1.

Identify the therapeutic problem(s) where the pharmacist’s intervention may

benefit the patient.

LM is a stage 1 (mild) hypertension patient is managed with an ACE inhibitor, enalapril.

She has the signs and symptoms of congestive heart failure (CHF) namely by loss of appetite,
constipation, ankle edema and slight hepatomegaly, indicative of right ventricular
dysfunction. The incidence of CHF also increases markedly with age in this case; LM is an
80 year old, black female. Plan treatment initiated by her physician is beneficial with a
cardiac glycoside or other positive inotropic agent and a diuretic, furosemide. Since ACE
inhibitor is somewhat less effective in black patients (produce relatively lesser renin) in
hypertension management, diuretic is used in combination. Digoxin is the only cardiac
glycoside extensively reviewed because of its predominant use in clinical medicine.

2. Identify and prioritize the patient specific factors that must be considered to
achieve the desired therapeutic outcomes.

 LM has congestive heart failure and high blood pressure is controlled by an ACE
inhibitor in reducing the generation of a potent vasoconstrictor, angiotensin II. ACE
inhibitor prolonged the survival of severe CHF patients and produce regression of left
ventricular hypertrophy. Positive inotropic drugs are in use to increase cardiac output
in CHF patient.
 LM’s a black female patient may be of less effectiveness with the use of ACE
inhibitor. Increase dosage of ACE inhibitor or use diuretic in combination for
hypertension management.
 The underlying reduction in cardiac output in CHF stimulates compensatory
mechanisms, leading to sodium and water retention and increased sympathetic
activity; liberating symptom of ankle edema. Systemic congestion of hepatomegaly
occur secondary to failure of the right ventricle. Restriction of fluid is vital to prevent
further congestions. Loop diuretic may help excrete most fluid.
 Generalized visceral edema may also occur, causing constipation, nausea (loss of
appetite) and abdominal distension.
 Age-related decreases in renal and hepatic function are normal in old people; may
require dose of drugs adjustment which are extensively metabolized by hepatic
enzymes and/ or renal excreted.
 3. Conduct a thorough and mechanistically oriented structure-activity analysis of
all therapeutic alternatives provided in the case.

Compound 1, high-ceiling/loop diuretic, furosemide, a derivatice of anthranilic acid or o-

aminobenzoic acid. The most active of a series of variously substituted derivatives are
furosemide. The sulphonamide group gives acidity to this molecure making possible for the
formation of water-soluble sodium salt which can be used for intravenous administration.
Replacement or removal of the sulphonamide group yields compound with little or no
diuretic activity. The chlorine and sulphonamide substitutions are features seen in other
diuretics as well. An electron-withdrawing group is necessary for diuretic activity.
Substitution with a lipophilic group on the aromatic amino group gives a marked increase in
diuretic potency. Furosemide is a stronger acid than that of thiazide diuretics (pKa 3.9) due to
its possession of a free carboxyl group. This drug is excreted primarily unchanged. A small
amount of metabolism (20%) may take place on the furan ring. Food affects its oral
absorption bioavailability. 80% is excreted in urine unchanged. It has a shorter duration of
action, about 6-8 hours and better effect than that of thiazide diuretics in electrolyte and water
excretion. Furosemide is effective in treatment of edemas connected with cardiac, hepatic,
and renal sites and is also used in the treatment of hypertension. Dosage of furosemide is 20-
80mg per day, and may be given in divided doses due to the short duration of action.

Compound 2 is milrinone, “non-glycoside” produce both positive inotropic and

concentration-dependent vasodilatory effects. Milrinone is a specific phosphodiesterase
inhibitor (phosphodiesterase fraction III) in the myocardium. This inhibition leads to elevated
levels of cAMP, increases in the intracellular calcium ions, followed by muscle contractility.
It undergoes some conjugative metabolism in the liver and is excreted unchanged in the
urine. Similar to its structurally related agent, inamrinone, it is of short-term intravenous
administration in patient with severe heart failure refractory to other measures. Unlike
Milrinon, inamrinone, orally active gives drawbacks of gastrointestinal disturbance,
thrombocytopenia, and impairement of the liver function. Milrinone is of an more potent than
inamrinone, reported to be better tolerated, with no apparent thrombocytopenia or
gastrointestinal disturbance. Renal impairment patients require reduced dosages of Milrinone.

