3. Basis: Chief Complaint:
increased shortness of
breath
History of Present Illness:
swolen legs
malaise
weakness
weight gain
paroxysmal nocturnal
dyspnea
ankle edema
PMH:
HF (LVEF of 15%)
orthopnea
HTN for 30 years
CAD
tachycardia
Medications:
Digoxin
Furosemide
Spirinolactone
Carvedilol
Amiodarone
4. Basis:
Physical Examination:
SOB
weight gain of 7 kg
hepatomegaly
+S1, S2
jugular venous
distention
edema
bibasal rales
Laboratory Findings:
2+ protein
BUN 32
SCr 1.9
5. Treatment Objectives
To decrease fluid retention
To decrease workload of the heart
To increase myocardial contractility
6. Pharmacologic intervention
1. Decreasing fluid retention
Drug of Choice: Loop Diuretics
Action: dec. NaCl and KCl reabsorption in
thick ascending limb of the loop of henle in
the nephron
Indication: antihypertensive, manifestation of
fluid overload, swollen legs, edema, weight
gain
7. Furosemide
Drug interactions:
Ace inhibitor – can cause hyperkalemia
Diuretics – may cause hypokalemia
Digoxin – may inc. its effect or may reach toxicity
8. Pharmacologic intervention2. To decrease workload of the heart
DRUGS EFFICACY SAFETY SUITABILITY COST
ACE inhibitor
++++ +++ ++++ ++
ARB +++ +++ +++ +++
Vasodilators ++ + + +
9. Drug of Choice: ACE inhibitorPharmacologic intervention
Alternative Drug: ARBs
ACEIs and ARBs ACTION:
Inhibits angiotensin converting
enzyme, thus, aldosterone and ADH secretion is
inhibited
ACE inhibitor will also inhibit the inactivation of
bradykinin, thus, prostaglandin synthesis will
increase
10. Drug of Choice: ACE inhibitorPharmacologic intervention
Alternative Drug: ARBs
ACE inhibitors:
Increase toxicity in patients with renal failure
Interaction with : K-sparing diuretics
Patient has ACEI-induced cough
12. Dobutamine ACTION:
directly binds to cardiac beta 1 receptors which
increase force of contraction
Pharmacologic interventionDrug of Choice:
Beta Adrenoceptor Agonist
16. Hypertension
One of the most common worldwide diseases
afflicting human and is a major risk factor for stroke,
myocardial infarction, vascular disease and CKD
HPN is defined as a Systolic Blood Pressure (SBP) of >
140 mmHg, or a Diastolic Blood Pressure (DBP) of >90
mmHg, or taking antihypertensive medication
17. Types of HPN Types:
1. Primary (Essential) 90-95%
Chronic High blood pressure without a source or
associated with any other disease
Most common form
2. Secondary 5-10%
• Elevation of BP associated with another disease such
as kidney disease
• Causes include: CKD, D/o of adrenal gland,
Pregnancy, Hyperparathyroidism
19. Risk factors
Family History of High BP
Family Hx of Premature
CVD
Diabetes
Race (African American)
Lifestyle Risk Factors:
Weight (BMI >30)
Stress
Sedentary lifestyle
Diet
Smoking
Alcohol (F:>1 Drink/day;
M: >2 Drinks/day)
Birth control pills
Can’t be changed Can be changed
20. Treatment Goals
Use and Maximize nonpharmacologic therapies in
combination with pharmacotherapy
Individualize all therapies based on compelling
indications and comorbid conditions
Treat systolic BP to recommended goal as primary
focus (esp. patients >50 yrs old)
Ultimate treatment goal is the reduction of
cardiovascular and renal morbidity & mortality
21. Basis of DiagnosisHistory:
59y/o, Male
African American
Hypertension for 30 years
Diabetes Mellitus (DM) type 2
for 5 years
Prior cigarette smoker 3-4
packs/week; quit 30 years ago
Social drinker; 6 cans of
beer/week
Medications:
Furosemide, 80mg PO
QAM
Spironolactone, 12.5mg
PO QD
Carvedilol, 25mg PO
QAM, 12.5mg PO QPM
Physical Examination:
BP 153/91 mmHg
BMI of 26.4 =
Overweight
22. Choice of Anti-HPN drugs depend
on:
Stage of hypertension
Physical factors( cardiac, renal complications)
Individualized
prescribed on a trial basis
25. Angiotensin-Receptor Blockers
Competitive angiotensin II receptor antagonists
Effect same as ACEIs
Vasodilatation and decreased sodium retention
Do not block bradykinin metabolism
Same efficacy with ACEIs; more expensive
For those unable to tolerate ACEIs
Losartan, Valsartan - first marketed AT1 receptor
blocker
27. NONPHARMACOLOGIC THERAPY
Appropriate lifestyle modifications are important therapies in
both the prevention and treatment of hypertension.
