Hypertension

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1.2 - Risk Startification

Ved Ikhwan Rosman

D2 Receptor Antagonists

Ved Ellen Murphy

MedChem of Antipsychotics

Ved Qabas Al-Jobori

1.3 Pharmacodynamics

Ved Shay Weimers

HF/CA/IHD/HL/VT/PAD

Peripheral Artery Disease

Cilostazol (pletal)

Improves exercise tolerance in intermittent claudication "IC" is cramping, pain, and aching of legs that typically comes with walking and subsides at rest

Contraindicated

HF decreased survival rates

phosphodiesterase inhibitor which suppress platelet aggregation and vasodilates

Clopidogrel (Plavix)

Prodrug

requires activation by CYP2C19 to activate drug

Effects platelets for entire lifespan 7-10 days D/C 5 days before surgery

To pt: prevents your platelets from sticking together to form a clot

blocks P2Y12 component of ADP receptors on platelets preventing activation of GPIIb/IIIa receptor complex reducing platelet aggregation

Chest Guidelines

For PAD refractory to exercise therapy and smoking cessation add cilostozal

For symptomatic PAD use ASA or clopidogrel for 2ndary prevention ^ NO DUAL therapy

Aspirin is 1st line for asymptomatic PAD

moderatlely reduces cardiovascular events if taken over 10 years

NonPharm TX

exercise therapy

smoking cessation

Goals of Tx

reduce cardiovascular complications and death

improve quality of life

control comorbid conditions

improving walking distance, duration, pain

DM

cigarette smoking

Age >40

Risk of CVD morbidity and mortality

Progressive narrowing of arteries due to atherosclerosis

Hyperlipidemia

Bile Sequestrants

Poorly tolerated (Dead Drugs)

Lower TC, LDL, TG, and increase HDL

bind w/cholesterol in intestine

NOT metabolized by liver

promoting an increase in bile acid excretion they enhance conversion of cholesterol to bile acids by the liver and increase uptake of LDL

Ezetimibe (Zetia)

Better effects when used in combo with statins

recent data showed improved outcomes w/simvastatin for 2ndary prevention (IMPROVE-IT Trial)

Effects on cholesterol

reduces triglycerides (5-10%)

Increases HDL (1-4%) modest

Reduces LDL (19%)

works at cells in the brush border of the small intestine to inhibit dietary cholesterol absorption also inhibits resorption of cholesterol secreted into bile

Niacin

Dosing is important: 1-3 grams

titrate slowly

avoid hot shower immediately after dose

take 30 min after aspirin 325mg w/snack

before bed

LA - hepatotoxicity

Immediate release: flushing

Long-acting Slo-niacin

Extended Release Niaspan

Immediate Release Niacor

Effects on Lipids

Increase HDL (modest)

Reduces Trigs (28-35%)

Reduces LDL (14-17%)

unknown works in liver and adipose tissue to inhibit synthesis of triglycerides reducing VLDL and subsequently LDL

Fibrates

Administration

With food Antara, lofibra

30 min prior to meals Gemfibrozil

nausea, diarrhea, Gi upset

Myopathy

Hepatotoxicity

Fenofibrate (tricor, antara, lofibra, triglide, lipidil)

Genfibrozil (lopid)

Slightly elevate HDL

Slightly reduce LDL

Reduce triglycerides (40-50%)

binds PPAR alpha receptors in liver accelerating clearance of triglycerides

Effects on lipids

Elevate HDL 5-17% (modest elevation)

Lower triglycerides 10-40% Atorvastatin and rosuvastatin

Lower LDL by >50% HIGH INTENSITY STATINS

Lower LDL by 30-50% MODERATE INTENSITY STATINS

drug interactions

rhabdomyolysis

Prevent Rhabdo educate pts to hold statin for a few days if recieving interacting short term drug therapy

SEVERE INTERACTIONS: clarithroycin, fluconazole, gemfibrozil, grapefruit, protease inhibitors, strong CYP 3A4 inhibs

may occur due to drug interactions or high dose statins

STOP STATIN

swelling of muscles, dark urine, fatigue, decreased urine output

breakdown of muscle tissue leading to accumulation of muscle fibers in blood

hepatoxicity

Diabetes (increase in A1C/BG)

cognitive dysfunction

myalgias

Plan: (if not rhabdomyolysis) try 6 week statin free Atorvastatin 10mg or Rosuvastatin 5mg dose every other day Coenzyme Q10?

