Digoxin & Nitroglycerin by Dr. Sanaullah AslamSanaullah Aslam
Your Feedback will be highly appreciated. This presentation was made for students at pharmacy institute in a project of clinical pharmacy and use of digoxin and nitroglycerin. This presentation is made so that you can present it in a same session, without any change.
Digoxin is an inotropic and antiarrhythmic drug that belongs to the class of cardiac glycosides.
Atrial fibrillation, atrial flutter, and heart failure can all be treated with digoxin. Moreover, it is utilised to treat foetal supraventricular tachyarrhythmia and supraventricular tachycardia.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
3. Introduction
Cardiac Glycosides (or Cardioactive
Steroids (CAS)) - organic compounds
containing a glycoside (sugar) and a
common steroid nucleus that act on the
contractile force of the cardiac muscle.
Because of their potency in disrupting the
function of the heart, most are extremely
toxic.
The most common pharmaceutical product is
digoxin. Other preparations available
internationally include digitoxin, ouabain,
lanatoside C, deslanoside, and gitaline.
5. Cardiac glycosides : Sources
Insects
Some Buttefly species
Amphibians
Some toad species
6. History
There is evidence in the Ebers
Papyrus (Papyrus Smith) that the
Egyptians used plants containing
CAS at least 3000 years ago.
William Withering, an english
Botanist
noticed a person with dropsy
(historical name of CHF) improve
remarkably after taking a
traditional herbal remedy
recognised that the active
ingredient in the mixture came
from foxglove
In 1785, published An Account of
the Foxglove and some of its
Medical Uses, which contained
reports on clinical trials and notes
8. Chemical structure
All cardiac
glycosides
Genin (active part) =
Steroid nucleus +
Lactone ring
“Digoxigenin”
Sugar (physical
properties)
Term ‘Digitalis’
refers to all cardiac
glycosides
10. Digoxin is a cardiac glycoside that binds to and
inhibits sarcolemma-bound (Naþ/Kþ-) Mg2þ-
ATPase. This ATPase catalyses both an active
influx of 2 K ions and an efflux of 3 Na ions
against their respective concentration gradients,
the energy being provided by the hydrolysis of
ATP.
The inhibition induced by digoxin leads to an
efflux of potassium from the cell and, in proportion
to the extent of inhibition of the ATPase, an
increase in internal sodium ion concentration [Na]
at the inner face of the cardiac membranes.
11. This local accumulation of sodium causes an
increase in free calcium concentrations via the
Na – Ca exchanger. This free cellular calcium
concentration [Ca] is responsible for the
inotropic action of digoxin, secondary to the
release of Ca from the sarcoplasmic reticulum.
12. Positive Inotropic Action
Positive inotropic effect on the intact ventricle,
or isolated ventricular muscle
Resulting in an increase in the rate of rise of
intracavitary pressure during isovolumic systole at
constant heart rate and aortic pressure
Present in normal as well as failing cardiac
muscle.
Shifts ventricular-function (Frank-Starling) curve
upward and to the left, so that more stroke work
would be generated at a given filling pressure.
13. Inhibits Na-K ATPase Pump
Increases intracellular Na Concentratio
Increases intracellular Ca concentration
Improved isolated myocyte contractile performance
(increased shortening velocity)
Improved overall left ventricular (LV) systolic function.
Shifts Frank starling curve upward and leftward
14. Neurally Mediated Actions
Intravenous ouabain increased mean arterial
pressure, forearm vascular resistance, and
venous tone in normal human subjects, probably
in part because of direct but transient effects on
vascular smooth muscle.
Patients with heart failure respond with a decline
in heart rate and other effects consistent with
enhanced baroreflex responsiveness.
15. In patients with moderate to severe heart failure,
cardiac glycosides increase forearm blood flow
and cardiac index and decreased heart rate
concomitant with a marked decrease in skeletal
muscle sympathetic nerve activity measured as
an indicator of centrally mediated sympathetic
nervous system activity.
In contrast, dobutamine, a sympathomimetic drug
that increased cardiac output to a similar degree,
did not affect muscle sympathetic nerve activity in
these patients.
16. Mason DT, Braunwald E. Studies on digitalis, X: effects of ouabain
on forearm vascular resistance and venous tone in normal
subjects and in patients in heart failure. J Clin Invest.
17. Therefore, Digoxin has parasympathomimetic
action, clinically manifests as increased central
and peripheral vagal tone.
In HF patients, digoxin also has anti-sympathetic
effect, it also restores baroreceptor sensitivity.
18. Electrophysiological effects
The major effect of digitalis preparations on
cardiac rhythm is believed to be due to modulation
of ANS.
