Tài liệu Color Atlas of Pharmacology (Part 25): Therapy of Selected Diseases pptx

The force driving myocardial blood flow is the pressure difference between the coronary ostia aortic pressure and the opening of the coronary sinus right atrial pressure.. As peripheral

Angina Pectoris

An anginal pain attack signals a

tran-sient hypoxia of the myocardium As a

rule, the oxygen deficit results from

in-adequate myocardial blood flow due to

narrowing of larger coronary arteries

The underlying causes are: most

com-monly, an atherosclerotic change of the

vascular wall (coronary sclerosis with

exertional angina); very infrequently, a

spasmodic constriction of a

morpholog-ically healthy coronary artery (coronary

spasm with angina at rest; variant

angi-na); or more often, a coronary spasm

oc-curring in an atherosclerotic vascular

segment

The goal of treatment is to prevent

myocardial hypoxia either by raising

blood flow (oxygen supply) or by

lower-ing myocardial blood demand (oxygen

demand) (A).

Factors determining oxygen

sup-ply The force driving myocardial blood

flow is the pressure difference between

the coronary ostia (aortic pressure) and

the opening of the coronary sinus (right

atrial pressure) Blood flow is opposed

by coronary flow resistance, which

in-cludes three components (1) Due to

their large caliber, the proximal

coro-nary segments do not normally

contrib-ute significantly to flow resistance

However, in coronary sclerosis or

spasm, pathological obstruction of flow

occurs here Whereas the more

com-mon coronary sclerosis cannot be

over-come pharmacologically, the less

com-mon coronary spasm can be relieved by

appropriate vasodilators (nitrates,

ni-fedipine) (2) The caliber of arteriolar

re-sistance vessels controls blood flow

through the coronary bed Arteriolar

caliber is determined by myocardial O2

tension and local concentrations of

metabolic products, and is

“automati-cally” adjusted to the required blood

flow (B, healthy subject) This metabolic

autoregulation explains why anginal

at-tacks in coronary sclerosis occur only

during exercise (B, patient) At rest, the

pathologically elevated flow resistance

is compensated by a corresponding

de-crease in arteriolar resistance, ensuringadequate myocardial perfusion Duringexercise, further dilation of arterioles isimpossible As a result, there is ischemiaassociated with pain Pharmacologicalagents that act to dilate arterioles wouldthus be inappropriate because at restthey may divert blood from underper-fused into healthy vascular regions onaccount of redundant arteriolar dilation.The resulting “steal effect” could pro-voke an anginal attack (3) The intra-myocardial pressure, i.e., systolicsqueeze, compresses the capillary bed.Myocardial blood flow is halted duringsystole and occurs almost entirely dur-

ing diastole Diastolic wall tension

(“pre-load”) depends on ventricular volumeand filling pressure The organic nitratesreduce preload by decreasing venousreturn to the heart

Factors determining oxygen mand The heart muscle cell consumes

de-the most energy to generate contractileforce O2demand rises with an increase

in (1) heart rate, (2) contraction velocity, (3) systolic wall tension (“afterload”).

The latter depends on ventricular ume and the systolic pressure needed toempty the ventricle As peripheral resis-tance increases, aortic pressure rises,hence the resistance against which ven-tricular blood is ejected O2demand islowered by β-blockers and Ca-antago-nists, as well as by nitrates (p 308)

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B Pathogenesis of exertion angina in coronary sclerosis

O2-supply

during

diastole

O2-demandduringsystoleFlow resistance:

1 Heart rate

2 Contraction velocity

Compensa-ContractionvelocityAfterload

Additionaldilationnot possible

Anginapectoris

Left atriumCoronary artery

Antianginal Drugs

Antianginal agents derive from three

drug groups, the pharmacological

prop-erties of which have already been

pre-sented in more detail, viz., the organic

nitrates (p 120), the Ca2+ antagonists

(p 122), and the β-blockers (pp 92ff)