Check: Vitamin D, TSH, CK

Assess: Is it severe? limiting everyday activity? in a large muscle?

arthralgia

persistent elevation of LFTs

acute liver disease

pregnancy X

Reduce C reactice protein

Pleiotroic effects

anticoagulant effects

inhibit platelet aggregation

improve endothelial function

reduce inflammation or coronary plaque

explained to pt: causes body to produce less cholesterol

inhibit HMG-CoA reductase, a rate limiting enzyme in cholesterol synthesis

As needed

repeat fasting lipid panel

repeat ALT

4-12 weeks

fasting lipid panel

Baseline

CK (if indicated)

ALT

Fasting Lipid panel

Benefits 4 groups

No ASCVD or diabetes, LDL 70-189, 10yr risk >7.5%

Diabetes, age 40-75, LDL 70-189

Primary LDL >190

Clinical ASCVD

HEART FAILURE

Classification

HFpEF (preserved EF)

use of beta blockers, ACEi, and ARBs reasonable in HTN

diuretics should be used for fluid overload

control BP based on current practice

Stage C HFrEF (reduced LVEF)

digoxin

Toxicity blue/green auras, NVD, confusion, palpitation

electrolyte abnormalities may cause toxicity

super narrow therapeutic index

MOA: increases myocardial contractility

Hydralazine and isosorbide dinitrate

can be used for pts with current or past sx who cannot tolerate ACE or ARB

rec'd for Black pts III-IV

Aldosterone receptor antagonists

rec'd to reduce morbidity and mortality followind acute MI

LVEF <40% or less or hx of DM

rec'd for LVEF <35%

potassium <5

creatinine <2.5 men, <2 women

Challenges: fatigue, edema, bradycardia, hypotension

Use of 1 of the 3 beta blockers proven to reduce mortality

Metorpolol succinate, carvedilol, bisoprolol

ARBS

Candesartan, Losartan, Valsartan preferred

can add ARB to ACE only if persistent sx and aldosterone antagonist indicated, but not tolerated

recommended for those w/ sx who could not tolerate ACEi

use caution in renal impairment and low BP

Recheck BMP in 1-2 weeks

recommended w/ current or prior sx to reduce morbidity and mortality

start low and increase

all equal in reducing death and hospitalizations

Diuretics

Adjust based on pt's weight

loop

may add metolazone to loop in renal impairment

supplement K+ if needed

eventually may need bumatanide d/t tolerance

1st line: furosemide

Stage B

Acei AND beta blocker in anyone with reduced EF to prevent sx HF (even w/o hx of MI)

Statin if hx of ACS or MI and reduced EF

Beta blocker if hx of ACS or MI

ACEi if hx ACS or MI and reduced EF

STAGE A

Control other contributors to HF

cardiotoxic meds

smoking

diabetes

obesity

Control HTN and lipids

Info

ACCF/AHA 2013 Guideline for management of HF

Tx based on EF

HFpEF EF >50% (diastolic heart failure)

HFrEF EF <40% (systolic heart failure)

Ejection Fraction (LVEF): measurement of how much blood is pumped out of the heart with each contraction

Mechanism

Activation of RAAS and SNS

Compensation Tachycardia, LV remodeling, vasoconstriction

Myocradial injury reduced contractility

Risk factors

Atherosclerotic disease (*MI*)

Metabolic Syndrome

50% mortality in 5yrs of dx (improvement!)

incidence increases with age

5.1 million ppl in US w/hf

Most common cause is impaired left ventricular function

Cardinal SX: dyspnea, fatigue, fluid retention

Complex clinical syndrome resulting from any structural or functional impairment of ventricular filling or ejection of blood

