Ahmed Rawajbeh

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-Dr Alia

8

In this lecture, we are going to finish the last two groups of drugs used in heart

failure and start with the last collection of drugs that are used in hyperlipidemia.

Note: unrequired explanations are marked with (+).

Positive inotropic agents:

1) cardiac glycosides (digitalis)/given orally:

2) cAMP-dependent agents/ only parenterally:

a) β-adrenergic agonists.

b) Phosphodiesterase inhibitors:

Three PDE-3 inhibitors: Inamrinone, Milrinone and Vesanirone, and one PDE-5:

Sildenafil

PDE inhibition leads to accumulation of cAMP and cGMP leading to positive

inotropic activity (more cAMP in cardiac muscles increases their contractility) and

peripheral vasodilation (more cAMP in vascular smooth muscles inhibits their

contraction).

Short acting drugs, so they are reserved for parenteral therapy of acute heart

failure.

Adverse effects: arrhythmias, and thrombocytopenia.

Vasodilators

Affect preload and/or afterload without directly affecting contractility.

(+) Preload-they cause vasodilation in veins which decreases the venous return

and the preload, and thus less blood will accumulate in the ventricles. Afterload-

they cause vasodilation in arterioles which reduces the resistance and

afterload(the pressure); consequently, cardiac output will increase.

They can decrease myocardial ischemia, enhance coronary blood flow and

decrease MVO2.

They are used in acute heart failure and for short periods in chronic heart failure.

Hydralazine-Isosorbide dinitrate combination was found to decrease mortality,

maybe by reducing remodeling of the heart.

They can be combined with ACE inhibitors, diuretics and digitalis.

(BNP)-Niseritide

Brain (B-type) natriuretic peptide (BNP) is secreted constitutively by ventricular

myocytes in response to stretch.

BNP binds to receptors in the vasculature, kidney, and other organs, producing

potent vasodilation with rapid onset and offset of action by increasing levels of

cGMP(that causes relaxation).

Niseritide is a recombinant human BNP approved for treatment of acute

decompensated chronic heart failure (when cardiac output becomes severely

insufficient).

It reduces systemic and pulmonary vascular resistances, causing an indirect

increase in cardiac output and diuresis.

Effective in HF because of reduction in preload( (+) although it decreases the

preload, niseritide indirectly increases the cardiac output by decreasing the

afterload/ the preload has exceeded the physiological limits of Frank-starling and

it no longer increases the stroke volume) and afterload.

Hypotension is the main side effect.

Lipid lowering drugs

Let’s briefly go over atherosclerosis since it is the most important disease

associated with hyperlipidemia.

It is obvious from the chart that the cholesterol is the major risk factor for

coronary heart disease (the most common killer globally).

Arteriosclerosis is characterized by the deposition of atheromatous plaques

containing cholesterol and lipids on the innermost layer of the walls of large and

medium-sized arteries.

Normal vs atheromatous coronary artery. Notice the narrowing of the lumen by

the atheromatous plaque. This narrowing reduces blood flow to the heart.

Many risk factors contribute in the development of atherosclerosis. They can be

divided into two groups depending on the possibility to modify them.

1-Non- modifiable Risk Factors

Age – Atherosclerosis begins in the young, but does not precipitate organ injury

until later in life Gender –

Men more prone than women (because men lack the protection of estrogen), but

by age of 60- 70, both genders have approximately equal frequency.

Family History and genetic factors (e.g. familial hypercholesterolemia)

*One mechanism involved in familial hypercholesterolemia is a genetic defect in

LDL receptors rendering the hepatocytes and other tissue cells unable of uptaking

the lipoprotein, and thus the blood concentration of LDL will increase.

2-Modifiable Risk Factors (potentially controllable)

Hyperlipidemia: elevated serum cholesterol and triglycerides levels.

