Beta Blockers and Alpha Blockers (LOL, OLOL, ALOL, DARONE, (Z)OSIN, ASTERIDE)

What drugs are considered the 1st line therapy of hypertension?

> ACE-I/ARB

> Thiazide

> calcium channel blockers (CCBs)

**What drugs are considered the 2nd line therapy for hypertension?**

Beta-blockers

**[...] are generally used for resistant hypertension and for the management of benign prostate hyperplasia (BPH) and some off-label indications**

Alpha-blockers

**Alpha-blockers**

- 3rd line agents for hyoertension

- More frequently used for prostate hypertension

**Which beta-blocker INCREASES heart rate (heart)?**

Beta-1

**Which beta-blocker relaxes smooth muscles (lungs)?**

Beta-2

**Which blocker is responsible for vasoconstriction?**

Alpha-1

**What 2 beta-blockers have alpha-blocking properties?**

- Labetalol

- carvedilol

Characteristics of LOL, OLOL, ALOL, ILOL: What is the Chemical nomenclature for LOL, OLOL, ALOL, ILOL?

Aryloxypropanolanimes (Multi-ring structures)

Characteristics of LOL, OLOL, ALOL, ILOL: What is the Pharmacologic nomenclature for LOL, OLOL, ALOL, ILOL?

> Beta-adrenergic receptor blockers (Beta blockers)

> Mechanism of action: Act at Beta-receptors located in various organs in the body

**Beta-1 receptors**

> Catecholamines (norepinephrine) bind here

> Causes an increase in cardiac automaticity and conduction velocity (increased heart rate)

> Also releases renin, which leads to blood pressure elevation

> More likely located on the cardiac muscles, but not exclusively

**Beta-2 receptors**

> Causes relaxation of smooth muscles, such as in the lungs

> Also results in peripheral vasodilation

> Skeletal muscle stimulation (tremors)

> Work primarily in the pulmonary tissue and the periphery

**Alpha-1 receptors**

> Involved in the bronchodilation and vasoconstriction effect

**Some β-blockers exhibit ⍺-blocking properties (e.g., Labetalol, Carvedilol). What are they referred to as?**

Mixed ⍺1/β-blocker

**What are the 2 β-blockers that exhibit ⍺-blocking properties?**

- Labetalol

- Carvedilol

Characteristics of LOL, OLOL, ALOL, ILOL: What is the Βeta-blocker Mechanism of action?

* Decrease blood pressure (BP) by competitively blocking both β1and β2 adrenergic receptors = decrease heart rate and myocardial contractility

> Some block ⍺1 receptors =Decreases peripheral vasoconstriction (lowers BP)

Characteristics of LOL, OLOL, ALOL, ILOL: Another Βeta-blocker Mechanism of action is the Intrinsic sympathomimetic activity, what is it?

Partially stimulates beta receptors while blocking catecholamines = Do not lower heart rate to the same degree as other βB

Characteristics of LOL, OLOL, ALOL, ILOL: Cardioselective Beta-blockers

*Target Beta-1 receptor preferentially

- Most become more non-selective in nature at higher doses

- Cause a larger effect on heart rate

- Have a smaller effect on blood pressure

Characteristics of LOL, OLOL, ALOL, ILOL: Non-cardioselective Beta-blockers

* Do not lower heart rate as much as selective β-blockers

- Causes lower blood pressure by either a-blocking properties or nitric oxide vasodilation

- Can cause bronchoconstriction

- Must be avoided in patients with a history of asthma

- Used with caution in patients with COPD

Cardioselectivity DOES NOT always correlate with WHAT?

Cardioselectivity DOES NOT always correlate with what the specific β-blockers are used for

Characteristics of LOL, OLOL, ALOL, ILOL: What are the Therapeutic categorization and indications?

> Hypertension (High blood pressure)

Characteristics of LOL, OLOL, ALOL, ILOL: Beta-blockers ONLY recommended as 2nd line treatment unless patient has another indication requiring Beta-blockers, like:

> Angina pectoris (help increase O2 supply)

> Cardiac arrhythmias (Atrial fibrillation)

> Myocardial Infarctions

> Migraine Prophylaxis

> Heart Failure

> Tremors

**Characteristics of LOL, OLOL, ALOL, ILOL: What are the Contraindications?**

> 2nd or 3rd degree AV block or sick sinus syndrome

> Cardiogenic shock

> Cardiac failure/decompensation

**Characteristics of LOL, OLOL, ALOL, ILOL: What are the Warnings?**

> Caution in patients with diabetes (mask signs of hypoglycemia; Except sweating)

> Use caution with bronchospastic diseases

> Peripheral vascular disease

> CNS depression

> Use in acute decompensated heart failure

**Characteristics of LOL, OLOL, ALOL, ILOL: What are the Adverse drug reactions?**

> Bradycardia

> Hypotension

> Fatigue

> Dizziness

> Depression

> Decreased libido

> Impotence

Characteristics of LOL, OLOL, ALOL, ILOL: What are the Drug interactions?