Compound 3, compound 4, and compound 5 are cardiac glycosides for they processed
two portions; the sugar and the non-sugar (aglycone) moiety. The aglycone portion has a
unique set of steroid rings. Rings A-B and C-D are cis fused, while B-D rings are of trans
configuration. This gives a “U-shape” characteristic to the aglycone nucleus of cardiac
glycosides. In most cases, there are two angular methyl groups at C-10 and C-13 on the
steroid nucleus. C-14’s hydroxyl group is normally unsubstituted. Additional hydroxyl
groups may be found at C-12 and C-16; distinguishes the important genins: digitoxigenin,
digoxigenin, and gitoxigenin. These additional hydroxyl groups signify its partitioning and
pharmacokinetic functions for each glycoside. Lactone ring is located at C-17, another major
structural feature of the cardiac aglycones. Cardenolines are of plant origin cardiac
glycosides, possess a five-membered α,β- unsaturated lactone ring, whereas bufadienolides,
derived from animal origin has a six-membered lactone ring with two conjugated double
bonds (α-pyrone). C-3 aglycone portion is usually conjugated to a monosaccharide or a
polysaccharide with β-1,4-glucosidic linkages. These sugar moieties usually exist in β-
conformation in cardiac glycosides. In some cases, the sugars exist in the acetylated form.
Presence of an O-acetyl group of a sugar has marked significance of lipophilic character and
pharmacokinetics of the entire glycoside. Compound 3 is Ouabagenin (Ouabain), derived
from the plant, Strophanthus gratus. Ouabagenin has a polyhydroxylated steroidal nucleus,
with an additional hydroxyl group at C-5 with an angular aldehyde group being replaced by
methyl group at C-10 position. Ouabagenin is conjugated only to L-rhamnose. Compound 4
and 5 are Digoxin differing in their steroid ring fusion configuration of A-B rings.
 4. Evaluate the SAR findings against the patient specific factors and desired
therapeutic outcomes and make a therapeutic decision.

Compound 1, furosemide, produces a peak dieresis – high ceiling diuretics (loop

diuretic). It acts on the thick ascending limb of Loop of Henle, inhibiting the luminal
Sodium/Potassium/Chloride symporter. It has a quick onset and short duration of activity;
taking effect in about 30 minutes and lasts for about 6 hours. This may be used to treat LM’s
ankle edema in association with heart failure and her hypertension management. Close
medical supervision and dose evaluation is required for any electrolyte disturbance.
Furosemide effect may be decreased if taken with food. Toxicity level of aminoglycoside,
ACE inhibitor, may be increased by furosemide and should be used with cautions.

Compound 2, milrinone, positive inotropic agents by inhibiting the specific

phosphodiesterase fraction III, in cardiac and vascular tissue, resulting in vasodilation and
inotropic effects with little chronotropic activity. Milrinone may kept for future use if LM
shows unresponsiveness to other acute heart failure therapies, and is mostly in used for for
hospitalized patient. The Institute for Safe Medication Practices (ISMP) includes this
medication among its list of drugs which have a heightened risk of causing significant patient
harm when used in error.

Compound 3 is Ouabagenin (Ouabain), digitalis glycoside are no longer used

therapeutically but had been previously administered only intravenously because of poor
absorption.