At therapeutic levels of digoxin, Digoxin acts by
enhancing both central and peripheral vagal tone.
These actions are largely confined to slowing of
the sinus node discharge rate, shortening of atrial
refractoriness, and prolongation of AV nodal
refractoriness.
It decreases automaticity and increase maximum
diastolic potential, effects that can be blocked by
atropine.
19. Electrophysiologic effects on the His-Purkinje
system and ventricular muscle are minimal,
except in toxic concentrations.
In studies of denervated hearts, digoxin has
relatively little effect on the AV node and causes a
mild increase in atrial refractoriness.
The sinus rate and P wave duration are minimally
changed in most patients. The sinus rate may
decrease in patients with heart failure whose left
ventricular performance is improved by the drug;
individuals with significant underlying sinus node
disease also have slower sinus rates or even
20. Similarly, the PR interval is generally unchanged,
except in patients with underlying AV node
disease.
QRS and QT intervals are unaffected. The
characteristic ST and T wave abnormalities seen
with digoxin use do not represent toxicity.
ANS modulation is an important mechanism
contributing to the efficacy of cardiac glycosides in
the treatment of patients with heart failure (and
may occur at blood levels of these drugs that are
below those necessary to achieve a direct
inotropic effect).
21. Pharmacokinetics
The elimination half-life for digoxin is 36 to 48
hours in patients with normal or near-normal
renal function. This permits once-a-day dosing;
near steady-state blood levels are achieved one
week after initiation of maintenance therapy.
Digoxin is excreted by the kidney with a clearance
rate that is proportional to the glomerular filtration
rate.
In patients with congestive heart failure and marginal
cardiac reserve, an increase in cardiac output and
renal blood flow with vasodilator therapy or
sympathomimetic agents may increase renal digoxin
22. Conversely, the half-life of the drug is increased
substantially in patients with advanced renal
insufficiency (to approximately 3.5 to 5 days);
both the volume of distribution and the clearance rate
of the drug are decreased in the elderly.
As a result, the drug must be used with caution in
patients with renal insufficiency and in the elderly.
Despite renal clearance, digoxin is not removed
effectively by hemodialysis due to the drug's large
(4 to 7 liters/kg) volume of distribution. The
principal tissue reservoir is skeletal muscle and
not adipose tissue, and thus dosing should be
based on estimated lean body mass.
23. Most digoxin tablets average 70% to 80% oral
bioavailability; however, approximately 10% of the
general population harbors the enteric bacterium
Eubacterium lentum, which can convert digoxin
into inactive metabolites, and this may account for
some cases of apparent resistance to standard
doses of oral digoxin.
Liquid-filled capsules of digoxin (LANOXICAPS)
have a higher bioavailability than do tablets
(LANOXIN) and require dosage adjustment if a
patient is switched from one dosage form to the
other.
24. Digoxin is available for intravenous administration,
and maintenance doses can be given
intravenously when oral dosing is impractical.
Digoxin administered intramuscularly is erratically
absorbed, causes local discomfort, and is not
recommended.
Serum Digoxin Concentration (SDC) should be
measured atleast after 6 hrs of dosing – after
initial serum distribution phase ends – to prevent
falsely high SDC; Ideally within 6-20 hrs.
28. HEART FAILURE WITH LOW EF
(HFLEF)
Digoxin has many beneficial characteristics
Only inotrope whose chronic therapy does not
increase long term mortality
Does not lower BP or adversely affect renal function
Very low cost drug
Few side effects when dosed appropriately
29. PROVED was a 12-week placebo-controlled,
digoxin-withdrawal study. This study enrolled
patients in sinus rhythm with reduce systolic
function and stable heart failure symptoms
who were receiving digoxin and diuretics.
Patients in whom digoxin was discontinued
had a 2-fold increase in worsening heart
failure and a decrease in both exercise
capacity and LVEF compared with patients
who continued on digoxin therapy.
30. The RADIANCE trial followed a similar
protocol; however, patients were receiving
ACE inhibitors in addition to diuretics and
digoxin. Digoxin discontinuation was
associated with a 6-fold increase in worsening
heart failure, despite the fact that ACE
inhibitors and diuretics were continued after its
withdrawal. Functional capacity worsened in
the withdrawal group, as did quality of life and
ejection fraction.
31. A pooled analysis of the RADIANCE and
PROVED trials suggested
a significant cost reduction related to hospitalizations
was associated with digoxin therapy.