)not for memorizing)>Hypertension, cigarette smoking, diabetes mellitus,

elevated Homocysteine factors that affect hemostasis and thrombosis,

infections(e.g. Herpes virus and chlamydia pneumoniae), obesity, sedentary

lifestyle, and stress.

• Among all these factors, elevated serum cholesterol levels are unique in the

ability to drive atherosclerosis in the absence of other risk factors

There are two major sources of cholesterol in human body:

1- endogenous: produced by the liver, 1g/day.

2- Exogenous: food (animal sources).

We need cholesterol in our bodies in order to produce hormones (adrenal

hormones) and vitamin D. Also, cholesterol is a major building block in the cellular

membranes (maintaining their fluidity). So, (الفضيلة تقع بين رذيلتين), we need serum

cholesterol to be maintained within a certain range.

*we use LDL level as the main indicative for cholesterol level because it is the

lipoprotein that has the highest concentration of cholesterol.(triglycerides level is

also indicative)

Recall:

1-lipids do not circulate freely in the blood; instead they are bound to proteins.

2-lipoproteins are classified according to their composition which affects their

density and size. As the density increases, the total lipid proportion decreases

(chylomicron> VLDL> IDL> LDL> HDL). Cholesterol concentration is the highest in

LDL.

3-LDL is the bad cholesterol and HDL is the good cholesterol. Why? (+) Because

HDL function is to transport cholesterol from body tissues into the liver. While LDL

function is to share cholesterol to the tissues. The hepatocytes have receptors

allowing them to recognize and uptake both types but they mainly uptake HDL

(more receptors favoring HDL) and the uptake of LDL is limited. So high HDL is

healthy, since it is easily uptaken by the live which converts its content of

cholesterol into bile(excreted through the intestines). High LDL level is risky, as

the tissues take only their needs and the excess remains and builds up in the

blood.

LDL Cholesterol levels:

Optimal: <100mg/dl

Near optimal/above optimal: 100 - 129mg/dl

Borderline high: 130 -159mg/dl

High: 160 - 189mg/dl

Very high: ≥190

Prevention through lifestyle changes:

• Diet – low in fat/cholesterol, increased fibers (fruits/vegetables), (vitamins

alone have not shown a protective effect against LDL), and fish (omega 3)

• Physical activity can increases HDL (higher HDL cholesterol is linked with a lower

risk of heart disease) and also help control weight (Decreasing body weight

increases HDL),

• Controlling diabetes and high blood pressure

• Quitting smoking (smoking is associated with low level of HDL)

• Decreasing stress

If these modifications do not reduce LDL level, then we should use the

medications. That means we have done with pathology and biochemistry, and

now, we will study pharmacology:

1-Statins

(simvastatin, atorvostatin, pravastatin)

Pharmacodynamics:

The HMG-CoA (3-hydroxy-3-

methylglutaryl-coenzyme A)

reductase catalyses the

conversion of HMG-CoA to

mevalonic acid( a step in the

pathway of cholesterol

synthesis)

They are HMG-CoA reductase

inhibitors >blocking the

synthesis of cholesterol in the

liver>decreasing hepatic

cholesterol synthesis>lowering total and LDL

The decrease is about 30-50%.

They indirectly increase expression of LDL receptor in the liver, further decreasing

circulating LDL. How? >> the liver cannot synthesis sufficient amounts of

cholesterol to satisfy their needs, so it expresses more receptors to uptake the

circulatory LDL(increasing clearance of LDL).

So, these drugs have two mechanisms:

1-↓liver synthesis>> ↓LDL

2-↑liver uptake>> ↓LDL

Several studies demonstrated positive

effects on morbidity and mortality.

They have other promising

pharmacodynamic actions not related

to LDL serum level lowering ability:

Inhibition of the synthesis of

mevalonic acid will decrease the

synthesis of geranylgeranyl-PP

GG-PP regulates the activation of

some proteins through a process

called prenylation.(addition of prenyl

groups). Examples of these proteins

are small G-proteins(Rho). Once the

G-proteins get prenylated(prenyl

groups are hydrophobic favor binding

to the cell membrane, they bind to

the cell membrane and become

active. Statins redcue the synthesis of

GG-PP reducing activation of G-

proteins and signaling of certain hormones.

