Color Atlas of Pharmacology (Part 14): Drugs used in Hyperlipoproteinemias

By virtue of binding bile acids, they promote consumption of choleste-rol for the synthesis of bile acids; the 154 li KT Lipid-Lowering Agents Triglycerides and cholesterol are essen-tia

Lipoprotein metabolism

Entero-cytes release absorbed lipids in the form

of triglyceride-rich chylomicrons

By-passing the liver, these enter the

circu-lation mainly via the lymph and are

hy-drolyzed by extrahepatic endothelial

lipoprotein lipases to liberate fatty

ac-ids The remnant particles move on into

liver cells and supply these with

choles-terol of dietary origin

The liver meets the larger part

(60%) of its requirement for cholesterol

by de novo synthesis from

acetylcoen-zyme-A Synthesis rate is regulated at

the step leading from

hydroxymethyl-glutaryl CoA (HMG CoA) to mevalonic

acid (p 157A), with HMG CoA reductase

as the rate-limiting enzyme

The liver requires cholesterol for

synthesizing VLDL particles and bile

ac-ids Triglyceride-rich VLDL particles are

released into the blood and, like the

chylomicrons, supply other tissues with

fatty acids Left behind are LDL particles

that either return into the liver or

sup-ply extrahepatic tissues with

choleste-rol

LDL particles carry apolipoprotein B

100, by which they are bound to

recep-tors that mediate uptake of LDL into the

cells, including the hepatocytes (recep-tor-mediated endocytosis, p 27) HDL particles are able to transfer cholesterol from tissue cells to LDL par-ticles In this way, cholesterol is trans-ported from tissues to the liver

Hyperlipoproteinemias can be

caused genetically (primary h.) or can occur in obesity and metabolic disor-ders (secondary h) Elevated LDL-cho-lesterol serum concentrations are asso-ciated with an increased risk of athero-sclerosis, especially when there is a con-comitant decline in HDL concentration (increase in LDL:HDL quotient)

Treatment Various drugs are

avail-able that have different mechanisms of action and effects on LDL (cholesterol)

and VLDL (triglycerides) (A) Their use is

indicated in the therapy of primary hy-perlipoproteinemias In secondary hy-perlipoproteinemias, the immediate goal should be to lower lipoprotein lev-els by dietary restriction, treatment of the primary disease, or both

Drugs (B) Colestyramine and

coles-tipol are nonabsorbable anion-exchange resins By virtue of binding bile acids, they promote consumption of choleste-rol for the synthesis of bile acids; the

154 li KT

Lipid-Lowering Agents

Triglycerides and cholesterol are

essen-tial constituents of the organism

Among other things, triglycerides

repre-sent a form of energy store and

choles-terol is a basic building block of

biologi-cal membranes Both lipids are water

insoluble and require appropriate

trans-port vehicles in the aqueous media of lymph and blood To this end, small amounts of lipid are coated with a layer

of phospholipids, embedded in which are additional proteins—the

apolipopro-teins (A) According to the amount and

the composition of stored lipids, as well

as the type of apolipoprotein, one dis-tinguishes 4 transport forms:

154 Drugs used in Hyperlipoproteinemias

in blood (nm) plasma (h)

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Drugs used in Hyperlipoproteinemias 155

Cell metabolism

A Lipoprotein metabolism

LDL

Dietary fats

LDL Chylomicron

Cholesterol

Lipoprotein

Triglycerides

Synthesis

Cholesterol-ester Triglycerides

B Cholesterol metabolism in liver cell and cholesterol-lowering drugs

Bile acids Lipoproteins

HMG-CoA-Reductase inhibitors

Fat tissue

Heart Skeletal muscle

LDL HDL HDL

VLDL Chylomicron

remnant

!-Sitosterol

Gut:

Cholesterol

absorption

Gut::

binding and

excretion of

bile acids (BA)

Liver:

BA synthesis

Cholesterol

consumption

Cholesterol store Colestyramine

Cholesterol

Fatty acids

Lipoprotein

Lipase

Cholesterol

Apolipo-protein

liver meets its increased cholesterol

de-mand by enhancing the expression of

HMG CoA reductase and LDL receptors

(negative feedback)

At the required dosage, the resins

cause diverse gastrointestinal

distur-bances In addition, they interfere with

the absorption of fats and fat-soluble

vi-tamins (A, D, E, K) They also adsorb and

decrease the absorption of such drugs as

digitoxin, vitamin K antagonists, and

diuretics Their gritty texture and bulk

make ingestion an unpleasant

experi-ence

The statins, lovastatin (L),

simvasta-tin (S), pravastatin (P), fluvastatin (F),

cerivastatin, and atorvastatin, inhibit

HMG CoA reductase The active group of

L, S, P, and F (or their metabolites)

re-sembles that of the physiological

sub-strate of the enzyme (A) L and S are

lac-tones that are rapidly absorbed by the

enteral route, subjected to extensive

first-pass extraction in the liver, and

there hydrolyzed into active

metab-olites P and F represent the active form

and, as acids, are actively transported by

a specific anion carrier that moves bile

acids from blood into liver and also

me-diates the selective hepatic uptake of

the mycotoxin, amanitin (A)

