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Group I PAH
- Cause: long term vasoconstriction of the pulmonary arteries; can be secondary to cirrhosis, hepatic portal hypertension, certain anemias; drug-induced by cocaine or fen-phen
- Presentation: vessels become stiff and think, loss of endothelium, smooth muscle proliferates, and fibrosis
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Fenfluramine-Phenteremine
- Sympathomimetic amines designed to induce serotonin release
- ADEs: Cardiac valve fibrosis and pulmonary hypertension, when Fen and Phen are taken together
- Wasn't tested in combination before selling
- MoA: targets 5-HT2B
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BMPR2
- Bone morphogenic receptor protein type II = serine/threonine kinase
- Key role in cellular differentiation/maturation
- Gene that encodes this protein also encodes 5-HT2B
- Disruption of the gene produces cellular overgrowth particularly in small arteries
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Pulmonary Hypertension Definition
- Normal PAP = 12-16 mmHg
- PH = >25 upon exercise
- Terminology:
- Idiopathic Pulmonary Arterial Hypertension (IPAH)
- Familial Pulmonary Arterial Hypertension (FPAH)
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Group II PVH (Pulmonary Venous Hypertension)
- Causes: left heart insufficiency leads to volume back-up in pulm vein; decreased PA emptying and thus pressure rises;
- Presentation: pooling of blood in lung, edema, effusions
- What used to be "Secondary Pulmonary Hypertension"
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Group III Hypoxic Pulmonary Vasoconstriction
- Causes: vasoconstriction in the face of hypoxia; Acute Mountain Sickness = low O2 lvls in air, so lung thinks you're not using the whole lung and responds by lowering blood flow to lungs.
- V/Q matching
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Group IV Thrombotic or Embolic Disease
- Blockage or narrowing of vessels, often occult
- Similar to Group 1 in terms of presentation (stiff vessels, fibrosis)
- i.e. Airplane employees
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Group V Miscellaneous
yep, way to go Venice...
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Sleep Apnea
- Usually only mild hypertension
- Pickwickian syndrome: hypoxia, hypercapnia (too much CO2), acidosis, obstruction
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Tx Group II PVH
- Treat the cause = congestive heart failure
- Diuretics, β-blockers, ACE inhibitors, Valve replacement
- Conventional: lifestyle, digoxin, oxygen, diuretics
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Calcium Channel Blockers
- NOT FOR PULM HYPERTENSION
- Goal: to reduce smooth muscle contraction, but it is not specific enough
- Ends up slowing down delivery of oxygenated blood to the rest of the body, and these patients are already hypoxic from PH!
- Only 5% of IPAH is vasoreactive
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Epoprostenol
- Synthetic prostacyclin
- PGI2 = most effective Tx for PAH
- Continuous infusion via in-dwelling central venous catheter
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Treprostinil
- IV or SC
- Synthetic prostaglandin
- Tx PAH
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Remodulin
- Synthetic prostaglandin
- Tx PAH
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Iloprost
- Synthetic prostaglandin
- MoA: systemic and pulmonary vasocontrictor
- Specificity achieved via Nebulizer delivery
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Endothelin Receptor Antagonists
- Bosentan- acts at both ETA and ETB sites
- Ambrisentan- specific for ETA (good because ETB antagonism on endothelial cells can inhibit prostacyclins and NO-induced relaxation)
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Phosphodiesterase V Inhibitors
- Sildenafil
- Tadalafil- longer half life
- Unknown specificity and effectiveness
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Vasoactive Intestinal Peptide
- Binds to GPCRs VPAC1 (lung) & 2 (heart)
- Potential vasodilator, but also potential positive chronotrope&inotrope
- Tx PAH?