The prevalence of hypertension is 50% greater in overweight
28. PATIENT EDUCATION
Immediate reporting of any adverse side effects,
especially slow or irregular heartbeat, dizziness,
weakness, breathing difficulty, gastric distress and
numbness or swelling of extremities
Taking medication on time as prescribed by the
physician, not skipping a dose or doubling a dose,
NOT discontinuing the medication, even, if the
patient is feeling well, without consulting the
physician first
29
29. PATIENT EDUCATION
Rising slowly from reclining position to reduce
lightheaded feeling,
Taking care in driving a car or operating machinery
if medication causes drowsiness.
Potentiation of adverse side effects by alcohol, esp
dizziness, weakness, sleepiness and confusion,
Reduction or cessation of smoking to help lower
blood pressure
30
PATIENT EDUCATION
30. PATIENT EDUCATION
Importance of diet in control of blood pressure ,
following the physician’s instructions regarding
appropriate diet for the individual, which may
include a low-salt diet or low sodium or weight
reduction diet if indicated.
Avoiding hot rubs and hot showers, which may
cause weakness or fainting.
Mild exercise on a regular basis as approved by the
physician.
31
PATIENT EDUCATION
31. SHERYL RAY YANG, MD
FEU-NRMF MEDICAL CENTER
Fairview, Quezon City
Tel no. 312-1234
Name:________________ Date: _______________
Age:_____ Sex:_____ Address:
__________________
Telmisartan 40 mg tablet # 7
(Micardis)
Sig. Take 1 tablet of Telmisartan daily for the
control of Hypertension. Follow up after 7
days.
Sheryl Ray B. Yang, M.D.
Lic. No. 3333_________
PTR no. 101010_______
33. Diabetes
Diagnosed as DM type 2 for 5 years.
Fasting glucose level of o f 210 mg/ dl
(Normal is 126 mg/dL/ 7 mmol/L)
HbA1C level of 7.2%
(Normal for the patient is less than 7 %)
34. Treatment Goals
1. Lower the fasting
glucose level less than
130 mg/dL.
2. Lower the HbA1c level
to 6.5-6.9 % in 3
months.
3. Follow a versatile diet
in relation to patient
preference.
4. Maintain the
therapeutic glucose level
for a long term and
educate the patient for
glucose monitoring.
5. Develop a routine
exercise for the patient.
35. Pharmacologic Intervention
Management of hyperglycemia in type 2 Diabetes: A
patient-centered Approach
A position statement of the American Diabetes
Association (ADA) and the European association for the
study of Diabetes (EASD)
PUBLISHED: APRIL 19, 2012
36.
37. 1. Classify the patient if its type 1 DM or type 2
-DM type 2
2. FBS level and HbA1c level?
- FBS- 210 mg/dL and HbA1c level of 7.2 %
3. Age of the patient and other pertinent data?
-59 years old
39. ARKEE REYLO P. JUSAY, MD
FEU-NRMF MEDICAL CENTER
Sta Mesa, Manila
Tel no. 312-1234
Name:________________ Date: _______________
Age:_____ Sex:_____ Address:
__________________
Glyburide 5 mg tablet # 7
(Micardis)
Sig. Take 1 tablet of Glyburide daily for the
control of Hyperglycemia. Follow up after 7
days.
ARKEE REYLO P. JUSAY, M.D.