Venous Thromboembolism

Enoxaparin (lovenox)

Spinal or epidural hematomas

observe for neuro impairment

Risk of paralysis

Renal dose adjustments

Risk for HIT

Prefilled syringes for at home self admin

Longer half life than UF Heparin

Fixed dosing does not require aPTT monitoring caution in obesity

rapidly inactivate factor Xa

Unfractionated heparin

Antidote: Protamine

longer duration of action in renal impairment

Freq dose adjustment based on aPTT

Heparin Induced Thrombocytopenia (HIT)

D/C heparin and do NOT rechallenge

Development of antibodies against heparin-plated protein

higher thrombosis risk

immune mediated disorder reduction in platelets

Monitor

platelets

aPTT

MI

Disseminated intravascular coag

surgical prophylaxis

Evolving stroke

DVT/PE

do NOT use heparin for lock flush for parenteral anticoag

VTE and to flush lines

Large polysaccharide structure - unable to cross membranes IV or SubQ Does not cross placenta or into breast milk

rapidly acting anticoag, helps antithrombin inactivate clotting factors (Xa and thrombin)

rapid onset of action

Dabigatran (Pradaxa)

Store in original container do not place in pill box expires in 4mo after opening unstable when exposed to moisture

GI upset

consider use w/PPI

Take with food

Risk of bleeding

directly inhibits free thrombin and thrombin bound to clots

Factor XA inhibitors

INdications

DVT/PE tx

DVT/PR prophylaxis

Nonvalvular atrial fib

Does not require INR monitoring

ApiXAban (Eliquis)

RivaroXAban (Xarelto)

selectively inhibits factor Xa inhibiting the production of thrombin

Warfarin (Coumadin)

Safety

long term use: risk of osteoporosis, alopecia

Bleed risk

Skin necrosis

usually within first several days check for black skin on toes

Pregnancy Xd

Dosing

INR less than goal

assess for clots

increase dose by 5-20%

INR greater than goal

assess for bleeding

reduce by 5-20%

>4 consider holding a dose

start 5mg/day 2.5 for elderly, Asian, hepatic impairment, poor nutrition

Drug-Drug interactions

Many herbals increase bleed risk ginseng, ginger, garlic

Avoid NSAIDs, increase bleeding

metabolized by CYP450 2C9

more freq INR checks with dose changes

MANY INTERACTIONS statins, fluconazole, FQs, SSRIs, levothyroxine

Vit K can reduce effect of warfarin

smoking may reduce INR/ increase clot risk

alcohol may increase bleeding risk

kale, spinach, broccoli, collard greens, brussel sprouts, fried food

assess diet each visit

therapeutic levels measured by INR

Testing frequency depends on stability of INR

low INR = clot risk

elevated INR = bleeding risk

Goal varies

could be increased if pt had clot while on wafarin/APLS

mechanical mitral valve 2.5-3.5

General 2-3

INR about 1 for pts not on warfarin

No effect on clotting factors that are already circulating

also inhibits Protein C and Protein S: body's natural anticoags = bridging

takes longer for the body to form clots

Vit K "antagonist" which inhibits vitamin k dependent clotting factors II, VII, IX, X

Risk Factors

Meds: estrogen, SERMSs, Chemo

pregnancy

malignancy

disorders of hypercoaguability

post surgery

immobility

clot in venous circulation resulting in DVT or PE

Angina (Ischemic Heart Disease)

TX

Aspirin and statins in angina

reduction in LDL cholesterol levels play a signiificant role in decreasing the formation of athersclerotic plaque

preventative

aspirin decreases platelet aggregation to prevent cycle of vasoconstriction and platelet buildup

ACEis reduce the secretion of aldosterone

reducing extracellular fluid volume and preload

decreased sodium and water retention

decreased peripheral vascular resistance decreased afterload

Subtopic

act on RAAS system

Calcium Channel Blockers in angina

CCBs may cause coronary vasodilation

atherosclerotic vessels do not dilate

cause arterial smooth muscle relaxation leads to peripheral vasodilation and decreased preload