The efficacy of 3 levels of serum digoxin concentration
(SDC) of 0.5 to 0.9 mg/mL, 0.9 to 1.2 ng/mL, and 1.2
ng/mL with regard to LVEF and patient outcomes were
evaluated. LVEF fell in patients assigned not to receive
digoxin and increased in those who received digoxin
(P<0.0001); treadmill times were reduced in those not
receiving digoxin and were unchanged in those receiving
digoxin (P<0.0001).
Risk of worsening HF was significantly less for all 3
subgroups of patients who continued to receive digoxin
after adjustment for LVEF, cardiothoracic ratio, age, HF
score, and ACE-I use.
32. There was no relation between SDC levels and changes in
LVEF, treadmill times, and development of worsening HF.
The incidence of worsening HF in the placebo group was
30% and in the 3 digoxin subgroups was 6%, 9%, and
12%, respectively (P<0.02 for no digoxin versus the digoxin
subgroups).
Triple therapy with digoxin, an ACE inhibitor, and a diuretic
was associated with the lowest risk of worsening heart
failure (5%).
33. The DIGITALIS INVESTIGATION GROUP
(DIG) trial is the largest trial of digitalis. It had
two parts: the main trial and the ancillary trial.
Main Trial
6800 patients with LVEF 0.45 were randomly assigned
to digoxin or placebo: The placebo group received
diuretics (82%) and ACE-I (95%) and the digoxin
group received digoxin, diuretics (81%), and ACE-I
(94%).
34. The main findings were that digoxin
Had no effect on total mortality rates
Reduced incidence of Death or hospitalization caused
by worsening HF [P<0.001 risk ratio was 0.75 in the
whole group and was 0.80 in all subgroups]
Reduced incidence of Hospitalization for worsening
HF (P<0.001)
Reduced incidence of Death caused by worsening HF
(P=0.06)
Benefits were incremental to use of diuretic and ACE-I
35. Ancillary Trial
988 patients with LVEF 0.45 were randomly assigned
to digoxin or placebo.
It showed Death or hospitalization for worsening HF
was lower in patients assigned to digoxin (risk ratio,
0.82; 95% CI, 0.63 to 1.07) and “were consistent with
the findings of the main trial”
36. Subgroup Analysis
At the end of 5 years that women had a higher mortality
rate than men (33.1% versus 28.9%; absolute difference,
4.2%)
At a 2-year follow-up, a reduction in total mortality and total
hospitalization was demonstrated in a prespecified
subgroup analysis of patients with an LVEF 25%,
cardiothoracic ratio 55%, or NYHA class III/IV symptoms. In
these subgroups, the relative reduction in heart failure
mortality or heart failure–related hospitalization was 39%
for patients with LVEF 25%, 35% for patients with
cardiothoracic ratio 55% on chest x-ray, and/or 35% for
patients with severe symptoms.
A recent comprehensive post hoc analysis of the DIG trial
that included all patients (preserved or reduced systolic
37. Digoxin in Women
Digoxin has not been well studied in women with heart
failure.
In the DIG trial, women made up only 22% of the study
population
One post hoc analysis of the DIG database suggested that
women randomized to digoxin had increased all-cause
mortality.
However, subsequent independent analyses of the same
database showed no evidence of increased mortality in
women with a serum concentration <1.0 ng/mL. A higher
risk of mortality (but not hospitalization) was observed only
in women with SDCs <1ng/mL.
An analysis of patients treated with digoxin in the Studies of
Left Ventricular Dysfunction (SOLVD) database also failed
38. Digoxin in the Elderly
Advanced age may predispose patients to an increased risk
for digoxin intoxication that is related to decreased renal
function, low lean body mass, and electrical conduction
abnormalities.
In the DIG trial, however, advanced age was not associated
with an increased risk of digoxin intoxication. The beneficial
effects of digoxin were found to be similar across all age
groups regardless of LVEF (and maximum in Low EF).
Digoxin remains a useful agent in elderly heart failure
patients when variables such as lean body mass and renal
function are taken into account.
39. Digoxin with Beta Blockers
The DIG study was conducted before -blockers were
proved conclusively to reduce mortality and morbidity in
heart failure. Most patients enrolled in trials of Beta-
blockers, however, were receiving digoxin. It is not known if
the findings of these trials would have been similar without
background digoxin therapy.
Digoxin as Background therapy in HF trials
40. Digoxin in children
Despite the lack of data regarding its use in children,
digoxin continues to be used by most clinicians in the
management of pediatric heart failure.
Primary Myocardial disease HF is most acceptable
indication of Digoxin in Pediatric HF.
Left to right shunts and Valvular heart disease patients
are treated with digoxin only after they become
symptomatic.