Lic. No. 3333_________
PTR no. 101010_______
42. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
Amiodarone Class III
antiarrhythmi
c
• K+ Channel
blocker
• Beta
adrenoreceptor
and Ca Blocker
• Na channel
blockage
• Prolongs atrial
and
ventricular
repolarization
• slows heart
rate and AV
node
conduction
• Slow
intraventricula
r conduction
Ventricular
arrhythmias,
tachycardia,
atrial
fibrillation
Furosemide Loop Diuretic Inhibition of the
Na/K/2Cl
transporter in the
ascending
limb of Henle’s
loop
Increased
excretion of salt
and water;
reduces cardiac
preload and
afterload, reduces
pulmonary and
peripheral edema
Acute &
chronic heart
failure, severe
hypertension,
edematous
conditions
43. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
(Avandia)
Rosiglitazon
e
thiazolidinedio
ne (TZD)
Bind and stimulate
the nuclear
hormone receptor
peroxisome
proliferator
activated receptor-γ
(PPARγ)
increasing
insulin
sensitivity in
adipose tissue,
liver, and
muscle
Diabetes
Mellitus type
2
Spironolacto
ne
Aldosterone
Antagonist
(Potassium
sparing)
Blocks cytoplasmic
aldosterone
receptors in
collecting
tubules of nephron
Decreased salt
and water
retention;
reduces cardiac
remodeling and
mortality
Chronic heart
failure,
aldosteronism
,
hypertension,
adrenal tumor
Carvedilol Sympatholytic mixed alpha- and
beta-adrenergic
blockers
Prevents
sympathetic
cardiac
stimulation,
reduce renin
secretion
Hypertension,
heart failure
44. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
(Coumadi
n)
Warfarin
Oral
Anticoagu
lant
inhibits synthesis of
biologically active
coagulation factors
II, VII, IX, and X and
anticoagulant
proteins C and S
Reduces formation
of blood lots
Prophylaxis for
thrombosis
and thrombo-
embolism
Digoxin Cardiac
Glycoside
Na+, K+ ATPase
inhibition
• positive
inotropy
• increase
parasympathetic
(vagal) tone
• prolong
effective
refractory
period and slow
conduction
velocity
Heart failure,
Atrial
fibrillation
46. Carvedilol Warfarin Furosemide
Amiodarone
Management:
Additive effects of
severe
bradycardia,
cardiac arrest,
ventricular
fibrillation
Clinical
monitoring of
patient
hemodynamic
status and
response is
recommended.
Increased effects of
Warfarin
30% to 50%
reduction in
anticoagulant dosage
has been
recommended, in
addition to frequent
monitoring of the
patient and the
prothrombin time or
INR.
Additive
arrythmogenic
potential;
Amiodarone causes
dose-related
prolongation of QT
interval
Coadministration of
amiodarone with
medications that can
cause potassium
and/or magnesium
disturbances should
generally be avoided
47. Amiodarone Carvedilol Furosemide Spironolacto
ne
Digoxin
Manage
ment
may increase
serum digoxin
concentration
s by up to
100%
Empirical
reduction of
digitalis
dosage by
one-third to
one-half
should be
considered
decreases AV
nodal
conduction;
increase the
risk of
developing
bradycardia
Serum
digoxin
levels, heart
rate, and
blood
pressure
should be
monitored
closely.
diuretic-induced
hypokalemia and
hypomagnesemi
a may predispose
patients on
digitalis to
arrhythmias.
Digoxin,
potassium and
magnesium
levels should be
followed closely.
Spironolactone
may reduce the
tubular
secretion of
digoxin.
patient should
be monitored
for signs and
symptoms of
digoxin toxicity
48. Spironolactone Furosemide
Coumadin
(Warfarin)
Management
Spironolactone may
cause diuresis and
hemoconcentration
of clotting factors.
The effects of some
anticoagulants may
be decreased.
The INR or PT
should be
monitored, and oral
coagulant dosage
should be increased
as needed.
Loop diuretics may
displace warfarin
from plasma protein
binding sites.
Plasma warfarin
concentrations and
warfarin effects may
be increased.
Close monitoring of
the INR is
recommended,
particularly if
diuretic dosage
must be high.
49.
50. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
Amiodaron
e
Class III
antiarrhythmi
c
• K+ Channel
blocker
• Beta
adrenoreceptor
and Ca Blocker
• Na channel
blockage
• Prolongs atrial
and
ventricular
repolarization
• slows heart
rate and AV
node
conduction
• Slow
intraventricula
r conduction
Ventricular
arrhythmias,
tachycardia,
atrial
fibrillation
Furosemide Loop Diuretic Inhibition of the
Na/K/2Cl
transporter in the
ascending
limb of Henle’s
loop
Increased
excretion of salt
and water;
reduces cardiac
preload and
afterload, reduces
pulmonary and
peripheral edema
Acute &
chronic heart
failure, severe
hypertension,
edematous
conditions
51. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
(Avandia)
Rosiglitazon
e
thiazolidinedione
(TZD)
Bind and stimulate
the nuclear
hormone receptor
peroxisome
proliferator
activated receptor-γ
(PPARγ)
increasing
insulin
sensitivity in
adipose tissue,
liver, and
muscle
Diabetes
Mellitus type
2
Spironolact
one
Aldosterone
Antagonist
(Potassium
sparing)
Blocks cytoplasmic
aldosterone
receptors in
collecting
tubules of nephron
Decreased salt
and water
retention;
reduces cardiac
remodeling and
mortality
Chronic heart
failure,
aldosteronism
,
hypertension,
adrenal tumor
Carvedilol Sympatholytic mixed alpha- and
beta-adrenergic
blockers
Prevents
sympathetic
cardiac
stimulation,
reduce renin
secretion
Hypertension,
heart failure
52. DRUG CLASS MOA EFFECTS CLINICAL
APPLICATIO
NS
(Coumadi
n)
Warfarin
Oral
Anticoagu
lant
inhibits synthesis of
biologically active
coagulation factors
II, VII, IX, and X and
anticoagulant
proteins C and S
Reduces formation
of blood lots
Prophylaxis for
thrombosis
and thrombo-
embolism
Digoxin Cardiac
Glycoside
Na+, K+ ATPase
inhibition
• positive
inotropy
• increase
parasympathetic
(vagal) tone
• prolong
effective
refractory
period and slow
conduction
velocity
Heart failure,
Atrial
fibrillation
54. Amiodarone Carvedilol Furosemide Spironolacto
ne
Digoxi
n
Manage
ment
may increase
serum digoxin
concentration
s by up to
100%
Empirical
reduction of
digitalis
dosage by
one-third to
one-half
should be
considered
decreases AV
nodal
conduction;
increase the
risk of
developing
bradycardia
Serum
digoxin
levels, heart
rate, and
blood
pressure
should be
monitored
closely.
diuretic-induced
hypokalemia and
hypomagnesemi
a may predispose
patients on
digitalis to
arrhythmias.
Digoxin,
potassium and
magnesium
levels should be
followed closely.
Spironolactone
may reduce the
tubular
secretion of
digoxin.
patient should
be monitored
for signs and
symptoms of
digoxin toxicity
55. Spironolactone Furosemide
Coumadin
(Warfarin)
Management
Spironolactone may
cause diuresis and
hemoconcentration
of clotting factors.
The effects of some
anticoagulants may
be decreased.
The INR or PT
should be
monitored, and oral
coagulant dosage
should be increased
as needed.
Loop diuretics may
displace warfarin
from plasma protein
binding sites.
Plasma warfarin
concentrations and
warfarin effects may
be increased.
Close monitoring of
the INR is
recommended,
particularly if
diuretic dosage
must be high.
56. Warfarin
Glyburide
Management
sulfonylureas may enhance or reduce the
hypoprothrombinemic response to oral
anticoagulants
The patient should be monitored for altered
anticoagulation (PT/INR) and altered
glycemic effect
spironolactone
Telmisartan
Management
may increase the risk of hyperkalemia
Caution is advised if angiotensin II receptor
blockers must be used concurrently with
potassium-sparing diuretics
Notas do Editor
Orthopnea is shortness of breath (dyspnea) which occurs when lying flat,causing the person to have to sleep propped up in bed or sitting in a chair. It is the opposite of platypnea.
Orthopnea is shortness of breath (dyspnea) which occurs when lying flat,causing the person to have to sleep propped up in bed or sitting in a chair. It is the opposite of platypnea.
Bec. Of signs of congestion of the patient. dyspnea, Orthopnea, edemaWHY WAS THERE CONGESTION?Bec. Lisinopril is discontinued, therefore angiotensin II is produced forming aldosterone-w/c is resp. for Na and water retention.