Rho activates another protein called Rho kinase which phosphorylates other

proteins enhancing the contraction of vascular smooth muscles. So, less

mevalonate>>less GG-PP>>less activated Rho>> less activated Rho

kinase>>decreased vascular contraction>>vasodilation>>effects that lower the

risk of CV diseases other than lipid lowering effect.

In addition to this mechanism, decreased Rho (which decreases the stability of

eNOS’s mRNA) activation will increase the synthesis of eNOS (endothelial nitric

oxide synthase), so more NO will be produced and more vasodilation. NO is an

antiplatelet, antithrombotic, and vasodilator (protective against CV diseases)

[a new mechanism involves the arginase. It is found that the level of arginase is

elevated in diabetics, hypertensives, and elders. It is an enzyme that converts

arginine into urea so upregulating it will decrease arginine level which is the

substrate in eNOS reaction. Rho is involved in the upregulation of this enzyme, so

inhibiting it will increase the available amounts of arginine>>more NO)

*endothelial dysfunction: is a condition characterized by decreased ability of the

endothelial cells to produce NO. It predisposes to atherosclerosis.

Two mechanisms: 1- less activated Rho kinase>> directly decrease contraction of

vascular smooth muscles

2-more stable INOS mRNA>>more NO >> decreased contraction.

The effects other than lowering lipid profile(Pleiotropic action):

1-improved endothelial function

2-reduced vascular inflammation and platelet aggregability

3-antithrombotic action

4-stabilisation of atherosclerotic plaques> reduce odds of plaque rupture

5-increased neovascularisation of ischaemic tissue

6-enhanced fibrinolysis

7-immune suppression

8-osteoclast apoptosis and increased synthetic activity in osteoblasts

It is recommended to give statins to patients susceptible to coronary heart

disease not only due to hyperlipidemia, but also to those who are diabetic or

hypertensive.

Pharmacokinetics :

well absorbed when given orally

extracted by the liver (target tissue), undergo extensive presystemic

biotransformation(Simvastatin is an inactive pro-drug)

Clinical uses:

1- Primary prevention of arterial disease in patients who are at high risk

because of elevated serum cholesterol concentration, especially it there are

other risk factors for atherosclerosis

2- Secondary prevention of myocardial infarction and stroke in patients who

have symptomatic atherosclerotic disease (angina, transient ischemic

attacks) following acute myocardial infarction or stroke(even if they do not

have elevated cholesterol level)

Atorvastatin (new drug): lowers serum cholesterol in patients with homozygous

familiar hypercholesterolemia.

Adverse effects:

- mild gastrointestinal disturbances

- severe myositis (rhabdomyolysis)/ it happens when statins are combined with

another lipid lowering drug(fibrate or niacin) although it is more beneficial to

combine two drugs but it increases the risk of developing this adverse effect. The

condition is very rare in patients taking statins only. So the patients suffer from

myopathy(muscle pain)which can progress into rhabdomyolysis( myoglobulin gets

released and it is toxic to the kidneys ) in rare cases.

angio-oedema and should not be given during pregnancy(not mentioned by the

doctor).

2-Fibrates

fenofibrate clofibrate gemfibrozil ciprofibrate

pharmacodynamics:

They activate PPAR-alpha (peroxisome proliferator-activated receptors) and

increase expression of genes facilitating lipid metabolism

They stimulate the β-oxidative degradation of fatty acids(by affecting gene

expression of certain proteins)>>liberate free fatty acids for storage in fat or for

metabolism in striated muscle.

Less effective than statins in decreasing LDL.

More effective at increasing HDL and lowering triglycerides.

They reduce hepatic VLDL production (circulating VLDL will be converted into LDL.