Atorvasta-tin has the longest duration of action

Normally viewed as presystemic

elimi-nation, efficient hepatic extraction

serves to confine the action of the

sta-tins to the liver Despite the inhibition of

HMG CoA reductase, hepatic cholesterol

content does not fall, because

hepato-cytes compensate any drop in

choleste-rol levels by increasing the synthesis of

LDL receptor protein (along with the

ductase) Because the newly formed

re-ductase is inhibited, too, the hepatocyte

must meet its cholesterol demand by

uptake of LDL from the blood (B)

Ac-cordingly, the concentration of

circulat-ing LDL decreases, while its hepatic

clearance from plasma increases There

is also a decreased likelihood of LDL

be-ing oxidized into its proatheroslerotic

degradation product The combination

of a statin with an ion-exchange resin

intensifies the decrease in LDL levels A

rare, but dangerous, side effect of the statins is damage to skeletal muscula-ture This risk is increased by combined use of fibric acid agents (see below)

Nicotinic acid and its derivatives

(pyridylcarbinol, xanthinol nicotinate, acipimox) activate endothelial lipopro-tein lipase and thereby lower triglyce-ride levels At the start of therapy, a prostaglandin-mediated vasodilation occurs (flushing and hypotension) that can be prevented by low doses of acetyl-salicylic acid

Clofibrate and derivatives (bezafi-brate, etofi(bezafi-brate, gemfibrozil) lower

plas-ma lipids by an unknown mechanism They may damage the liver and skeletal muscle (myalgia, myopathy, rhabdo-myolysis)

Probucol lowers HDL more than LDL; nonetheless, it appears effective in reducing atherogenesis, possibly by re-ducing LDL oxidation

!3 -Polyunsaturated fatty acids (ei-cosapentaenoate, docosahexaenoate) are abundant in fish oils Dietary sup-plementation results in lowered levels

of triglycerides, decreased synthesis of VLDL and apolipoprotein B, and im-proved clearance of remnant particles, although total and LDL cholesterol are not decreased or are even increased High dietary intake may correlate with a reduced incidence of coronary heart disease

156 Drugs used in Hyperlipoproteinemias

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Drugs used in Hyperlipoproteinemias 157 Low systemic availability

Fluvastatin

A Accumulation and effect of HMG-CoA reductase inhibitors in liver

Inhibition of HMG-CoA reductase

LDL-Receptor

Expression

B Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL-receptors

LDL

in blood

Oral administration

Extraction

of lipophilic lactone

Active uptake of anion

HMG-CoA

reductase

Increased receptor-mediated uptake of LDL

Cholesterol

Cholesterol

Lovastatin

Mevalonate

3-Hydroxy-3-methyl-glutaryl-CoA

HMG-CoA Reductase

Active form

Expression Expression

Bio-activation

O

O

CH3 O

O

HO

H3C

N

OH F

COOH HO

CH3

CH3

H3C

H3C

Diuretics – An Overview

Diuretics (saluretics) elicit increased

production of urine (diuresis) In the

strict sense, the term is applied to drugs

with a direct renal action The

predomi-nant action of such agents is to augment

urine excretion by inhibiting the

reab-sorption of NaCl and water

The most important indications for

diuretics are:

Mobilization of edemas (A): In

ede-ma there is swelling of tissues due to

ac-cumulation of fluid, chiefly in the

extra-cellular (interstitial) space When a

diu-retic is given, increased renal excretion

of Na+and H2O causes a reduction in

plasma volume with

hemoconcentra-tion As a result, plasma protein

concen-tration rises along with oncotic

pres-sure As the latter operates to attract

water, fluid will shift from interstitium

into the capillary bed The fluid content

of tissues thus falls and the edemas

re-cede The decrease in plasma volume

and interstitial volume means a

dimi-nution of the extracellular fluid volume

(EFV) Depending on the condition, use

is made of: thiazides, loop diuretics,

al-dosterone antagonists, and osmotic

diu-retics

Antihypertensive therapy Diuretics

have long been used as drugs of first

choice for lowering elevated blood

pres-sure (p 312) Even at low dosage, they

decrease peripheral resistance (without

significantly reducing EFV) and thereby

normalize blood pressure

Therapy of congestive heart failure.