Loop (furosemide)– 2-4hrs duration of action (shorter), IVMOA-dec. Nacl and KCl reabsorption in thick ascending limb of the loop of henle in the nephron.efficaceous for acute CHF bec. Of rapid onset of action, and can maximally reduce fluid (good for severe HPN).not for maintenance bec. Of shorter duration of actionThiazide – inhibits Na/Cl transporter in the distal convoluted tubule, 25mg/day PO, 8-12hrs Doa (longer)
Loop (furosemide)– 2-4hrs duration of action (shorter), 80 mg/day BID, POMOA- dec. Nacl and KCl reabsorption in thick ascending limb of the loop of henle in the nephron.efficaceous for acute CHF bec. Of rapid onset of action, and can maximally reduce fluid (good for severe HPN).not for maintenance bec. Of shorter duration of actionAdministration of drugs – may be taken with meals to reduce GI discomportToxicity: hypovolemia, hypokalemia, orthostatic hypotension, ototoxicity, allergic reaction,
Effect of diuretics to potassium:-decrease or hypokalemiaDigoxin – binds with Na K ATPase binding site (phosphorilated – binding will be greater), potassium dephosphorilates the binding site of Na k ATPase so if hypokalemic, Na K ATPase is more phosphorilated w/c has more higher affinity to digoxin – increase digoxin effect or may reach toxicity
VasodilatorsWhy more efficaceous? – bec. Arterioles – for afterload and veins – for preloadThe fastest way to reduce the afterload and preload is to reduce blood going back to the heart. So that the pressure will be reduced. Ace inhibitor – reduce peripheral resistance thereby reduce afterload and preload( reduce salt and water retention), 12-24hrs duration of action, 5 mg/ OD oral, toxicity – hyperkalemia, cough, edema, Cardiac glycosides – inhibits sodium pump, increase cardiac contractility,. 0.25mgx500 oral, 36-40hrs duration, toxicity-nausea and vomiting, diarrhea, cardiac arrhythmias (choice for chronic heart failure)
For maintenance – oral nitratesAdvantage-longer duration of action compare to nitroglycerine
For maintenance – oral nitratesAdvantage-longer duration of action compare to nitroglycerine
Symptoms of diabetes plus casual plasma glucoseconcentration 200 mg/dL (11.1 mmol/L). Casual isdefined as any time of day without regard to time sincelast meal.The classic symptoms of diabetes include polyuria, polydipsia,and unexplained weight loss.OrFasting plasma glucose 126 mg/dL (7.0 mmol/L). Fastingis defined as no caloric intake for at least 8 hours.OrTwo-hour plasma glucose 200 mg/dL during an oralglucose tolerance test. A 75-g glucose load or equivalent isrecommended when performing this test.(From Expert Committee on the Diagnosis and Classification ofDiabetes Mellitus. Report of the expert committee on the diagnosisand classification of diabetes mellitus. Diabetes Care20:1183–1197, 1997; and Expert Committee on the Diagnosis andClassification of Diabetes Mellitus. Follow-up report on the diagnosisof diabetes mellitus. Diabetes Care 26:3160–3167, 2003.)
Safety: adverseSuitability: interactionEfficacy: moa & therapeutic goal
1. AF occurs if rapid, disorganized electrical signals cause the heart's two upper chambers—called the atria (AY-tree-uh)—to fibrillate. The term "fibrillate" means to contract very fast and irregularly.2. The high sodium reabsorption capacity of the TAL makes loop diuretics a front-line therapy for acute relief of pulmonary and peripheral edema in the context of heart failure
3.binding to the β1- and β2-adrenergic receptors. Carvedilol blocks the binding to those receptors,which both slows the heart rhythm and reduces the force of the heart's pumping. This lowers blood pressure thus reducing the workload of the heartbinds to the α1-adrenergic receptors on blood vessels, causing them to constrict and raise blood pressure. Carvedilol blocks this binding to the α1-adrenergic receptors too,which also lowers blood pressure.
Coumarin anticoagulants block the γ-carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as the endogenous anticoagulant proteins C and S. The blockade results in incomplete coagulation factor molecules that are biologically inactive. The protein carboxylation reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to reactivate it. Warfarin prevents reductive metabolism of the inactive vitaminK epoxide back to its active hydroquinone form1) In myocardium, inhibit plasma membrane Na+/K+-ATPase, leading to increased cytoplasmic Ca2+ concentration, which results in positive inotropy; 2) in autonomic nervous system, inhibit sympathetic outflow and increase parasympathetic (vagal) tone; 3) at AV node, prolong effective refractory period and slow conduction velocity
1. (moderate) Amiodarone enhances the B-blocking effects of carvedilol since it is an inhibitor of hepatic CYP2C9 and P-glycoprotein which increases carvedilol’s concentration by inhibiting 1st pass metabolism. 2. (major) Amiodarone inhibition of CYP450 2C9, preventing Warfarin’s metabolism; may lead to significant hypoprothombinemia and bleeding; resulting to life-threatening bleeding complications.3. (major) Theoretically, coadministration with agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, because of additive arrhythmogenic potential.
