Ca2+ from entering voltage sensitive areas of the myocardium o ADR: Bradycardia – complete heart block. Heart failure exacerbation, Edema, HA, Constipation

§ Hella constipation from Verapamil o ConraX: Do not use with b-blockers, HFrEF, Sick Sinus Syndrome, and 2nd/3rd Heart block

§ CYP3A4 Substrate and Inhibitor Class: Anti-Andrenergic

- Beta-Blockers (BB) o Place in Therapy: 2nd line/Add-on therapy. They have a

critical role in CAD and may be first line in those case. There are excellent studies supporting the great value of BB

o Subtype: § b1 Selective Antagonist “Cardioselective”: Atenolol, Bisoprolol, Metoprolol, Nebivolol § Mixed a/b Antagonists: Carvedilol, Labetalol § Nonselective: Propranolol. Hits both b1 and b2

o ADR: Lethargy, Sexual dysfunction, bronchoconstriction, exacerbation of Raynaud’s phenomenon - Alpha-Blockers (a-Antags) (Doxazosin, Terazosin, Prazosin)

o Place in Therapy: Rarely used. ALLHAT trial showed weak efficacy, only used for BPH, PTSD o MoA: Inhibit sympathetically mediated arterial vasoconstriction via blockade of a1 receptors on vascular

smooth muscle. o ADR: First dose orthostatic effect, dizziness, fatigue, HA.

- Centrally-Acting a2 Agonist – Clonidine o Place in Therapy: Add-on therapy way late. Benefit – has a patch, good for people with adherence issues. o MoA: Binds to central presynaptic a-2 adrenergic receptors, reducing sympathetic outflow from the CNS

- Others o Methyldopa: Result in false SNS NT. Used infrequently, rebound effects. Good in preeclampsia o Reserpine: Depletes sympathetic Amines. Used infrequently, poor tolerance.

Class: Vasodilators - Hydralazine: Direct vasodilation of arterioles. Has been associated with edema, drug-induced Lupus (check for

anti-histone Ab), orthostasis, and reflex tachycardia o Place in therapy: 3rd or 4th line add-on therapy. IV dosage form used in hospitals for quick onset short

duration. High prevalence of use in AA patients with HF using nitrates. - Minoxidil: Vasodilation via smooth muscle relaxation, likely mediated by cAMP. This is a very effective drug,

however it is limited by its AE: Hirsutism, edema, T-wave changes – gotta’ use it with a BB o Place in Therapy: Limited 3rd/4th line therapy. Better used for hair regrowth!

(2/9) Jun Lecture: Pathophysiology and Pharmacotherapy of Hypertension III Choosing how to treat HT: When choosing initial anti-hypertensive drug therapies, the two most important determinants are (1) Comorbidities, (2) Race

- Comorbidities o No Pertinent Comorbidities à Primary Agents: Thiazide/Thiazide-type Diuretics, ACE-I, ARBs, CCB o Compelling Indications à Secondary Agents: Treatment options are more tailored to the comorbidity

§ Gout: No Thiazides Asthma/COPD: BB Concern HyperK+: Avoid ACE-I/ARB/Spiro § Pregnancy: Avoid ACE/ARB/Renin-I § HFrEF: This is a heart pumping problem, Avoid Non-DHP CCB, they will slow it further – bad. § CAD/MI/CHF: Beta-blockers are the cornerstone therapy of secondary prevention of MI. While

BB have been shown to be inferior, for this subset of patients BB reduce mortality. - Race

o Non-Black: ACE-I, ARB, CCB, Thiazide (CKD: ACE-I/ARB are preferred > CCB) o Black: Thiazides, CCBs > ACE-I, ARB (CKD: proteinuria = ACE-I/ARB, none = Thiazide/CCB

§ HF/CHD: BB and ACE-I/ARB Anti-hypertensive Drug Combinations

- Indication: Initiating therapy with two 1st line agents may be appropriate for pt with Stage 2 HT. So if patients are BP > 20/10mmHg over goal, it is likely they need 2+ anti-hypertensive drugs to reach their goal.

- Nice Combos o ACE-I/ARB + Thiazide Diuretic: Both ACE-I and and Arb raise K+, Thiazides lower it. Complementary

§ Additionally, Thiazides may trigger RAAS, so adding ACE-I to blunt it can be beneficial o ACE-I/ARB + DHP-CCB: ACE-I can lessen the CCB-induced peripheral edema o Vasodilator + BB + Diuretic: Helps blunt reflex tachycardia, Diuretic compensates the Na+ H2O retention