Organic nitrates (A) increase blood

flow, hence O2supply, because diastolic

wall tension (preload) declines as

ve-nous return to the heart is diminished

Thus, the nitrates enable myocardial

flow resistance to be reduced even in

the presence of coronary sclerosis with

angina pectoris In angina due to

coro-nary spasm, arterial dilation overcomes

the vasospasm and restores myocardial

perfusion to normal O2 demand falls

because of the ensuing decrease in the

two variables that determine systolic

wall tension (afterload): ventricular

fill-ing volume and aortic blood pressure

Calcium antagonists (B) decrease

O2demand by lowering aortic pressure,

one of the components contributing to

afterload The dihydropyridine

nifedi-pine is devoid of a cardiodepressant

ef-fect, but may give rise to reflex

tachy-cardia and an associated increase in O2

demand The catamphiphilic drugs

ve-rapamil and diltiazem are

cardiode-pressant Reduced beat frequency and

contractility contribute to a reduction in

O2demand; however, AV-block and

me-chanical insufficiency can dangerously

jeopardize heart function In coronary

spasm, calcium antagonists can induce

spasmolysis and improve blood flow

(p 122)

β-Blockers (C) protect the heart

against the O2-wasting effect of

sympa-thetic drive by inhibiting

β-receptor-mediated increases in cardiac rate and

speed of contraction

Uses of antianginal drugs (D) For

relief of the acute anginal attack,

rap-idly absorbed drugs devoid of

cardiode-pressant activity are preferred The drug

of choice is nitroglycerin (NTG,

0.8–2.4 mg sublingually; onset of action

within 1 to 2 min; duration of effect

~30 min) Isosorbide dinitrate (ISDN)

can also be used (5–10 mg ly); compared with NTG, its action issomewhat delayed in onset but of long-

sublingual-er duration Finally, nifedipine may beuseful in chronic stable, or in variant an-gina (5–20 mg, capsule to be bitten andthe contents swallowed)

For sustained daytime angina

pro-phylaxis, nitrates are of limited value

because “nitrate pauses” of about 12 hare appropriate if nitrate tolerance is to

be avoided If attacks occur during the

day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morn-ing and at noon (e.g., ISDN 40 mg in ex-tended-release capsules) Because ofhepatic presystemic elimination, NTG isnot suitable for oral administration.Continuous delivery via a transdermalpatch would also not seem advisablebecause of the potential development of

tolerance With molsidomine, there is

less risk of a nitrate tolerance; however,due to its potential carcinogenicity, itsclinical use is restricted

The choice between calcium onists must take into account the diffe-rential effect of nifedipine versus verap-amil or diltiazem on cardiac perfor-

antag-mance (see above) When β-blockers are

given, the potential consequences of ducing cardiac contractility (withdraw-

re-al of sympathetic drive) must be kept inmind Since vasodilating β2-receptorsare blocked, an increased risk of va-sospasm cannot be ruled out Therefore,monotherapy with β-blockers is recom-mended only in angina due to coronarysclerosis, but not in variant angina