This increase occurs because of the inhibition of digoxin secretion from renal tubules and the inhibition of the P-glycoprotein membrane transporter system.(major) Amiodarone has been suggested to increase intestinal transit time, reduce renal clearance and volume of distribution, displace digoxin from protein binding sites, as well as induce hypothyroidism, all of which may contribute to increased serum digoxin levels. In addition, both drugs may have additive bradycardic effects. Management: continued digitalis therapy should be evaluated if amiodarone is prescribed to patients treated with digitalis. Empirical reduction of digitalis dosage by one-third to one-half should be considered in patients who require concomitant treatment with these drugs.(moderate) Concomitant use of digitalis glycosides and beta-blockers including carvedilol may increase the risk of bradycardia. These agents slow atrioventricular conduction and decrease heart rate, hence they may have additive cardiac effects during coadministration. Pharmacokinetically, carvedilol has been shown to modestly increase the systemic bioavailability of digoxin. The mechanism may involve enhanced absorption as well as reduced renal excretion of digoxin due to inhibition of intestinal and renal P-glycoprotein efflux transporter by carvedilol. Management: monitored closely, particularly during the first few weeks of concomitant therapy(moderate) decreases plasma potassium concentration, which can increase the affinity of digoxin for the Na/K- ATPase predisposing to Digoxin toxicity; diuretic-induced hypokalemia and hypomagnesaemia may predispose patients to arrhythmias.(minor) Plasma clearance of digoxin may be decreased, and plasma levels may increase. Reduces tubular secretion of digoxin; Increased plasma digoxin levels
(minor) (minor)
1. Extracardiac effect: Peripheral vasodilation- Hypotension. Block thyroid conversion of T3-T4. AF occurs if rapid, disorganized electrical signals cause the heart's two upper chambers—called the atria (AY-tree-uh)—to fibrillate. The term "fibrillate" means to contract very fast and irregularly.2. The high sodium reabsorption capacity of the TAL makes loop diuretics a front-line therapy for acute relief of pulmonary and peripheral edema in the context of heart failure
The TZDs do not affect insulin secretion, but rather enhance the action of insulin at target tissues. TZDs are agonists for the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ).Mineralocorticoid receptor antagonists such as spironolactone competitively inhibit the interaction of aldosterone with the mineralocorticoid receptor, and thereby decrease expression of ENaC(apical membrane sodium channel).binding to the β1- and β2-adrenergic receptors. Carvedilol blocks the binding to those receptors,which both slows the heart rhythm and reduces the force of the heart's pumping. This lowers blood pressure thus reducing the workload of the heartbinds to the α1-adrenergic receptors on blood vessels, causing them to constrict and raise blood pressure. Carvedilol blocks this binding to the α1-adrenergic receptors too,which also lowers blood pressure.
1. Warfarin acts on the carboxylation pathway, not by inhibiting the carboxylase directly, but by blocking the epoxide reductase that mediates the regeneration of reduced vitamin K.Coumarinanticoagulants block the γ-carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as the endogenous anticoagulant proteins C and S. The blockade results in incomplete coagulation factor molecules that are biologically inactive. The protein carboxylation reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to reactivate it. Warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form2. 1) In myocardium, inhibit plasma membrane Na+/K+-ATPase, leading to increased cytoplasmic Ca2+ concentration, which results in positive inotropy; 2) in autonomic nervous system, inhibit sympathetic outflow and increase parasympathetic (vagal) tone; 3) at AV node, prolong effective refractory period and slow conduction velocitydigoxin exerts autonomic effects through its binding to sodium pumps in the plasma membranes of neurons in the central and peripheral nervous systems. These effects include inhibition of sympathetic nervous outflow, sensitization of baroreceptors, and increased parasympathetic (vagal) tone. Digoxin also alters the electrophysiologic properties of the heart by a direct action on the cardiac conduction system. At therapeutic doses, digoxin decreases automaticity at the AV node, prolonging the effective refractory period of AV nodal tissue and slowing conduction velocity through the node.