Low VLDL>>Low LDL) and increase hepatic LDL uptake.

They produce a modest decrease in LDL (~ 10%) and increase in HDL (~ 10%), but

a marked decrease in TGs (~ 30%), so they are drugs of choice in severe

hypertriglyceridemia

Other effects : they improve glucose tolerance and inhibit vascular smooth

muscle inflammation

Adverse effects:

Combination of statins and fibrates increases risk of rhabdomyolysis by 10+ fold.

And, in patients with renal impairment,myositis (rhabdomyolysis)

myoglobulinuria (↑myoglobulin which is toxic to the kidneys) causes acute renal

failure.

can improve insulin resistance and mild GIT symptoms(not mentioned)

Toxicity:

• Rashes, urticaria, hair loss, headache, GIT symptoms, impotence, and anemia.

• Myalgia, fatigue, myopathy and rhabdomyolysis.

• Risk of cholesterol gallstones.

• Interacts with statins, levels of both drugs will increase.

• Used with caution in renal failure.

• Elevated transaminasesor alkaline phosphatase.

3-Niacin

Pharmacodynamics:

Nicotinic Acid or Vitamin B3, one of the oldest drugs.

It is the best agent to increase HDL-C(35-40%). It also lowers triglycerides (35-

45%) and decreases LDL-C production(20-30%).

Other effects: Reduction of fibrinogen levels and increasing plasminogen

activator.

In adipose tissue, it inhibits the lipolysis of triglycerides by inhibiting adipocyte

adenylyl cyclase, which reduces transport of free fatty acids to the liver and

decreases hepatic triglyceride synthesis and LDL synthesis. Also, it inhibits a rate –

limiting enzyme of triglyceride synthesis, diacylglycerol acetyltransferase 2.

This reduction of triglyceride synthesis reduces hepatic VLDL and consequently

LDL.

It also inhibits intracellular lipase in adipose tissues leading to decreased FFA flux

to the liver.

Pharmacokinetics:

Completely absorbed, peaks within 1hr, half-life is about 1 hr(short half life), so

need to be given by twice or thrice daily administration.

Toxicity:

• Harmless cutaneous vasodilation and sensation of warmth.

• Pruritus, rashes, dry skin or mucus membranes (acanthosis nigricans).

• Nausea, vomiting, abdominal discomfort, diarrhea.

• Elevations in transaminases(liver enzyme) and possible hepatotoxicity.

• Insulin resistance and hyperglycemia.

•Hyperuricemia and gout.

• Cardiac arrhythmias.

• Amblyopia, blurring of vision.

4-Bile Acid –Binding Resins

• Colestipol. • Chlestyramine. • Colesevelam.

Pharmacodynamics:

• These are large polymeric anionic- exchange resins, insoluble in water, which

bind the negatively charged bile acids in the intestinal lumen and prevent their

reabsorption leading to depletion of bile acid pool and increased hepatic

synthesis.

• Consequently, hepatic cholesterol content is decreased, stimulating the

production of LDL receptors. This leads to increased LDL clearance and lowers

LDL-C levels.

• However, this effect is partially offset by the enhanced cholesterol synthesis

caused by upregulation of HMG-CoA reductase(so they are combined with

statins).

•they may increase triglyceride levels.

Clinical uses:

•They lower LDL as much as 25%, but will cause GI side effects.

• Relieve pruritus in cholestasis.

• Digitalis toxicity, can bind digitoxin and enhance its excretion.

Toxicity:

Probably the safest drugs, since they are not absorbed from the intestine

because of their large size. Maximal doses are effective but cause side effects.

• Gritty sensation is unpleasant but can be tolerated. • Constipation and bloating.

• Heartburn. • Malabsorption of Vitamin K. • Gall stones. • Impaired absorption

of many drugs ( digitalis, propranolol, thiazides, warfarin, folic acid, statins,

aspirin….etc)..