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

D Clinical uses of antianginal drugs

B Effects of Ca-antagonists

O2-supply O2-demand

Afterload

RateContractionvelocity

β-blocker

Relaxationofresistancevessels

Relaxation ofcoronary spasm

antagonists

Relaxation ofcoronary spasm

Venous

capacitance

vessels

Resistancevessels

Vasorelaxation

Angina pectorisCoronary sclerosis Coronary spasm

GTN, ISDNNifedipineLong-acting nitratesCa-antagonistsβ-blocker

Therapy of attack

Anginal prophylaxis

Acute Myocardial Infarction

Myocardial infarction is caused by

acute thrombotic occlusion of a coronary

artery (A) Therapeutic interventions

aim to restore blood flow in the

occlud-ed vessel in order to rocclud-educe infarct size

or to rescue ischemic myocardial tissue

In the area perfused by the affected

ves-sel, inadequate supply of oxygen and

glucose impairs the function of heart

muscle: contractile force declines In the

great majority of cases, the left ventricle

(anterior or posterior wall) is involved

The decreased work capacity of the

in-farcted myocardium leads to a

reduc-tion in stroke volume (SV) and hence

cardiac output (CO) The fall in blood

pressure (RR) triggers reflex activation

of the sympathetic system The

resul-tant stimulation of cardiac

β-adreno-ceptors elicits an increase in both heart

rate and force of systolic contraction,

which, in conjunction with an

α-adren-oceptor-mediated increase in

peripher-al resistance, leads to a compensatory

rise in blood pressure In ATP-depleted

cells in the infarct border zone, resting

membrane potential declines with a

concomitant increase in excitability

that may be further exacerbated by

acti-vation of β-adrenoceptors Together,

both processes promote the risk of fatal

ventricular arrhythmias As a

conse-quence of local ischemia, extracellular

concentrations of H+and K+rise in the

affected region, leading to excitation of

nociceptive nerve fibers The resultant

sensation of pain, typically experienced

by the patient as annihilating, reinforces

sympathetic activation

The success of infarct therapy

criti-cally depends on the length of time

between the onset of the attack and the

start of treatment Whereas some

thera-peutic measures are indicated only after

the diagnosis is confirmed, others

ne-cessitate prior exclusion of

contraindi-cations or can be instituted only in

spe-cially equipped facilities Without

ex-ception, however, prompt action is

im-perative Thus, a staggered treatment

schedule has proven useful

The antiplatelet agent, ASA, is

ad-ministered at the first suspected signs ofinfarction Pain due to ischemia is treat-

ed predominantly with antianginal

drugs (e.g., nitrates) In case this

treat-ment fails (no effect within 30 min,

ad-ministration of morphine, if needed in combination with an antiemetic to pre-

vent morphine-induced vomiting, is dicated If ECG signs of myocardial in-farction are absent, the patient is stabi-lized by antianginal therapy (nitrates, β-blockers) and given ASA and heparin.When the diagnosis has been con-firmed by electrocardiography, at-tempts are started to dissolve thethrombus pharmacologically (thrombo-

in-lytic therapy: alteplase or nase) or to remove the obstruction by

streptoki-mechanical means (balloon dilation or

angioplasty) Heparin is given to

pre-vent a possible vascular reocclusion, i.e.,

to safeguard the patency of the affectedvessel Regardless of the outcome ofthrombolytic therapy or balloon dila-

tion, a β-blocker is administered to

sup-press imminent arrhythmias, unless it iscontraindicated Treatment of life-threatening ventricular arrhythmiascalls for an antiarrhythmic of the class

of Na+-channel blockers, e.g., lidocaine.

To improve long-term prognosis, use ismade of a β-blocker (! incidence of re-infarction and acute cardiac mortality)

and an ACE inhibitor (prevention of

ventricular enlargement after

myocar-dial infarction) (A).

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

A Drugs for the treatment of acute myocardial infarction

A Algorithm for the treatment of acute myocardial infarction

noyes

Sympatheticnervous system

Peripheralresistance

no

Standard therapyβ-blocker, ACE-inhibitor, optional heparin

ST-segment

elevation

left bundle block

Thrombolysissuccessful

no

Angioplastyopt GPIIb/IIIA-blocker

yes

yes

no

Arterial hypertension (high blood

pres-sure) generally does not impair the

well-being of the affected individual;

however, in the long term it leads to

vascular damage and secondary

compli-cations (A) The aim of antihypertensive

therapy is to prevent the latter and,

thus, to prolong life expectancy

Hypertension infrequently results

from another disease, such as a

cate-cholamine-secreting tumor

(pheochro-mocytoma); in most cases the cause

cannot be determined: essential

(pri-mary) hypertension Antihypertensive

drugs are indicated when blood

pres-sure cannot be sufficiently controlled by

means of weight reduction or a

low-salt diet In principle, lowering of either

cardiac output or peripheral resistance

may decrease blood pressure (cf p 306,

314, blood pressure determinants) The

available drugs influence one or both of

these determinants The therapeutic

utility of antihypertensives is

deter-mined by their efficacy and tolerability

The choice of a specific drug is

deter-mined on the basis of a benefit:risk

as-sessment of the relevant drugs, in

keep-ing with the patient’s individual needs

In instituting single-drug therapy

(monotherapy), the following

consider-ations apply: β-blockers (p 92) are of

value in the treatment of juvenile

hy-pertension with tachycardia and high

cardiac output; however, in patients

disposed to bronchospasm, even β1

-se-lective blockers are contraindicated

Thiazide diuretics (p 162) are

potential-ly well suited in hypertension

associat-ed with congestive heart failure;

how-ever, they would be unsuitable in

hypo-kalemic states When hypertension is

accompanied by angina pectoris, the

preferred choice would be a β-blocker

or calcium antagonist (p 122) rather

than a diuretic As for the calcium

an-tagonists, it should be noted that

verap-amil, unlike nifedipine, possesses

car-diodepressant activity α-Blockers may

be of particular benefit in patients with

benign prostatic hyperplasia and

im-paired micturition At present, only blockers and diuretics have undergonelarge-scale clinical trials, which haveshown that reduction in blood pressure

