§ 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

- Combos to Avoid: In general, we want to avoid using two agents for the same system/mechanism o ACE-I/ARB + Renin Inhibitor: Higher CVD risk o ACE-I + ARB: Similar AE profile, risks HyperK+ and Nephrotoxicity o BB + Non-DHP CCB: Additive Bradycardia, Reduced Contractility o BB + CNS Agents: Additive Bradycardia, Reduced Contractility

ALLHAT: 40k patient trial, 5 year follow-up. Primary endpoint was fatal CHD or non-fatal MI - Big Result: a-blockers increased the risk of CVD, this arm was prematurely d/c due to the study. - CCB and ACE-I compared to Thiazides showed equal efficacy for the combined CVD outcomes - BB are less

Resistant Hypertension - Defined to be when you are not at goal on 3 BP meds (1 is a diuretic), OOOOR you ARE controlled on ³4 meds - Risk Factors: Elderly, Obesity, African American, DM - Method of Treatment

o Assess and Improve Adherence – THIS IS KEY o Fix your Diuretic: Chlorthalidone is preferred

§ PATHWAY-2 Trial: Shows adding an anti-aldosterone diuretic (Spiro) is the super choice o Discontinue offenders: Some meds cause HT, such as NSAIDs, decongestants, AMP

§ Treat obesity, become more active, Avoid high salt diets o Add new agents with different MoA

Secondary Hypertensions Common causes:

- Obstructive Sleep Apnea (25-50%) - Renovascular disease (5-34%) - Aldosteronism (8-20%)

Adherence

- Upon initiating/titrating anti-hypertensive therapy, it is most important to address the patient’s adherence. EVERY visit, adherence should be discussed, especially at the 1-month follow-up after a new med is introduced

o Assessing Adherence: Use open-ended questions, the “teach back” method. Call the patients pharmacy to harass the technicians and check the refill history. Encourage the outpatient pharmacist to get involved

- Non-Adherence: Patients generally do not have Sx from HT, it is the silent killer. When we treat them, they do not feel better, they feel worse due to the side effects.

o Frequency: Drugs like Hydralazine need to be taken multiple times a daily. With higher dosing schedules, adherence worsens.

- Counseling: Review the goals of therapy, so they know what is normal and abnormal. It may be useful to mention that BPÝ as we age, so their medication therapy may be life-long. Review offending medications (adrenergic agonists and NSAIDs)

Hypertensive Urgency and Emergency - Malignant HT can progress into an acute, accelerated HT that

threatens or damages target organs - Urgency: SBC > 180 or DBP > 120 - Emergency: When there are signs of organ damage - Treating Urgency: Do not go fast! Aggressive tx often worsens the condition. Abrupt normalization may

precipitate organ damage (stroke, renal failure). This often occurs because the organs/vessels become acclimated to the extremely high BP. à Tx with PO meds

- Treating Emergency: o Goal is to reduce BP by 25% in the first hour, then to 160/110 over the next 2-6 hours, and end at normal

at the end of 24-48 hours. Emergencies are severe cases in which parenteral agents are used, as they provide greater control and responsiveness, though they require more frequent monitoring

o Special Emergencies: Aortic Dissection: Reduce SBP < 120 in the 1st hour § Preeclampsia/Pheochromocytoma Crisis: Reduce SBC < 140 in the 1st hour

As always, please let me know if you find mistakes in my information. I think I’ll make a practice exam again to help myself study – hopefully it helps you as well!