Beta Blockers

decrease force of myocardial contractility and decrease HR and conduction velocity

1st line

Nitrates

ADRs: HA, Bradycardia, orthostatic, hypotension

Pregnancy C

Transdermal patches, allergy to adhesives may limit use

Contraindicated: hypersens

Nitrate prep - prophylaxis

Isosorbide dinitrate (Isordil)

to maintain nitrate free period

TID: 8am 1pm, 6pm

BID: 8am, 1pm

sustained release 1-2 times daily

immediate release dosed 2-3 times daily

Isosorbide mononitrate (Imdur)

extended release dosed once daily

immediate release dosed twice daily 7 hours apart

TAPER DOWN! DO NOT DC ABRUPTLY

NTG patch

apply in AM and leave on for 12-24 hours

apply once daily to hairless area, rotate

NTG ointment

cover with plastic

best to rotate sites

Apply to skin of chest, back , abdomen, or thigh

Nitrate preparations - acute

Take at first signs of chest pain, may repeat after 5 minutes for a total of 3 doses If CP not relieved 5 min after 1st dose, call 911

Translingual spray

DO NOT INHALE

spray onto oral mucosa

0.4mg sublingual tablets

educate pts: SL only! do not swallow

store in original bottle

used for immediate relief or prophylaxis

Nitrate free period to prevent tolerance

Some dilation of coronary arteries ATHEROSCLEROTIC VESSELS DO NOT DILATE

Higher doses dilate arterial vessels DECREASED VASCULAR RESISTANCE (afterload)

low doses of NTG dilate veins decreasing venous return to heart DECREASES PRELOAD

coronary vasodilators

Statins

ACEi

Calcium channel blockers

beta-blockers

nitrates

Aspirin

lifestyle changes: smoking cessation

Unstable

SX occur at rest or as worsening sx of stable angina

Sx occur as result of severe CAD with

transient coronary thombi or emboli

vasospasm

platelet aggregation

Medical emergency

Chronic Stable

TX goal

reduce risk of MI and death

reduce intensity and frequency of attacks

partial restriction of arteries results in angina

underlying cause is CAD (plaque in arterial wall)

triggered by physical activity, stress, or large meal

Oxygen demand

afterload arterial pressure that the left ventricle must overcome in order to contract

preload amount of tension from ventricular filling

myocardial contractility

heart rate

Cardiac Arrest

Vasopressin

vasoconstricts w/o effects on HR and contractility

increases water permeability at the renal tubule resulting in reduced urinary output of water

ADH analog

Epinephrine

Also used in anaphylaxis

increases blood pressure to perfuse the heart and brain

Alpha1 is majority of action in cardiac arrest

Agonizes alpha and beta receptors leading to vasoconstriction, increasing inotropy and increased chronotropy

Sympathomimetic

Tx

Electrical Defib

ACLS

CPR

main tx is nonpharm

HTN

Autonomic Nervous System

Beta actvity

Beta 2 receptor stimulation

bronchial dilation

Beta 1 receptor stimulation

increased heart rate/contractility

uterine relaxation

bronchial relaxation

vasodilation of arterioles supplying skeletal muscle

cardiac acceleration and increased contractility

Alpha activity

Alpha 2 receptor stimulation:

Vasodilation

Alpha 1 receptor stimulation:

Vasoconstriction

relaxation of gut

Pupil dilation

vasconstriction of arterioles (=HTN)

Parasympathetic

Acetylcholine

SLUDGE

Emesis

Gastric Distress

Digestion

Urination

Lacrimation

Salivation

Rest and digest

Sympathetic

AntiSLUDGE

No emesis

No gastric distress

No digestion

No urination

No lacrimation

No Salivation

dopamine

fight or flight

Renin-Angiotensin-Aldosterone System

Angiotensin II

activates Aldosterone and ADH

lead to Sodium& water retention, vasoconstrictor

vasoconstrictor

Guidelines (All differ)

JNC 8 (not endorsed)