β-is associated with decreased morbidityand mortality due to stroke and conges-tive heart failure

In multidrug therapy, it is

neces-sary to consider which agents rationallycomplement each other A β-blocker(bradycardia, cardiodepression due tosympathetic blockade) can be effective-

ly combined with nifedipine (reflextachycardia), but obviously not with ve-rapamil (bradycardia, cardiodepres-sion) Monotherapy with ACE inhibitors(p 124) produces an adequate reduc-tion of blood pressure in 50% of pa-tients; the response rate is increased to90% by combination with a (thiazide)diuretic When vasodilators such as di-hydralazine or minoxidil (p 118) aregiven, β-blockers would serve to pre-vent reflex tachycardia, and diuretics tocounteract fluid retention

Abrupt termination of continuoustreatment can be followed by reboundhypertension (particularly with short

nitrogly-in pheochromocytoma

Antihypertensives for sion in pregnancy are β1-selectiveadrenoceptor-blockers, methyldopa(p 96), and dihydralazine (i.v infusion)for eclampsia (massive rise in bloodpressure with CNS symptoms)

hyperten-Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

In severe cases further combination with

A Arterial hypertension and pharmacotherapeutic approaches

Diur etics

β-blockers

antagonists

Drug selectionaccording to conditionsand needs of theindividual patient

Heart failure Coronary atherosclerosis angina pectoris, myocardial infarction, arrhythmia Atherosclerosis of cerebral vessels cerebral infarction stroke Cerebral hemorrhage

Atherosclerosis of renal vessels renal failure

Decreased life expectancy [mm Hg]

α-blockere.g.,prazosine

Central

α2-agoniste.g., clonidine

Vasodilatione.g.,dihydralazineminoxidilReserpine

The venous side of the circulation,

ex-cluding the pulmonary circulation,

ac-commodates ~ 60% of the total blood

volume; because of the low venous

pressure (mean ~ 15 mmHg) it is part of

the low-pressure system The arterial

vascular beds, representing the

high-pressure system (mean pressure,

~ 100 mmHg), contain ~ 15% The

arteri-al pressure generates the driving force

for perfusion of tissues and organs

Blood draining from the latter collects in

the low-pressure system and is pumped

back by the heart into the high-pressure

system

The arterial blood pressure (ABP)

depends on: (1) the volume of blood per

unit of time that is forced by the heart

into the high-pressure system—cardiac

output corresponding to the product of

stroke volume and heart rate (beats/

min), stroke volume being determined

inter alia by venous filling pressure; (2)

the counterforce opposing the flow of

blood, i.e., peripheral resistance, which

is a function of arteriolar caliber

Chronic hypotension (systolic BP

< 105 mmHg) Primary idiopathic

hypo-tension generally has no clinical

impor-tance If symptoms such as lassitude

and dizziness occur, a program of

physi-cal exercise instead of drugs is

advis-able

Secondary hypotension is a sign of

an underlying disease that should be

treated first If stroke volume is too low,

as in heart failure, a cardiac glycoside

can be given to increase myocardial

contractility and stroke volume When

stroke volume is decreased due to

insuf-ficient blood volume, plasma

substi-tutes will be helpful in treating blood

loss, whereas aldosterone deficiency

re-quires administration of a

mineralocor-ticoid (e.g., fludrocortisone) The latter

is the drug of choice for orthostatic

hy-potension due to autonomic failure A

parasympatholytic (or electrical

pace-maker) can restore cardiac rate in

bradycardia

Acute hypotension Failure of

or-thostatic regulation A change from therecumbent to the erect position (ortho-stasis) will cause blood within the low-pressure system to sink towards the feetbecause the veins in body parts belowthe heart will be distended, despite a re-flex venoconstriction, by the weight ofthe column of blood in the blood ves-sels The fall in stroke volume is partlycompensated by a rise in heart rate Theremaining reduction of cardiac outputcan be countered by elevating the pe-ripheral resistance, enabling blood pres-sure and organ perfusion to be main-tained An orthostatic malfunction ispresent when counter-regulation failsand cerebral blood flow falls, with resul-tant symptoms, such as dizziness,