By lowering peripheral resistance,

diu-retics aid the heart in ejecting blood

(re-duction in afterload, pp 132, 306);

car-diac output and exercise tolerance are

increased Due to the increased

excre-tion of fluid, EFV and venous return

de-crease (reduction in preload, p 306)

Symptoms of venous congestion, such

as ankle edema and hepatic

enlarge-ment, subside The drugs principally

used are thiazides (possibly combined

with K+-sparing diuretics) and loop

diu-retics

Prophylaxis of renal failure In circu-latory failure (shock), e.g., secondary to massive hemorrhage, renal production

of urine may cease (anuria) By means of diuretics an attempt is made to main-tain urinary flow Use of either osmotic

or loop diuretics is indicated

Massive use of diuretics entails a

hazard of adverse effects (A): (1) the

decrease in blood volume can lead to

hypotension and collapse; (2) blood

vis-cosity rises due to the increase in eryth-ro- and thrombocyte concentration, bringing an increased risk of

intravascu-lar coagulation or thrombosis.

When depletion of NaCl and water (EFV reduction) occurs as a result of diu-retic therapy, the body can initiate

counter-regulatory responses (B),

namely, activation of the renin-angio-tensin-aldosterone system (p 124) Be-cause of the diminished blood volume, renal blood flow is jeopardized This leads to release from the kidneys of the hormone, renin, which enzymatically catalyzes the formation of angiotensin I Angiotensin I is converted to angioten-sin II by the action of angiotenangioten-sin-con- angiotensin-con-verting enzyme (ACE) Angiotensin II stimulates release of aldosterone The mineralocorticoid promotes renal reab-sorption of NaCl and water and thus counteracts the effect of diuretics ACE inhibitors (p 124) augment the effec-tiveness of diuretics by preventing this counter-regulatory response

158 Diuretics

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Diuretics 159

B Possible counter-regulatory responses during long-term diuretic therapy

A Mechanism of edema fluid mobilization by diuretics

Edema

Hemoconcentration

Collapse, danger of thrombosis

Salt and

fluid retention

Mobilization of

edema fluid

Protein molecules

Colloid osmotic pressure

Diuretic

EFV:

Na + , Cl - ,

H2O

Angiotensinogen Renin Angiotensin I ACE Angiotensin II Aldosterone

NaCl Reabsorption in the Kidney (A)

The smallest functional unit of the

kid-ney is the nephron In the glomerular

capillary loops, ultrafiltration of plasma

fluid into Bowman’s capsule (BC) yields

primary urine In the proximal tubules

(pT), approx 70% of the ultrafiltrate is

retrieved by isoosmotic reabsorption of

NaCl and water In the thick portion of

the ascending limb of Henle’s loop (HL),

NaCl is absorbed unaccompanied by

water This is the prerequisite for the

hairpin countercurrent mechanism that

allows build-up of a very high NaCl

con-centration in the renal medulla In the

distal tubules (dT), NaCl and water are

again jointly reabsorbed At the end of

the nephron, this process involves an

al-dosterone-controlled exchange of Na+

against K+or H+ In the collecting tubule

(C), vasopressin (antidiuretic hormone,

ADH) increases the epithelial

perme-ability for water, which is drawn into

the hyperosmolar milieu of the renal

medulla and thus retained in the body

As a result, a concentrated urine enters

the renal pelvis

Na + transport through the tubular

cells basically occurs in similar fashion

in all segments of the nephron The

intracellular concentration of Na+is

sig-nificantly below that in primary urine

This concentration gradient is the

driv-ing force for entry of Na+into the cytosol

of tubular cells A carrier mechanism

moves Na+across the membrane

Ener-gy liberated during this influx can be

utilized for the coupled outward

trans-port of another particle against a

gradi-ent From the cell interior, Na+is moved

with expenditure of energy (ATP

hy-drolysis) by Na+/K+-ATPase into the

ex-tracellular space The enzyme molecules

are confined to the basolateral parts of

the cell membrane, facing the

interstiti-um; Na+can, therefore, not escape back

into tubular fluid

All diuretics inhibit Na+

reabsorp-tion Basically, either the inward or the

outward transport of Na+can be

affect-ed

Osmotic Diuretics (B)

Agents: mannitol, sorbitol Site of action: mainly the proximal tubules Mode of action: Since NaCl and H2O are reab-sorbed together in the proximal tubules,

Na+concentration in the tubular fluid does not change despite the extensive reabsorption of Na+and H2O Body cells lack transport mechanisms for polyhy-dric alcohols such as mannitol (struc-ture on p 171) and sorbitol, which are thus prevented from penetrating cell membranes Therefore, they need to be given by intravenous infusion They also cannot be reabsorbed from the tubular fluid after glomerular filtration These agents bind water osmotically and re-tain it in the tubular lumen When Na ions are taken up into the tubule cell, water cannot follow in the usual amount The fall in urine Na+ concentra-tion reduces Na+reabsorption, in part because the reduced concentration gra-dient towards the interior of tubule cells means a reduced driving force for Na+

influx The result of osmotic diuresis is a large volume of dilute urine

Indications: prophylaxis of renal hypovolemic failure, mobilization of brain edema, and acute glaucoma