This increase occurs because of the inhibition of digoxin secretion from renal tubules and the inhibition of the P-glycoprotein membrane transporter system.(major) Amiodarone has been suggested to increase intestinal transit time, reduce renal clearance and volume of distribution, displace digoxin from protein binding sites, as well as induce hypothyroidism, all of which may contribute to increased serum digoxin levels. In addition, both drugs may have additive bradycardic effects. Management: continued digitalis therapy should be evaluated if amiodarone is prescribed to patients treated with digitalis. Empirical reduction of digitalis dosage by one-third to one-half should be considered in patients who require concomitant treatment with these drugs.(moderate) Concomitant use of digitalis glycosides and beta-blockers including carvedilol may increase the risk of bradycardia. These agents slow atrioventricular conduction and decrease heart rate, hence they may have additive cardiac effects during coadministration. Pharmacokinetically, carvedilol has been shown to modestly increase the systemic bioavailability of digoxin. The mechanism may involve enhanced absorption as well as reduced renal excretion of digoxin due to inhibition of intestinal and renal P-glycoprotein efflux transporter by carvedilol. Management: monitored closely, particularly during the first few weeks of concomitant therapy(moderate) decreases plasma potassium concentration, which can increase the affinity of digoxin for the Na/K- ATPase (since digoxin normally competes with K+ ions for the same binding site on the Na+/K+ ATPase pump.) predisposing to Digoxin toxicity; diuretic-induced hypokalemia and hypomagnesaemia may predispose patients to arrhythmias.(minor) Plasma clearance of digoxin may be decreased, and plasma levels may increase. Reduces tubular secretion of digoxin; Increased plasma digoxin levels
(minor) (minor)
Oral sulfonylureas may enhance or reduce the hypoprothrombinemic response to oral anticoagulants. The mechanism may be related to displacement from plasma protein binding sites. In addition, coumarin anticoagulants may cause an increase in blood levels of hypoglycemic agents, possibly by inhibiting their hepatic metabolism. Clinical data have been highly variable. MANAGEMENT: The patient should be monitored for altered anticoagulation (PT/INR) and altered glycemic effect when either of these drugs is added to or removed from a patient's regimen. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations), and to promptly report any signs of bleeding 2. Concomitant use of angiotensin II receptor blockers (ARBs) and potassium-sparing diuretics may increase the risk of hyperkalemia. Inhibition of angiotensin II results in decreased aldosterone secretion, which can lead to increases in serum potassium that may be additive with that induced by potassium-sparing diuretics. Life-threatening and fatal hyperkalemia can occur, especially when the combination is used in patients with risk factors such as renal impairment, diabetes, old age, severe or worsening heart failure, dehydration, and concomitant use of other agents that block the renin-angiotensin-aldosterone system or otherwise increase serum potassium levels. Individually, both ARBs and potassium-sparing diuretics have been associated with hyperkalemia in patients with renal impairment. ARBs may also cause deterioration of renal function in patients with chronic heart failure, and the risk is increased if they are sodium-depleted or dehydrated secondary to excessive diuresis. A retrospective analysis of the incidence of hyperkalemia in the CHARM study (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) found that the addition of candesartan to standard medical therapy for heart failure was associated with a 2- to 3-fold increase in risk of hyperkalemia, which was further amplified by cotreatment with spironolactone or ACE inhibitors.MANAGEMENT: Caution is advised if angiotensin II receptor blockers must be used concurrently with potassium-sparing diuretics, particularly in patients with renal impairment, diabetes, old age, severe or worsening heart failure, dehydration, or concomitant therapy with other agents that increase serum potassium such as nonsteroidal anti-inflammatory drugs, beta-blockers, cyclosporine, heparin, tacrolimus, and trimethoprim. Serum potassium and renal function should be checked prior to initiating therapy and regularly thereafter, and potassium supplementation as well as the use of potassium-containing salt substitutes should be avoided unless absolutely necessary and the benefits outweigh the potential risks. Patients should be given counseling on the appropriate levels of potassium and fluid intake, and advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. If spironolactone is prescribed with an ARB, some investigators recommend that its dosage not exceed 25 mg/day in high-risk patients.