“black-out,” or even loss of

conscious-ness In the sympathotonic form,

sympa-thetically mediated circulatory reflexesare intensified (more pronouncedtachycardia and rise in peripheral resis-tance, i.e., diastolic pressure); however,there is failure to compensate for the re-duction in venous return Prophylactictreatment with sympathomimeticstherefore would hold little promise In-stead, cardiovascular fitness trainingwould appear more important An in-crease in venous return may beachieved in two ways Increasing NaClintake augments salt and fluid reservesand, hence, blood volume (contraindi-cations: hypertension, heart failure).Constriction of venous capacitance ves-sels might be produced by dihydroer-gotamine Whether this effect could al-

so be achieved by an metic remains debatable In the very

α-sympathomi-rare asympathotonic form, use of

sympa-thomimetics would certainly be able

reason-In patients with hypotension due tohigh thoracic spinal cord transections(resulting in an essentially completesympathetic denervation), loss of sym-pathetic vasomotor control can be com-pensated by administration of sympa-thomimetics

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

β-SympathomimeticsCardiac

glycosides Parasym-patholytics

Redistribution of blood volume

Initial condition

Constriction of venous capacitance

vessels, e.g., dihydroergotamine if

appropriate, α-sympathomimetics

Increase of blood volume

BP

Sa lt

NaCl + H2O

0,9%

NaCl

NaCl+ H2O

corticoidBP

Mineralo-BP

Gout is an inherited metabolic disease

that results from hyperuricemia, an

el-evation in the blood of uric acid, the

end-product of purine degradation The

typical gout attack consists of a highly

painful inflammation of the first

meta-tarsophalangeal joint (“podagra”) Gout

attacks are triggered by precipitation of

sodium urate crystals in the synovial

fluid of joints

During the early stage of

inflamma-tion, urate crystals are phagocytosed by

polymorphonuclear leukocytes (1) that

engulf the crystals by their ameboid

cy-toplasmic movements (2) The

phago-cytic vacuole fuses with a lysosome (3)

The lysosomal enzymes are, however,

unable to degrade the sodium urate

Further ameboid movement dislodges

the crystals and causes rupture of the

phagolysosome Lysosomal enzymes

are liberated into the granulocyte,

re-sulting in its destruction by

self-diges-tion and damage to the adjacent tissue

Inflammatory mediators, such as

pros-taglandins and chemotactic factors, are

released (4) More granulocytes are

at-tracted and suffer similar destruction;

the inflammation intensifies—the gout

attack flares up

Treatment of the gout attack aims

to interrupt the inflammatory response

The drug of choice is colchicine, an

alka-loid from the autumn crocus (Colchicum

autumnale) It is known as a “spindle

poison” because it arrests mitosis at

metaphase by inhibiting contractile

spindle proteins Its antigout activity is

due to inhibition of contractile proteins

in the neutrophils, whereby ameboid

mobility and phagocytotic activity are

prevented The most common adverse

effects of colchicine are abdominal pain,

vomiting, and diarrhea, probably due to

inhibition of mitoses in the rapidly

di-viding gastrointestinal epithelial cells

Colchicine is usually given orally (e.g.,

0.5 mg hourly until pain subsides or

gas-trointestinal disturbances occur;

maxi-mal daily dose, 10 mg)

Nonsteroidal anti-inflammatory

drugs, such as indomethacin and nylbutazone, are also effective In se- vere cases, glucocorticoids may be in-

phe-dicated

Effective prophylaxis of gout tacks requires urate blood levels to be

at-lowered to less than 6 mg/100 mL

Diet Purine (cell nuclei)-rich foods

should be avoided, e.g., organ meats.Milk, dairy products, and eggs are low inpurines and are recommended Coffeeand tea are permitted since the meth-ylxanthine caffeine does not enter pu-rine metabolism

Uricostatics decrease urate duction Allopurinol, as well as its accu-

pro-mulating metabolite alloxanthine purinol), inhibit xanthine oxidase,which catalyzes urate formation fromhypoxanthine via xanthine These pre-cursors are readily eliminated via theurine Allopurinol is given orally(300–800 mg/d) Except for infrequentallergic reactions, it is well toleratedand is the drug of choice for gout pro-phylaxis At the start of therapy, gout at-tacks may occur, but they can be pre-vented by concurrent administration of