Recommendation 8

18yo+ with CKD Regardless of race or diabetes status

ACEi or ARBs to improve kidney outcomes

Recommendation 7

Black +those w/diabetes

thiazide or calcium channel blocker

Recommendation 6

NonBlacks <60 including diabetes

initial tx: thiazide diuretic, calcium channel blocker, ACEi or ARBs

Recommendation 5

18yo+ with DIABETES treat & target <140/90

Recommendation 4

Any age with ALBUMINURIA (>30mg albumin) at any GFR

18-70 with GFR <60

18yo+ with CKD, target <140/90

Recommendation 3

<60yo, initiate pharm to lower SBP >140 mmHg goal SBP <140

Recommendation 2

18-29yo: expert opinion

30-59yo: strong evidence

<60yo initiate drug tx to target DBP of <90

Recommendation 1

If a lower BP is achieved without adverse effects, no modification necessary

>60yo initiate pharm to treat and target <150/90

Main Objective to reach and maintain a goal BP

DO NOT USE ACEi and ARB together

If goal is not reached w/2 agents, titrate a 3rd med

Continue to assess BP and adjust tx until goal BP is achieved

If goal BP not reach w/n 1 mo, consider increasing dose or adding 2nd agent

ASH/ISH

Heart Failure (w/ or w/o HTN)

(ACEi or ARB) + beta blocker + diuretic +spironolactone

StrokeHx

CAD

Beta blocker + ACEi or ARB

CKD

ACE or ARB

Diabetes

ARB or ACE (acceptable to start with CCB/thiazide in Black pts)

Essential HTN first line

Non Black >60: CCB or thiazide

Non Black <60: ACEi or ARB

Black: CCB or Thiazide diuretic

Non Pharm Therapy

Smoking cessation

Reduce alcohol

2 drinks M, 1 drink F

2-4 mmHg

Exercise

30 minutes/day

4-9 mmHg

Salt Reduction

DASH diet

8-14mmHg

Weight loss

For every 10kg lost

5-20 mmHg SBP

ANS: Peripheral Vasodilators

minoxidil

hirtsuism

fluid retention

use w/ beta blocker

hydralazine

drug-induced lupus

tachycardia

use w/ beta blocker

Not first line

Directly relax smooth muscles causing vasodilation

ANS: Centrally Acting Alpha 2 Agonists

Rebound HTN - taper dose down

methyldopa (Aldomet)

preferred agent in pregnancy

guanfacine (Tenex)

clonidine (Catapress)

stimulate alpha 2 receptors decreasing cardiac output, peripheral resistance, and sympathetic outflow (reduced HR)

ANS: Alpha1 blockers

dry mouth

drowsiness

palpitation

First does phenomenon

caution in elderly

start at low doses

take first dose at night/in bed

syncope

ANS: Beta Blockers

Monitor heart rate

DO NOT abruptly discontinue

ischemic events

Rebound tachycardia/HTN

fatigue

sexual dysfunction

Contraindicted

Severe bronchospastic disease

AV node dysfunction

acebutolol (Sectral)

pindolol (Visken)

nebivolol (Bystolic)

labetalol (Trandate)

propranolol (Inderal)

carvedilol (Coreg)

bisoprolol (Zebeta)

atenolol (Tenormin)

metoprolol

tartrate (Lopressor)

dosed twice daily

succinate (Toprol XL)

dosed once daily

Indicated

Arrhythmias

Migraine prophylaxis

Angina

Post MI

HF

NOT first line for hypertension

Negative inotropes and chronotropes

MOA:

selectively or non selectively inhibit beta1 receptors

Calcium Channel Blockers

2 Classes of CCBs

NON Dihydropyridines (Non-DHP)

CAUTION: if concomitant use with Beta-blocker and in HF w/reduced ejection fracture

Benefit in atrial fibrillation and stable angina

bradycardia

Sick sinus syndrome

Heart block

MOA: potent vasodilator of coronary vessels increasing blood flow and reducing heart rate by reducing AV node conduction

diltiazem (Cardizem)

verapamil (Calan)

Dihydropyridines (DHP)

