respiratory pharmacology: pulmonary vascular...

Dr. Tillie-Louise HackettDepartment of Anesthesiology, Pharmacology and Therapeutics

University of British Columbia

Associate Head, Centre of Heart Lung Innovation, St Paul’s HospitalTillie.hackett@hli.ubc.ca

Respiratory Pharmacology:

Pulmonary vascular diseases

Aims of Lecture

Define the differences in the structure of alveolar epithelium and endothelium with regards to function

Describe the pathologies associated with pulmonary vascular disease

What are the treatment strategies used to treat pulmonary embolism and pulmonary hypertension

Pulmonary Vasculature

Weibel, 2009, Swiss Med Wkly

GAS EXCHANGE STRUCTURE

~ 300 million alveoli units in a human lung

Pulmonary Blood-Gas Barrier

Pulmonary Blood-Gas BarrierEPI: Type I alveolar

epithelial cell

IN: Interstitium (ECM)

EN: Endothelial Cell

Endothelium highly

permeable to water,

solutes, ions and some

proteins (albumin)

Alveolar impermeable!

EPI

IN

EN

Pulmonary Blood-Gas Barrier: cell Junctions

Endothelium

Gap junctions

Buffered together

Weak

Epithelium

Tight Junctions

Velcro

Strong

Pulmonary verses systemic circulation

Pressure difference: Pul: 15-5 = 10 Sys: 100-2 = 98

(10x that of pulmonary pressure)

High Flow, Low Pressure System

Enables extremely thin walls for gas exchange

Increased alveolar pressures at high altitudes leads

to compression of capillaries

Low Flow, High Pressure System

When the system is overloaded:

Pulmonary Edema

Definition:

An abnormal accumulation of fluid in the

extravascular spaces and tissues of the lung

= means fluid should be within the capillaries and fluid

has leaked out

Can accompany many pulmonary vascular

diseases and is often lethal

Two Types of Pulmonary Edema

Filling of peri vascular

space

Epithelial damage results

in RBCs in alveoli

Interstitial Edema

Pulmonary Edema

Conducting airways Alveoli

Peri vascular cuff

Pulmonary edema

Two Types of Pulmonary Edema

Interstitial edema

Two Types of Pulmonary Edema

White lines due to

interstitial edema

Increased opacity due

to pulmonary edema

Effect’s of Pulmonary edema

Interstitial edema

Generally little effect on lung function

Some evidence that lung compliance is reduced

Alveolar Edema

Lung compliance is reduced

Seriously reduced O2 – CO2 transfer

Pulmonary vascular diseaseAny condition that affects the vessels along the route between the heart and lungs

Pulmonary embolism

Common condition that results in the occlusion of the pulmonary arteries by thrombotic material (deep vein thrombosis, DVT).

Causes acute life threatening, but potentially reversible, right heart failure.

Incidence 6-20 cases per 100,000 people

Clinical manifestations

Breathlessness, chest pain, tachycardia, fainting, hypotension and shock, DVT.

Diagnosis

Electrocardiogram, arterial blood gases & chest radiograph

Treatment for Pulmonary embolism

Predisposing risk factors

High = lower limb fracture or trauma

Moderate = oral contraceptive, pregnancy, chronic heart problems

Low = bed rest >3 days, age, obesity, prolonged travel

Prevention

Anticoagulants (prevent further clots) – low-molecular weight heparin, warfarin

High risk – filter places in inferior vena cava

Management

Heparin, supplemental oxygen, warfarin, surgical pulmonary embolectomy

Thrombolytics (remove the blockage)

Alteplase – Converts trapped plasminogen

to plasmin, initiates local fibrinolysis

Prognosis

Fatality rate 7-11%

60% undergo a recurrent event

Pulmonary vascular disease

Pulmonary Arterial Hypertension

Progressive disease characterized by vascular proliferation and vasoconstriction of the small pulmonary arteries that eventually leads to right-sided heart failure and death.

Defined as an increase in mean pulmonary arterial pressure to at least 25 mmHg at rest.

Common cause is left heart disease (congenital, connective tissue disorders, high altitude, COPD).

Causes chronic remodeling of the small pulmonary arteries leading to progressive vascular obstruction.

Incidence 1.5-5.2 cases per 100,000 people

Clinical manifestations

Breathlessness, fatigue, chest pain, haemoptysis.

Diagnosis

Notoriously difficult to detect early stages of disease, patients asymptomatic

Invasive right heart catheterization is mandatory to confirm PAH.

Treatment for Pulmonary arterial hypertension

Predisposing risk factors

Chronic cardiovascular and respiratory diseases

Prevention

Appropriate treatment of chronic heart diseases

Chronic respiratory diseases should be treated with O2 therapy to prevent hypoxaemia.

Management

Oral anticoagulation, diuretics and oxygen.

PAH results in elevated vascular resistance defective endothelium

secrete increased levels of endothelin-1 and decreased levels of prostacyclin.

Results in contraction of vascular smooth muscle and vasoconstriction remodeling

New drugs - Prostacyclin derivatives, endothelin receptors antagonists

Lung transplantation.

Prognosis

Mean survival 2.8 years in 1980’s now 67-87% survival rates.

60% undergo a recurrent event