3 Drugs for Coronary Heart Disease (CHD)

Question 1

Drugs for Coronary Heart Disease (CHD)

Answer 1

Definitions (NICE guidance):
Cardiovascular disease (CVD): disease of the heart & blood vessels.
- most common manifestation of CVD: coronary heart disease (CHD)
- also known as coronary artery disease and ischaemic heart disease.

CHD is caused by the narrowing of the arteries that supply the heart and is due to a gradual build-up of fatty material called atheroma.”

Question 2

Angina pectoris

Answer 2

Crushing pain in chest that may radiate to arm, neck or jaw
- Most commonly on exertion

The pain results from cardiac ischaemia

Question 3

CVD stats:

Answer 3

CVD single most common cause of death in the UK
(238,000 in 2002: 50% CHD, 25% stroke).

• approx. 30% of deaths “premature” (

Question 4

What are the pathophysiological problems in CHD?

Answer 4

narrowing of coronary arteries by atheroma (fatty gunge)

so. .. not enough oxygen reaches heart muscle
so. .. Oxygen DEMAND exceeds SUPPLY

So… Heart muscle is HYPOXIC

CONSEQUENCES:
Artery BLOCKED - HEART CELLS DIE

Anaerobic metabolism – cells don’t work well (less blood pumped);
- may “misbehave” electrically (conduction problems & arrhythmias)
Pain: ? Metabolites ? Mediators

Question 5

Drugs for today’s lecture:

Answer 5

1. Nitrovasodilators
2. Statins (lipid-lowering drugs)
   History / background
   Key information
   In use

Question 6

Nitrates - history

Answer 6

1844: Amyl nitrite synthesised
1847: Sobrero synthesised the explosive nitroglycerin
‘. . . a very minute quantity put upon the tongue produces a violent headache for several hours’

1850s: Doctors experimenting with taking amyl nitrite notice “pounding of blood”, dizziness, & flushing

1867 Physician Thomas Lauder Brunton publishes Lancet paper describing treating angina patient w. amyl nitrite

1867: Alfred Nobel patents “dynamite” – nitroglycerin absorbed into porous earth

1860s-70s: Various nitrates tested in angina

1878: Nitroglycerin (aka “Glyceryl trinitrate”) used for angina; becomes standard therapy by
1890s

1895: Nobel signs his will which will establish Nobel Prizes after his death the following yr.

‘. . isn’t it the irony of fate that I have been prescribed [nitroglycerine]! They call it Trinitrin, so as not to scare the chemist & the public.’ - Alfred Nobel in 1896

Question 7

Nitrates (nitrovasodilators)

Answer 7

Commonest: Glyceryl Trinitrate (GTN)
Used for > 100 yrs for angina pain
Fast-acting
Sublingual tablet, nasal spray, transdermal patch
Unwanted effects common
Tolerance develops
Preparations differ in “shelf-life” (tablets go off quickest)
Short- and longer-acting nitrates used

Rapidly metabolized by liver (esp. GTN)

Question 8

Some early occupational medicine- explosives factory workers and nitroglycerin

Answer 8

“Severe headaches, dizziness and postural weakness are common occurrences during the first days of handling nitroglycerin (NG).“

“However, tolerance towards these symptoms then develops and workers are more easily able to cope with their duties.”

“Workers not exposed to NG over the weekend suffer from a recurrence of malaise on return to work: ‘Monday disease’.”

“[It is] common practice for men to carry small pieces of NG home, rubbing it on their skin or wearing work clothes impregnated with the material over rest periods.”

Question 9

Nitrates – Common unwanted effects

Answer 9

Throbbing headache - cerebral vasodilatation
Dizziness (esp. on getting up) – lowered blood pressure

Caution with:
Other BP-lowering drugs (BP can be too low!)
Other drugs acting on NO pathway e.g. Sildenafil

Question 10

An imminent “epidemic” of problems related to diet, obesity and lack of exercise?

Answer 10

Schools told to tackle teenage obesity crisis
· Minister demands action · 50% of population obese in next 25 years - study Monday October 15, 2007The Guardian
“An official study to be published on Wednesday will predict that half the population could be obese within the next 25 years”

Question 11

STATINS: (developed as HMG-CoA reductase inhibitors BUT may work via other mechanisms)

Answer 11

HMG-CoA red‘ase is rate-limiting step in cholesterol synthesis
dose-dep. reduction total [cholesterol] AND [LDL cholesterol]
latter via upregulation of LDL receptors
first available on prescription 1987
(relatively) few side-effects
GI upset (usually wears off)
abnormal liver tests (usually mild)
muscle problems (myopathy – rare but serious)
Trials show effective in 2o AND 1o prevention of heart attacks
2o – existing CHD 1o – no CHD yet but high future risk
works any age, + diabetes, ♂ / ♀