Good first line option for HTN

benefit in Black pts

Side effects

flushing

palpitations

peripheral edema

constipation

MOA: relax smooth muslce vasodilating arterial walls which lowers total peripheral resistance and increases blood flow to the heart muscle

nifedipine (Procardia)

felodipine (Plendil)

amlodipine (Norvasc)

RENIN-ANGIOTENSIN-ALDOSTERONE: Angiotensin II receptor blockers

hypotension

Contraindicated in pregnancy

Alternative to patients who cannot tolerate ACEi

less incidence of angioedema and cough

ACE not inhibited = normal breakdown of bradykinin

Valsartan (Diovan)

Temlisartan (Micardis)

Olmesartan (Benicar)

Irbesartan (Avapro)

Candesartan (Atacand)

Losartan (Cozaar)

angiotensin II receptor antagonist inhibting the RAAS system

Reduces peripheral resistance

RENIN-ANGIOTENSIN-ALDOSTERONE ACE inhibitors

First Line if....

Post MI/Stroke

Diabetes - prevent nephropathy

Heart Failure

CKD - reduce progression

Proteinuria

Up to 30% bump in Scr normal

50% stop ACE inhibitor

> 30% reduce dose

becomes new baseline

Less effective in black patients

renal function deterioration

cough and angioedema

likely d/t bradykinin accumulation

Contraindications

Bilateral renal artery stenosis

Angioedema due to ACEi

Pregnancy

Not a great choice for women of childbearing age

Trandolapril (Mavik)

Ramipril (Altace)

Quinapril (Accupril)

Moexipril (Univasc)

Fosinopril (Monopril)

Benazepril (Lotensin)

Captopril (Capoten)

Enalapril (Vasotec)

Lisinopril (Zestril)

competitive inhibitor of Angiotensin Converting Enzyme (ACE) preventing the conversion of angiotensin I to angiotensin II

causes increase in plasma renin activity and reduced aldosterone secretion

DIURETICS: Potassium Sparing

WARNINGs

anuria

hyperkalemia

Uses

HYPERKALEMIA

CAUTION using w/ACE-I and ARBs

use in combo w/another diuretic (commonly thiazide)

mostly used in edema/HF sx management

Not very potent in BP reduction/diuresis

Triamterene (Dyrenium)/ (Dyazide w/HCTZ)

Amiloride (Midamor)

Eplerenone (Inspra)

Spironolactone (Aldactone)

WARNING: gynecomastia

STOP if any sign of

aldosterone receptor blocker

Magnesium, calcium, and hydrogen excretion

Potassium retention

Not as potent as other diuretics

decreases function of the Na/K ATPase

block distal sodium channels in distal convulted tubule (DCT) inhibiting sodium resorption from the lumen.

DIURETICS: Loop

hyperglycemia

HA

dizziness

Diuretic resistance

Ototoxicity

Electrolyte imbalance

BUN

Renal function

VERY potent diuretics

may need K+ supplements

NOT generally used for BP

Agents

Torsemide (Demadex)

Ethacrynic Acid (Edecrine)

Does not have sulfa group

Bumetanide (Bumex)

Furosemide (Lasix)

interferes with cholride-binding cotransport system causing increased excretion of water, sodium, chloride, potassium, magnesium, and calcium

Inhibits resorption of sodium and chloride in ascending loop of Henle and distal renal tubules

DIURETICS: Thiazides

Warnings

MAY INCREASE CALCIUM

electrolyte disturbances

gout

Sulfa allergy

Side Effects

skin rash

orthostasis

dizzness

urinary frequency

Photosensitivity

Monitoring

renal function

electrolytes

BP

Administer in morning

AGENTS

Metolazone (Zaroxolyn)

EFFECTIVE even if eGFR <30ml/miin

Indapamide (Lozol)

Chlorthalidone (Microzide)

Hydrochlorothiazide (HCTZ)

ineffective if eGFR <30ml/min

MOA

inhibits sodium resorption in distal tubule leading to increased excretion of sodium and water, potassium and hydrogen ions (reducing blood volume)

reduces vascular resistance