Dr.Zulcaif Ahmad 1

Contents:•Pulmonary hypertension.

•Drug induced pulmonary hypertension •Pathophysiology of drug induced pulmonary hypertension

•Toxic Dose•Diagnosis

•Treatment and management

Dr.Zulcaif Ahmad 2

Drug induces lung disorderPulmonary hypertension:Pulmonary hypertension is a type of pulmonary vascular disease.What happens in pulmonary hypertension?Narrowing of the blood vessels.Stiffer and thicker blood vesselBlood flow from heart to lung is decreased and not enough oxygen is

supplied that leads to hypoxia pulmonary vasoconstriction.Blood flows from right ventricular to left ventricular happens without

going to lungs can leads to blood clots in the vessel embolism can occur beacuse also the workload to right heart increase that may lead to hypertrophy of the muscle.

Dr.Zulcaif Ahmad 3

Symptoms of pulmonary hypertension :Dyspnea (Shortness of breath)Fatigue (tirednesslSyncope (loss of consciousness )Cyanosis (bluish colour of skin and lips)Angle and leg swelling Hemoptysis (blood in sputam)Chest pain

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Drugs:Drugs induced pulmonary hypertension :Appetite suppressants: aminorex,

fenfluramine,dexfenfluramine .Cocaine, amphetamine ProtamineRadiation and busuflun

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Mechanism of drug inducedpulmonary hypertension :

Drug like appetite suppressants that are used in the treatment of obesity. These drugs inhibit release answer re uptake of serotonin transporter and increased levels of serotonin cause vasoconstriction.

These drug also inhibit K+channel and activate Ca+ that cause vasoconstriction. Relaxing factor NO and PGI2 that cause vasodilation in the smooth muscle of heart it’s activity is reduce in pulmonary hypertension and contracting factor thromboxane and endothelian-1 which is present in smooth muscle that cause vasoconstriction in the smooth muscle these factors are enhance in pulmonary hypertensi.on

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Protamine are used in the reverse the effect of heparin administration which in turn increase thromboxane activity which involves in vasoconstriction as well as in proaggregatory.

Radiation which are given to cancer patients the endothelial cells in the smooth muscle are sensitive to radiation .when the patient expose to radiation they are ionising in the lung smooth muscle that in result cause lung injury.

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Dose:Fenfluramine toxic dose is 28-80mg/kgCocaine >1g/kgProtamine injection Protamine sulfate injection should be administered at

a rate of 5 mg per minute, not to exceed 50 mg in any ten-minute period.protamine has anticoagulant activity so it is not advisable to administer more than 100 mg of protamine sulfate over a two-hour period of time.

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Diagnosis Diagnosis based upon pt. symptoms: Patients with mild PAH may have only minimal symptoms with exertion,

whilst those with more advanced disease may experience dyspnea at rest, exertional lightheadedness, syncope or chest pain, which are indicative of impaired right ventricular performance.

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1-Patients with pulmonary hypertension in whom there is no limitation of usual physical activity. Ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain, or syncope.

2-Patients with pulmonary hypertension who have mild limitation of usual physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope.

3-Patients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope.

4-Patients with pulmonary hypertension who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnoea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity.

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Diagnosis from lab. Values:

Sampling of blood to measure oxygen saturation from the vena cava and right heart chambers could lead to the diagnosis of an intracardiac left-to-right shunt by demonstrating the presence and location of a ‘step-up’.

PAH requires documentation of a mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg with exercise with a normal pulmonary artery occlusion pressure.

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ECG:ECG is used to measure the rate of heart beat and tell whether you have any

condition of the heart.in case of PAH, ECG will show problem with right side of heart.

Chest X-Ray:X-Ray will show if the right side of heart or pulmonary arteries are bigger

than usual.

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Management and TreatmentDiuretics:

Loop diuretics and potassium-sparing aldosterone inhibitors can be used to control signs and symptoms of volume overload from right ventricular failure, such as hepatic congestion, ascites and lower extremity oedema. Diuretics should be used cautiously to avoid precipitous reductions in preload.

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Supplemental oxygen:

Hypoxia is a potent pulmonary vasoconstrictor, leading to increased pulmonary arterial pressure both acutely and chronically. supplemental oxygen can improve haemodynamics by decreasing the mean pulmonary artery pressure and increasing the cardiac index, thus decreasing the calculated pulmonary vascular resistance.The use of supplemental oxygen to maintain arterial oxygen saturation above 90% both at rest and with exercise is recommended.

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Cardiac glycosides:The role of cardiac glycosides (e.g. digoxin) in PAH is unclear.Acute increase in cardiac output.

