Drug Induce Pulmonary Hypertension and Management

1. •Pulmonary hypertension.
•Drug induced pulmonary hypertension
•Pathophysiology of drug induced pulmonary hypertension
•Toxic Dose
•Diagnosis
•Treatment and management
Dr.Zulcaif Ahmad 1

2. Drug induces lung disorder
 Pulmonary hypertension:
 Pulmonary hypertension is a type of pulmonary vascular disease.
 What happens in pulmonary hypertension?
 Narrowing of the blood vessels.
 Stiffer and thicker blood vessel
 Blood 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 2

3. Symptoms of pulmonary
hypertension :
 Dyspnea (Shortness of breath)
 Fatigue (tirednessl
 Syncope (loss of consciousness )
 Cyanosis (bluish colour of skin and lips)
 Angle and leg swelling
 Hemoptysis (blood in sputam)
 Chest pain
Dr.Zulcaif Ahmad 3

4. Drugs:
 Drugs induced pulmonary hypertension :
 Appetite suppressants: aminorex, fenfluramine,dexfenfluramine .
 Cocaine, amphetamine
 Protamine
 Radiation and busuflun
Dr.Zulcaif Ahmad 4

5. Mechanism of drug induced
pulmonary 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
Dr.Zulcaif Ahmad 5

6.  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.
Dr.Zulcaif Ahmad 6

7. Dose:
 Fenfluramine toxic dose is 28-80mg/kg
 Cocaine >1g/kg
 Protamine 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.
Dr.Zulcaif Ahmad 7

8. 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.
Dr.Zulcaif Ahmad 8

9.  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.
Dr.Zulcaif Ahmad 9

10.  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.
Dr.Zulcaif Ahmad 10

11.  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.
Dr.Zulcaif Ahmad 11

12. Management and Treatment
 Diuretics:
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.
Dr.Zulcaif Ahmad 12

13.  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.
Dr.Zulcaif Ahmad 13

14.  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.
Dr.Zulcaif Ahmad 14

15.  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.
Dr.Zulcaif Ahmad 15

16.  Prostanoids:
 Epoprostenol:
Most potent and efficacious treatment for PAH.
Only medication for PAH that has shown a survival benefit in a
randomized clinical trial.
Dr.Zulcaif Ahmad 16

17.  Acute effects:
potent vasodilator,
inotropic actions,
whilst the long-term effects
antithrombotic properties
effects on vascular remodeling.
 Chronic effects:
lowers pulmonary vascular resistance to a level beyond that achieved during
acute vasodilator testing.
Dr.Zulcaif Ahmad 17

18.  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.
Dr.Zulcaif Ahmad 18

19. 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.
Dr.Zulcaif Ahmad 19

20.  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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21. 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 congestionDr.Zulcaif Ahmad 21

22. 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.
Dr.Zulcaif Ahmad 22