Compound 4 and 5 are digoxin derivatives differing in cis and trans A-B fusion rings of
the steroid nucleus. They are indicated to treat mild-to-moderate heart failure. This is also
under the high alert medication list of ISMP. Digoxin has a long half-life and maintenance
doses need to be given only once daily. Renal function is the most important determinant of
digoxin dosage, whereas elimination of digoxin depends on metabolism by the liver.
Hypokalaemia predisposes to digitalis toxicity may be given potassium supplement if
necessary. Digoxin peak serum concentration may be decreased if taken with food. Maintain
adequate intake of potassium to decrease the risk of hypokalaemia. C-17 lactone has an
important role in receptor binding. Unsaturated lactone ring gives a more promising activity
than saturated lactone ring. This ring structure may be replaced by several α,β-unsaturated
open chain groups with little or no loss in activity. The steroid nucleus (A-B, C-D) ring
system, lead structure should not be neglected for cardiac glycoside activity for lactone alone
show no sodium, potassium inhibitory activity. C-D cis ring juncture appears critical for
activity could be a requirement of changes in the spatial orientation of the 17-substituent. C-
14 β-OH is to be dispensable. It is needed to retain the sp3 and cis character of the C-D ring
juncture. Lastly, the A-B cis ring (compound 5) may not be mandatory for cardiac glycoside
activity. However, conversion to an A-B trans ring system (compound 4) leads to a
significant drop in activity.

LM’s should firstly initiate on low dose furosemide (compound 1) to decrease the risk of
drug interactions but may increase dosage if her ankle edema shows no sign of improvement.
Enalapril medication is continued for her hypertension management. Monitor patient’s blood
pressure on a regular basis. Digoxin (compound 5) is in used for LM’s CHF treatment.
Constant monitoring of plasma-digoxin concentration is necessary to avoid hypokaleamia
occurrence. Toxicity can often be managed by discontinuing digoxin. Digoxin offers several
benefits for patients in normal sinus rhytim with CHF secondary to systolic dysfunction who
are receiving concurrent treatment with diuretics and ACE inhibitors. Digoxin decreases
symptoms, increases exercise performance, improves sympathetic/parasympathetic
imbalances, reduces levels of harmful circulating neurohormones, and decreases hospital
admission secondary to HF. Other suggestions on LM’s CHF may be of vasodilators, nitrates,
beta-adrenergic blocking agents (may reverse the remodelling process occurring in HF),
dobutamine.
 5. Counsel your patient.

Therapeutic goals are achieved using a combination of patient and family education and

support, nonpharmacologic and pharmacologic therapies, surgical interventions, and device

therapy. LM should restrict her salt intake (taking in account of her old age; higher sodium

sensitivity), initial reduction of the heart’s workload with abbreviated rest followed by

exercise training upon recovery, lifestyle changes, and identification, treatment, and removal

of precipitating causes. CHF therapy consists of neurohormonal blockade with ACE inhibitor

(enalapril). diuretics are prescribed as needed to manage fluid overload with the lowest dose

which maintains euvolemia. Prior notification is to be noted by doctors or pharmacist if LM

were to take NSAIDs, which would lead to a reduction in GFR and renal blood flow and an

increase in sodium and water retention. In addition, COX-2 inhibitors may constitutively

expressed in the kidney and is partially responsible for the synthesis of some renal

prostaglandins and edema is reported as its adverse effect. This both NSAIDs and COX-2

inhibitors are to be avoided in HF patients.

Patient and family education are vital with the aids of discussion, pamphlets on signs and

symptoms of heart failure, medications, aiding in emphasizing on patient’s compliance, and

routine follow-up medical appointments. Diet management with a daily weight chart, sodium

restriction (<2g/day), alcohol restriction, fluid restriction ( ~ 2L/day). Patients are advice to

cease smoking, opt for regular exercise according to doctor’s instructions and orders.

Psychologically, patients are in need to express their feelings to friends and family. This may

help in evaluating her emotional needs and presence of depression. Facing death with end-of-

life issues may be brought in a discussion and not neglecting the moral supports and financial

needs of the patient. She may register for cardiac rehabilitation program which is beneficial
to patient with CHF. Frequent/intensive follow-up with LM is beneficial in monitoring her

progression.

Pharmacist-conducted “brown-bag” reviews may be of particular importance in patients

with CHF exacerbations. Stricter attention to these precipitating factors could markedly

reduce the number of hospitalization and ease the clinical and economic burden of CHF for

patients and society.