Indirect-Acting Adrenergic Agonists These agents increase the concentration of NE at the receptor, without directly interacting with the receptor. As a result, these are not selective. Their structure involves an A group, which can be any aromatic or carbocyclic ring. The ethylamine side chain may be separate, or part of the cyclic ring.

- Activity: (1) Inhibit Reuptake, similar to cocaine. (2) Increase NE Release - Effect: Recall these are non-selective. Put vaguely, these agents increase the tone of the adrenergic system. - Amphetamine (Adderall, AMP): CNS Stimulant, aka speed, stimulates the release of NE and other NT such as

DA and 5-HT in the periphery/brain. Non-selective action: appetite suppression. (C-II) - Methamphetamine (Desoxyn, MAMP): More lipophilic CNS stimulant. Highly abused. (C-II) - 3,4-Methylenedioxymethamphetamine (MDMA): aka Ecstasy. Potent, Lipophilic, ~Neurotoxic

o Neurotoxicity MoA: The methylene of the methylenedioxy group confers excellent lipophilicity and avoidance of COMT. Once in the CNS, CYP with metabolize the methylene, producing the catechol. COMT becomes overwhelmed, leading to the production of orthoquinones and other neurotoxic compounds. Damage to the brain may ensue, as neuronal nucleophiles begin to irreversibly engage the metabolites. It may show benefit in treating PTSD, but its therapeutic window is trash. (C-I)

- Pseudoephedrine (Sudafed, PSE): Non-selective action: Raise BP. (C-V) - Tyramine: Tyramine is a product of Tyr decarboxylation by L-Amino Acid-Decarboxylase.

Tyramine is found in cheese and red wine, capable of inhibiting reuptake of NT. People taking MAOIs should avoid this compound.

(1/31) Jun Lecture: Pathophysiology and Pharmacotherapy of Hypertension I Hypertension (HT) Epidemiology

- HT is the most common and modifiable Cardiovascular Disease (CVD) risk factor, accounting for more CVD deaths than all other modifiable risk factors. 1 in 3 adult Americans have HT. AA > Cauc > Hisp

o CVD Risk doubles: For every 20mm Hg Systolic BP, and 10mmHg Diastolic BP > 115/75 - CVD Risk factors associated with Hypertension

o Modifiable: Smoking, Obesity, Diet (Na+Ý), Boozing, Inactivity, DM o Fixed/Difficult: Age, Family history (x2Ý), CKD, Male, Socioeconomic status, stress, race, sleep apnea

- Framingham Heart Study: Determined top risk factors: HT, HL, Smoking, Obesity, DM, and physical inactivity “Silent-Killer”

- Most people with HT usually do not have Sx. Left unchecked, it can go on to develop target organ damage. As a result, it should be identified, monitored, and treated appropriately

- Complications: Heart (CVD, LV-Hypertrophy), Kidney (Albuminuria, CKD), Vascular (Atherosclerotic Disease) and many more!

Dx: Primary HT - Cx: Comprises 90% of the cases, where there is an unknown etiology, likely associated with numerous causes.

o Genetics is not well understood, though family history has a positive association. Top theories include genetic coding for the handling of Na+ by the kidneys, and mutation may contribute to HT

- Tx: Control BP Dx: Secondary HT

- Cx: Comprising 10% of cases, this version of HT is causes by comorbid conditions or medications o Major: Renovascular (kidney disease), Obstructive sleep apnea, Primary aldosteronism, Booze/pills o Minor: Cushing’s, Pheochromocytoma, Thyroid disease, primary hyperparathyroidism o Meds/Food: AMP, Roids, CNI, Decongestants, ESA, NSAIDs, Na+, Booze, old man licorice

- Tx: Remove the causative agent, or treat the underlying condition Components of Blood Pressure BP = CO•PR CO = SV•HR

- When we speak of blood pressure, we regularly refer to Arterial BP. It is the measure of the peak pressure during contraction (Systolic) and the pressure following contraction during filling (Diastolic) in mmHg.