160 Diuretics

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Diuretics 161

A Kidney: NaCl reabsorption in nephron and tubular cell

dT

BC

C

pT

Cortex Medulla Thick

portion

of HL

Inter-stitium

Na/K-ATPase

Na+

Na+ "carrier"

ADH HL

Mannitol

B NaCl reabsorption in proximal tubule and effect of mannitol

[Na+]inside = [Na+]outside [Na+]inside < [Na+]outside

Na+

Na+, Cl

-Na+, Cl- + H2O

H2O Aldosterone

K+

Diuretics

Diuretics of the Sulfonamide Type

These drugs contain the sulfonamide

group -SO2NH2 They are suitable for

oral administration In addition to being

filtered at the glomerulus, they are

sub-ject to tubular secretion Their

concen-tration in urine is higher than in blood

They act on the luminal membrane of

the tubule cells Loop diuretics have the

highest efficacy Thiazides are most

fre-quently used Their forerunners, the

carbonic anhydrase inhibitors, are now

restricted to special indications

Carbonic anhydrase (CAH)

inhibi-tors, such as acetazolamide and

sulthi-ame, act predominantly in the proximal

tubules CAH catalyzes CO2

hydra-tion/dehydration reactions:

H++ HCO3 ↔H2CO3↔H20 + CO2

The enzyme is used in tubule cells

to generate H+, which is secreted into

the tubular fluid in exchange for Na+

There, H+captures HCO3, leading to

for-mation of CO2via the unstable carbonic

acid Membrane-permeable CO2is taken

up into the tubule cell and used to

re-generate H+and HCO3 When the

en-zyme is inhibited, these reactions are

slowed, so that less Na+, HCO3 and

wa-ter are reabsorbed from the fast-flowing

tubular fluid Loss of HCO3 leads to

aci-dosis The diuretic effectiveness of CAH

inhibitors decreases with prolonged

use CAH is also involved in the

produc-tion of ocular aqueous humor Present

indications for drugs in this class

in-clude: acute glaucoma, acute mountain

sickness, and epilepsy Dorzolamide can

be applied topically to the eye to lower

intraocular pressure in glaucoma

Loop diuretics include furosemide

(frusemide), piretanide, and

bumeta-nide With oral administration, a strong

diuresis occurs within 1 h but persists

for only about 4 h The effect is rapid,

in-tense, and brief (high-ceiling diuresis)

The site of action of these agents is the

thick portion of the ascending limb of

Henle’s loop, where they inhibit

Na+/K+/2Cl– cotransport As a result,

these electrolytes, together with water,

are excreted in larger amounts

Excre-tion of Ca2+ and Mg2+ also increases

Special toxic effects include: (reversible)

hearing loss, enhanced sensitivity to

renotoxic agents Indications:

pulmo-nary edema (added advantage of i.v in-jection in left ventricular failure: imme-diate dilation of venous capacitance vessels ! preload reduction); refrac-toriness to thiazide diuretics, e.g., in re-nal hypovolemic failure with creatinine clearance reduction (<30 mL/min); pro-phylaxis of acute renal hypovolemic failure; hypercalcemia Ethacrynic acid

is classed in this group although it is not

a sulfonamide

Thiazide diuretics (benzothiadia-zines) include hydrochlorothiazide,

benzthiazide, trichlormethiazide, and cyclothiazide A long-acting analogue is chlorthalidone These drugs affect the intermediate segment of the distal tu-bules, where they inhibit a Na+/Cl– co-transport Thus, reabsorption of NaCl and water is inhibited Renal excretion

of Ca2+decreases, that of Mg2+increases

Indications are hypertension, cardiac failure, and mobilization of edema

Unwanted effects of

sulfonamide-type diuretics: (a) hypokalemia is a

con-sequence of excessive K+loss in the ter-minal segments of the distal tubules where increased amounts of Na+ are available for exchange with K+; (b) hy-perglycemia and glycosuria; (c) hyper-uricemia—increase in serum urate lev-els may precipitate gout in predisposed patients Sulfonamide diuretics com-pete with urate for the tubular organic anion secretory system

162 Diuretics

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Diuretics 163

e.g., furosemide

Loop diuretics

Na+

K+

2 Cl

-A Diuretics of the sulfonamide type

Anion

secretory

system

e.g., acetazolamide

Carbonic anhydrase inhibitors

Na+

H+

HCO-3

H2O

CO2

CAH

HCO-3 Na+

HCO-3

H+

CO2 H2O

e.g., hydrochlorothiazide

Thiazides

Na+

Cl

-Sulfonamide

diuretics

Uric acid

Gout

Hypokalemia

Normal state

Loss of

Na+, K+

H2O