Anticoagulation:Patients with PAH are likely at higher risk for thromboembolic complications because of their decreased activity level, slower blood blow, dilated right-sided heart chambers, and for some, the presence of an implanted central catheter for administering PAH medications. Anticoagulation may also reduce the propensity for in situ microvascular thrombosis in the distal pulmonary arterial circulation that is commonly observed pathologically in PAH.

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Calcium channel blockers:

Treatment of PAH with calcium channel blockers (CCBs) is reserved for patients who demonstrate evidence of acute vasoreactivity, currently defined as a reduction in mean pulmonary artery pressure ≥10 mmHg to a level that is ≤40 mmHg, with a normal cardiac output during testing with an acute, short-acting vasodilator such as inhaled nitric oxide or iloprost or I/v epoprostenol or adenosine.

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Prostanoids:

Epoprostenol:

Most potent and efficacious treatment for PAH.Only medication for PAH that has shown a survival benefit in a

randomized clinical trial.

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Acute effects:potent vasodilator,inotropic actions,

whilst the long-term effectsantithrombotic propertieseffects on vascular remodeling.

Chronic effects:lowers pulmonary vascular resistance to a level beyond that achieved during

acute vasodilator testing.

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Endothelin receptor antagonists:ET-1, the endothelin that is thought to play the most prominent role in PAH, exerts its actions via two receptor subtypes: ETA, which is located on vascular smooth muscles cells, and ETB, which is found on both vascular smooth muscle cells and vascular endothelium. Activation of ETA by ET-1 leads to potent vasoconstriction due to an increase in cytosolic calcium levels via influx of extracellular calcium and release of intracellular calcium stores: The actions of ETB are more complicated. Like ETA, activation of ETB on vascular smooth muscles cells leads to vasoconstriction.

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Blockade of both ETA and ETB is necessary to achieve maximal vasodilation in the pulmonary hypertensive state.Studies suggest a protective role of ETB in pulmonary hypertension by producing nitric oxide and prostacyclin and clearing circulating ET-1. Therefore, the overall net effect of ETB in regulating pulmonary vasomotor tone is unclear. There may be theoretical benefit in selectively blocking ETA whilst leaving ETB unopposed.

Bosentan: In a preliminary study, the orally administered dual endothelin-receptor antagonist

bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension.

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Phosphodiesterase-5 inhibitors:

Cyclic guanosine monophosphate (cGMP) is an intracellular second messenger that is responsible for mediating the vasodilatory activity of nitric oxide. cGMP is rapidly inactivated by PDE-5, an enzyme abundantly found in lung tissue. In the pulmonary circulation, PDE-5 inhibition promotes vascular relaxation by inhibiting the breakdown of cGMP.

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Drug (class) Route Dose range Major class Functional side effects

Epoprostenol (prostanoid)

i.v. 2 ng kg−1 min−1 and up III-IV Flushing, headache, nausea, diarrhoea, jaw pain, lightheadedness, arthralgias

Iloprost (prostanoid)

Inh. 2.5–5 mcg 6–9 times daily during waking hours; total daily dose usually <45 mcg

III-IV Flushing, cough, headache, jaw pain, insomnia, nausea, hypotension

Treprostinil (prostanoid)

s.c. 1.25 ng kg−1 min−1 and up, i.v. usually <40 ng kg−1 min−1 (s.c. and i.v. routes are bioequivalent

II-IV Infusion site pain and reaction (i.v./s.c.), headache, diarrhoea, nausea, jaw pain, flushing

Bosentan (Dual ERA)

p.o. 62.5 mg q.d. ×4 weeks, then 125 mg b.i.d.

III-IV Hepatocellular injury, flushing, headache, oedema, sinus congestion, haemoglobin decrease

Sildenafil (PDE-5 inhibitor)

p.o. 20 mg t.i.d. I-IV Headache, dyspepsia, epistaxis, back pain, sinus congestion

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Treatment decisions: All patients should receive treatment with an anticoagulant. Diuretics and

oxygen should be added as necessary.  For acutely vasoreactive patients with functional class I to early III IPAH or

PAH associated with anorexigen use, an initial strategy using a CCB is reasonable.

 PDE-5 inhibitor, endothelin receptor antagonist (ERA), or prostanoid can be given as first-line treatment instead of a CCB, in those with PAH that is not IPAH or PAH associated with anorexigen use.

The risks and benefits of treatment in early PAH should be considered. First-line therapy for FC III includes bosentan, epoprostenol, inhaled iloprost,

sildenafil, and s.c./i.v. treprostinil. Most experts recommend i.v. epoprostenol as first-line treatment for unstable

patients in FC IV.