> Diltiazem/verapamil

> Digoxin

> Carvedilol, metoprolol, and propranolol are major substrates of CYP2D6

> Carvedilol and propranolol are inhibitors of p-gp (Cyclosporine, dabigatran, digoxin, ranolazine)

> Diabetes medications

Characteristics of LOL, OLOL, ALOL, ILOL: What are the Counseling points?

> Do not abruptly discontinue β-Blockers after using for an extended period of time (Can lead to rebound tachycardia)

> Taper β-Blockers slowly to avoid rebound effects

> If symptoms of HF appear (SOB, dyspnea, swelling of ankles)

> Masks signs of hypoglycemia (Patient will still have sweating and hunger)

Characteristics of LOL, OLOL, ALOL, ILOL: NON-selective Individual compounds?

> '67 - propranolol (Inderal®)

> '78 - timolol (Blocadren®) - 5 mg, 10 mg, 20 mg tablets

> '79 - nadolol (Corgard®) - 20 mg, 40 mg, 80 mg tablets

> '82 - pindolol (Visken®) - 5 mg, 10 mg tablets

Characteristics of LOL, OLOL, ALOL, ILOL: Cardio-selective beta blocker drugs

> '78 - metoprolol tartrate/succinate(Lopressor®, Toprol XL®)

> '81 - atenolol (Tenormin®) - 25 mg, 50 mg, 100 mg tablets

> '84 - acebutolol (Sectral®) - 200 mg, 400 mg capsules

> '86 - esmolol (Brevibloc®) - 100 mg/ 10 mL, 2000 mg/100 mL, 2500 mg/250mL IV

> '89 - betaxolol (Kerlone®) - 10 mg, 20 mg tablets

> '92 - bisoprolol (Zebeta®) - 5 mg, 10 mg tablets

> '07 - nebivolol (Bystolic®) - 2.5 mg, 5 mg, 10 mg, 20 mg tablets18

Characteristics of LOL, OLOL, ALOL, ILOL: Mixed non-selective and alpha-1 blocker drugs

> '34 - carvedilol (Coreg®)

> 54 - labetalol (Trandate®, Normodyne®)

Characteristics of LOL, OLOL, ALOL, ILOL: Ophthalmic Beta-blockers

> Levobunolol (Betagan Liquifilm®)

> Betaxolol (Betoptic®)

> Metipranolol (Optipranolol®)

> Carteolol (Ocupress®)

> Timolol Maleate (Timoptic®)

> Levobetaxolol (Betaxin®)

> Glaucoma is their sole indication

**Characteristics of DARONE: What are the available products for DARONE?**

- Amiodarone Hydrochloride

- Dronedarone Hydrochloride

**Characteristics of DARONE: What are the 3 Amiodarone indications?**

> Antiarrhythmic agent used primarily for ventricular arrhythmias

> Off-label

> Dose used is dependent on the type of arrhythmias being treated

**What are the traits of an Antiarrhythmic agent used primarily for ventricular arrhythmias, specifically in Amiodarone indications?**

> Non-sustained ventricular tachycardia (VT)

> Sudden cardiac arrest due to ventricular fibrillation/pulseless VT

**What are the traits of Off-label, specifically in Amiodarone indications?**

> Pharmacological cardioversion in atrial fibrillation (Afib)

> Maintenance of sinus rhythm

> Prevention of postoperative atrial arrhythmias

**What are the traits of Dose used, specifically in Amiodarone indications?**

> Dependent on the type of arrhythmias being treated

> Lower doses are generally used for atrial arrhythmias (paroxysmal Afib)

**Characteristics of DARONE: What is the Amiodarone mechanism of action?**

*Inhibits adrenergic alpha and beta receptors

> Class III antiarrhythmic

> Affects sodium, potassium, and calcium channels

> Prolongs the action potential and refractory period and decreases AV conduction and sinus node function

What is the T 1/2 of Amiodarone?

T 1/2 is ~40-55 days!

**Characteristics of DARONE: What are the Adverse events of Amiodarone?**

> Most side effects are seen after the patient is on for an extended period of time

> Affects several systems

**What are the systems that Amiodarone's adverse effects disturb?**

> Pulmonary - fibrosis, pneumonitis

> Thyroid - hypo/hyperthyroidism

> Ophthalmic - blurred vision, visual halos

> Gastrointestinal - anorexia, nausea, vomiting

> Cardiovascular - hypotension, bradycardia, QT prolongation

> Dermatologic - photosensitivity

> Hepatic - abnormal LFT

Characteristics of DARONE: What are the Black Box Warnings of Amiodarone?