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Serotonin antagonism
- PRX-08066 specific 5HT2B receptor antagonist
- Opposes hypoxic vasoconstriction
- Phase II trials
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Endothelial Progenitor Cells
Under investigation for PAH, which has a loss of endothelial cells
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Persistent Pulmonary Hypertension of Newborns
- Not based on remodeling;
- When neonates don't transition from in utero-style breathing (high PVR w/ hypoxic constriction) to outdoors breathing (low PVR w/ more blood flow)
- = high PVR and PAP, low Qp, shunting continues
- Causes: Zoloft effect (mothers taking Zoloft), Capillary dysplasia, Maternal diabetes; meconium aspiration; lung hypoplasia (lung doesn't fully inflate)
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Tx PPHN
- Oxygen
- Correct acidosis w/ bicarbonate, THAM
- Dilate the lung w/ dopamine
- High Frequency Oscillating Ventilation
- Extracorporal Membrane Oxygenation (not a good option, hooking up the lil one to machina)
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iNO
- Tx PPHN
- Beware rebound hypertension, takes 3 days to wean off
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NONOates
- Liquid based, but arterial oxygenation does not get better since V/Q gets mismatched
- Reduces PAP and PVR
- iNO preferred?
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Shock
- Inadequate perfusion of vital capillary beds
- Key elements: hypoperfusion --> cellular injury --> systemic damage; Reperfusion injury; Infammatory response to cellular injury
- Lactic acid accumulation: anaerobic metabolism
- Metabolic acidosis: vasoconstriction
- Intracellular lysosomes released: efflux of potassium, but influx of sodium/water
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Four Stages of Shock
- Initial: shift to anaerobic metabolism
- Compensatory
- Progressive: failure to compensate leads to more injury
- Refractory: organ shock occurs, and Tx cannot be applied
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Hypovolemic Shock
- Most common form
- Significant loss in preload
- Attempts to correct BP end up decreasing organ perfusion (i.e. vasoconstriction + RAS)
- Classes I-IV based on blood pressure, % blood loss, pulse, respiratory rate, and urine output
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Cardiogenic Shock
- Primary pump failure, but no always MI
- Causes include: loss of myocardium, reduced contractility, filling anomalies, acute valvular failure, dysrhythmias
- Peripheral vasoconstriction
- Oliguria
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Distributive Shock
- High cardiac output
- Systemic hypotension
- Decreased vascular resistance
- Perfusion/metabolic demand mismatch
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Neurogenic Shock
- Subset of Distributive Shock
- Loss of autonomic control due to spinal injury: hypotension, bradycardia, warm dry skin
- Euvolemic with reduced peripheral tone
- Tx: Atropine
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Anaphylaxis
- Subset of Distributive shock
- Respiratory obstructive processes can result in myocardial depression
- Usually low central venous pressure
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Four main things to correct in shock:
- 1. Preload: crystalloid vs colloid fluids
- 2. Contractility: Ca2+/glucagon if β-blocked
- 3. Afterload:
- 4. Oxygen delivery
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Dopamine
- Catecholamine Tx Contractility
- Low dose improves renal fxn
- Medium dose increases cardiac contractility & HR
- High dose increases systemic blood pressure
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Dobutamine
- Catecholamine Tx Contractility-help shock
- Minimal chronotropy
- Increased inotropy
- Systemic vasodilator
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Norepinephrine
- Positive chronotropic
- Positive inotropic
- Systemic vasoconstrictor
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Levosimendan
- Inodilator
- MoA: binds to troponin C (but Ca2+ dependent), thus sensitizing the myocyte to calcium; opens ATP-K channels in smooth muscle
- ADE: renal impairment
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Arginine Vasopressin
- Normally released in posterior pituitary in response to severe hypotension
- Septic patients have low lvls of AVP
- MoA: blocks ATP-K channel, which restores responsiveness to catecholamines in the septic patient
- NOT FOR CARDIOGENIC
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Reduction in Afterload
- Improves cardiac function, but can cause hypotension
- Nitroprusside/nitroglycerin IV
- ACEIs "-prils"
- Mechanical aids
- NOT IN AORTIC STENOSIS
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