- Heart Rate (HR): ANS-controlled, HR factors into Cardiac Output o Parasympathetic: ‘Rest/digest’ – ACh acts on pacemaker cells, HRß o Sympathetic: ‘Fight/Flight’ – NE/E acts on pacemaker cells, HRÝ

§ NE/E also produce systemic vasoconstriction, increasing BPÝ! - Stroke Volume (SV): Has 2 major mechanisms of control. SV is best portrayed by the Frank-Starling Curve

o Intrinsic: Self-regulation, moderating its own HR and Contractility o Extrinsic: b-Adrenergic stimulation by E and NE increases the force of contraction, SVÝ

Mechanisms of HT - Increased Cardiac Output (CO)

o ÝPreload: With increased Na+ consumption and reuptake, water will follow leading to fluid retention and increased preload. Having a greater volume to push out, this will increase the CO

o ÝVenous Constriction: As mentioned previously, the Sympathetic stimulation by E/NE will induce vasoconstriction. When the veins constrict, their blood supply enters the heart, increasing CO

§ Renin-Angiotensin-Aldosterone System (RAAS): Stimulation of RAAS will similarly produce vasoconstriction. In cases of dehydration, low BP, or in general arterial vasoconstriction, blood perfusion of the kidneys will decrease. The Juxtoglomerular apparatus baroreceptors will detect the lowered pressure, and attempt to correct it by releasing Renin. Renal Renin stimulates the Liver to release Angiotensinogen, initiating a cascade eliciting water retention and increased PR.

- Increased Peripheral Resistance (PR) o Temporary vascular constriction or long-term development of vascular hypertrophy will result in

increased peripheral resistance. Contributing factors include: ÝRAAS, ÝSNS, Genetic-derived changes in the cell membranes, and endothelial-made factors

Defining HT - There is more than 1 way to make a turkey sandwich. What I

mean is, there are multiple sets of guidelines - JNC8: In 2014, the Eight Joint National Commission chose to

update the BP thresholds for HT dx by relaxing the guidelines - ACC/AHA: In 2017, to account for new RCT data (SPRINT

trial) and address controversies of not treating enough high-risk patients, the American College of Cardiology (ACC) and American Heart Association (AHA) submitted new guidelines. For the purpose of testing, we will go by ACC/AHA

- With the goal range (<120/80) and dx range (>130/80) lowered, the Incidence of HT in the US grew from 23% to 46%

- Despite the increased incidence, the writing a pharmacological prescriptions did not grow as proportional to dx, rather, lifestyle modifications and home BP monitoring were promoted for heathy living

Criteria for HT Tx - Treatment with BP medications is guided by BP, CVD risk, and comorbid conditions (DM/CKD) - SPRINT (Systolic BP Intervention Trial): RCT evaluating the outcomes of Intensive vs Standard Tx for HT pts

o Intensive Tx: Goal SBP < 120mmHg. Standard Tx: Goal SBP < 140mmHg o Inc/Excl: Excluded DM, Stroke, and Severe Proteinuria. Included a buncha 50yo with 130/80 + 1 Rf o Primary Outcome: CVD Composite – The first occurrence of MI, Non-

MI acute coronary syndrome, Stroke, Acute HF, CVD Death o Result: 54% decrease in the composite score for the intensive group.

Hazard ratio favors the intensive HT tx protocol. NNT = 61 o Frailty and Gait Speed: Intensive group did better globally, Standard tx

had far more AE o Caveats and Conspiracy Theories: White coat syndrome, biased pt pop,

invalid patient pop, early trial termination - ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood

Pressure): RCT evaluating the outcomes of intensive vs standard tx for DM pts with HT + CVD or High-risk o Intensive Tx: Goal SBP < 120mmHg. Standard Tx: Goal SBP < 140mmHg o Result: There was NO benefit in the primary endpoint (MI, stroke, death). The reduction of stroke risk

was not sustained through follow-up, and in fact, there was more AE in the intensive group. § à ADA still recommends goal < 140/90, with tighter control (<130/90) for those at risk

- Come test day… o Goal: < 130/80 o Threshold for Treatment: 140/90

JNC8

ACC/AHA