> Hepatotoxicity

> Pulmonary toxicity

> Ability to worsen arrhythmias

> Use should be limited to patients with life-threatening arrhythmias

Characteristics of DARONE: What are the Drug interactions of Amiodarone?

> Drug that prolongs QTc (fluoroquinolones, macrolides, etc.)

> Warfarin

> Substrate: CYP3A4, CYP2C8

> Inhibits: CYP2C9, CYP2D6, CYP3A4 (grapefruit juice)

Characteristics of DARONE: What is the availability of Amiodarone?

> Brand names: Cordarone, Pacerone®

> Strengths: 100 mg, 200 mg, 400 mg tablets. 50 mg/mL IV injection

Characteristics of DARONE: What is the chemical class of Dronedarone?

Structurally similar to amiodarone, but lacks the iodine moiety

Characteristics of DARONE: What is the pharmacologic class of Dronedarone?

Class III antiarrhythmic agent indicated to reduce the risk of cardiovascular hospitalization

Characteristics of DARONE: What is the therapeutic class of Dronedarone?

For a patient with paroxysmal or persistent atrial fibrillation or atrial flutter with a recent episode

Characteristics of DARONE: What are the risk factors of Dronedarone?

- Age >70, HTN, diabetes, prior stroke, etc.

Characteristics of DARONE: What are the adverse effects of Dronedarone?

> Slightly better side effect profile when compared to amiodarone

> Generally lacks thyroid toxicity

> Other side effects are similar

Characteristics of DARONE: What are the Black Box warnings of Dronedarone?

> Increase risk of death when used with patients with class III or IV congestive heart failure (CHF)

> Increase risk of death in patients with chronic atrial fibrillation

Characteristics of (Z)OSIN: What is the Chemical nomenclature of ZOSIN?

> Quinazolines (with a piperazine ring and acyl moiety)

> Aryl Sulfonamides

What are the ⍺-blockers, two distinct types?

> ⍺1 - adrenergic receptor blockers

> ⍺1a - adrenergic receptor blockers

Characteristics of (Z)OSIN: What is the Pharmacologic nomenclature of ZOSIN?

* Selectively block ⍺1 receptors on smooth muscle cells of the peripheral vasculature

> Decreases BP by vasodilation and total peripheral resistance

> Increases urine flow and decreases frequency in BPH because ⍺1 receptor on the prostate

Characteristics of (Z)OSIN: What are the indications of ZOSIN?

> Hypertension

> Benign Prostatic Hyperplasia (BPH) - only ⍺1a blockers

Characteristics of (Z)OSIN: What is the main Adverse drug reaction of ZOSIN?

Priapism (especially with ⍺1a blockers) - a rare but serious ADR resulting in a painful, prolonged penile erection, leading to permanent impotence if not treated immediately

Characteristics of (Z)OSIN: What are the main Warnings for ZOSIN?

> Orthostatic hypotension

> Retrograde ejaculation

> Nasal congestion, dizziness, tiredness

> Sulfonamide allergy (tamsulosin)

Characteristics of (Z)OSIN: What are the Available products of ZOSIN?

> '87 - Terazosin HCl (Hytrin®)

> '87 - Prazosin HCl (Minipress®)

> '05 - Doxazosin mesylate (Cardura®/Cardura XL®)

> '97 - Tamsulosin HCl (Flomax®)

> '03 - Alfuzosin HCl (Uroxatral®)

> '08 - Silodosin (Rapaflo®) - 4 mg, 8 mg capsules34

Characteristics of ASTERIDE: What is the Chemical nomenclature of ASTERIDE?

> 4-azasteroids - synthetic steroid-like structures

Characteristics of ASTERIDE: What is the Pharmacologic nomenclature of ASTERIDE?

* Competitively inhibits type-II 5-⍺ reductase -> inhibits reduction of testosterone to dihydrotestosterone

- Androgen hormone inhibitors/ 5-⍺ Reductase inhibitors

Characteristics of ASTERIDE: What are the indications of ASTERIDE?

> Benign Prostatic Hyperplasia (BPH)

> Alopecia

Characteristics of ASTERIDE: What are the warnings/Adverse drug reactions of ASTERIDE?

> Pregnancy category X!

> Use with care in patients who have diminished urinary flow(obstructive uropathy)

> Use with caution in patients with hepatic insufficiency

> Not indicated in the US for the prevention of prostate cancer38

Characteristics of ASTERIDE: What are the available products of ASTERIDE?

> Finasteride (Proscar®, Propecia®)

> Dutasteride (Avodart®)