(oxy-colchicine (0.5–1.5 mg/d) Uricosurics, such as probenecid, benzbromarone (100 mg/d), or sulfinpyrazone, pro-

mote renal excretion of uric acid Theysaturate the organic acid transportsystem in the proximal renal tubules,making it unavailable for urate reab-sorption When underdosed, they inhib-

it only the acid secretory system, whichhas a smaller transport capacity Urateelimination is then inhibited and a goutattack is possible In patients with uratestones in the urinary tract, uricosuricsare contraindicated

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

A Gout and its therapy

Hypoxanthine

LysosomePhagocyte

Allopurinol

Osteoporosis is defined as a generalized

decrease in bone mass (osteopenia) that

affects bone matrix and mineral content

equally, giving rise to fractures of

verte-bral bodies with bone pain, kyphosis,

and shortening of the torso Fractures of

the hip and the distal radius are also

common The underlying process is a

disequilibrium between bone formation

by osteoblasts and bone resorption by

osteoclasts

Classification: Idiopathic

osteopor-osis type I, occurring in postmenopausal

females; type II, occurring in senescent

males and females (>70 y) Secondary

osteoporosis: associated with primary

disorders such as Cushing’s disease, or

induced by drugs, e.g., chronic therapy

with glucocorticoids or heparin In these

forms, the cause can be eliminated

Postmenopausal osteoporosis

represents a period of accelerated loss

of bone mass The lower the preexisting

bone mass, the earlier the clinical signs

become manifest

Risk factors are: premature

meno-pause, physical inactivity, cigarette

smoking, alcohol abuse, low body

weight, and calcium-poor diet

Prophylaxis: Administration of

es-trogen can protect against

postmeno-pausal loss of bone mass Frequently,

conjugated estrogens are used (p 254)

Because estrogen monotherapy

increas-es the risk of uterine cancer, a gincreas-estagen

needs to be given concurrently (except

after hysterectomy), as e.g., in an oral

contraceptive preparation (p 256)

Under this therapy, menses will

contin-ue The risk of thromboembolic

disor-ders is increased and that of myocardial

infarction probably lowered Hormone

treatment can be extended for 10 y or

longer Before menopause, daily

cal-cium intake should be kept at 1 g

(con-tained in 1 L of milk), and 1.5 g

thereaf-ter

Therapy Formation of new bone

matrix is induced by fluoride

Adminis-tered as sodium fluoride, it stimulates

osteoblasts Fluoride is substituted for

hydroxyl residues in hydroxyapatite toform fluorapatite, the latter being moreresistant to resorption by osteoclasts Tosafeguard adequate mineralization ofnew bone, calcium must be supplied insufficient amounts However, simulta-neous administration would result inprecipitation of nonabsorbable calcium

fluoride in the intestines With sodium monofluorophosphate this problem iscircumvented The new bone formedmay have increased resistance to com-pressive, but not torsional, strain andparadoxically bone fragility may in-crease Because the conditions underwhich bone fragility is decreased re-main unclear, fluoride therapy is not inroutine use

Calcitonin (p 264) inhibits

osteo-clast activity, hence bone resorption As

a peptide it needs to be given by tion (or, alternatively, as a nasal spray).Salmonid is more potent than humancalcitonin because of its slower elimina-tion

injec-Bisphosphonates structurallymimic endogenous pyrophosphate,which inhibits precipitation and disso-lution of bone minerals They retardbone resorption by osteoclasts and, inpart, also decrease bone mineralization.Indications include: tumor osteolysis,hypercalcemia, and Paget’s disease.Clinical trials with etidronate, adminis-tered as an intermittent regimen, haveyielded favorable results in osteoporo-sis With the newer drugs clodronate,pamidronate, and alendronate, inhibi-tion of osteoclasts predominates; a con-tinuous regimen would thus appear to

be feasible

Bisphosphonates irritate

esophage-al and gastric mucus membranes; lets should be swallowed with a reason-able amount of water (250 mL) and thepatient should keep in an upright posi-tion for 30 min following drug intake

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