Also, any HF due to digoxin responsive
Tachyarrhythmia is a strong indication – needs Rapid
digitalisation
Lower starting dose (½ to ¾ maintenance) is indicated
in acute phase of myocarditis, renal failure, and with
drugs which increase SDC.
41. HEART FAILURE WITH Preserved
EF (HFpEF)
Approximately 50% of patients hospitalized for
acute heart failure syndromes have relatively
preserved systolic function. These patients are older
and more likely to have a history of hypertension
and atrial fibrillation.
To date, only 3 relatively large studies have been
conducted in heart failure patients with preserved
systolic function:
DIG Ancillary - The effect of digoxin in 988 patients with heart
failure and preserved systolic function (mean LVEF, 55%) was
examined in the ancillary component of the DIG trial.. The
addition of digoxin to ACE inhibitors and diuretics resulted in a
nonsignificant 12% reduction in heart failure mortality or heart
failure hospitalizations. The direction and magnitude of this
finding are similar to that observed in patients with decreased
42. Effects of Candesartan in Patients With Chronic Heart Failure
and Preserved Left-Ventricular Ejection Fraction or (CHARM-
Preserved study) - Therapy with candesartan resulted in an
11% relative risk reduction in cardiovascular death or heart
failure hospitalization in patients with heart failure and
preserved systolic function. In this trial, however, patients
randomized to candesartan developed more hypotension,
worsening renal function, and hypokalemia compared with the
placebo group.
Treatment of Preserved cardiac function HF with an
Aldosterone Antagonist (TOPCAT study) - patients who took
the aldosterone inhibitor spironolactone failed to show benefit
for primary end point composite of death from cardiovascular
causes, aborted cardiac arrest, or hospitalization for heart
failure. But they did have significantly fewer heart-failure
hospitalizations, a part of the primary end point, over the
43. Acute Heart Failure Syndromes
Hospitalizations for worsening heart failure are a
major problem in HF spectrum. Also This is
associated with a readmission rate as high as
30% within 2 months after discharge.
To date, no single agent used to improve
presenting symptoms has been shown to be safe
and effective. These include nesiritide, milrinone,
tezosentan, levosimendan, etc.
The effects of intravenous digoxin, alone or with
other vasodilators, are seen within an hour of its
administration and result in increasedcardiac
output, decreased pulmonary wedge pressure,
increased ejection fraction, and improved
neurohormonal profile without changes in blood
pressure. This therapy may be continued during
44. Despite its potential benefits, no study to date has
evaluated digoxin in the setting of acute heart
failure.
Accordingly, digoxin is not recommended for the
management of acute heart failure syndromes by
the ACC/AHA heart failure guidelines. However,
given its acute positive hemodynamic effects and
long-term safety data, digoxin should be evaluated
in this setting by future trials.
45. Coronary Artery Disease
Myocardial ischemia may cause inhibition of the
sodium potassium pump, rendering myocardial
tissue more sensitive to the arrhythmogenic
effects of digitalis, even at lower doses.
In a retrospective analysis, digoxin has been
associated with an increase in postdischarge
mortality in patients surviving myocardial
infarction. However, in other studies, analysis
failed to show that digoxin is an independent
predictor of increased mortality.
In the DIG trial, 70% of patients had ischemic
heart disease, 65% had a history of myocardial
infarction, and 30% had angina at the time of
enrollment. Patients with an ischemic origin had a
reduction in heart failure–related death or
46. The DIG trial, however, did not examine the effects
of digoxin in the settings of acute coronary
syndromes.
Because its safety has not been evaluated in this
setting, digoxin should be avoided if possible during
acute myocardial infarction or in patients with
ongoing ischemia.
47. Atrial Fibrillation
Atrial fibrillation is present in 30% of heart failure
patients.
At rest, digoxin can effectively control the ventricular
response in atrial fibrillation by enhancing vagal
tone. However, it may be less effective at controlling
the ventricular response during exercise or in the
setting of enhanced sympathetic tone.
In patients with heart failure and reduced systolic
function, the combination of digoxin and a -blocker
reduces symptoms, improves ventricular function,
and leads to better rate control than either agent
alone.
48. The best strategy for rate control is a 2-drug
combination, usually consisting of digoxin and a -
blocker. Using a -blocker and digoxin in combination
allows lower doses to be used, thus improving
tolerability and decreasing the risk of toxicity.
Diltiazem and verapamil also are options, but these
agents should not be used in the setting of systolic
dysfunction. Caution should be used when
combination therapy with digoxin and amiodarone is
chosen for rate control because amiodarone can
significantly increase SDC.
50. Dosing
There are many problems encountered in writing a program
to effectively dose a drug such as digoxin. It is inherently
difficult because of such components as narrow therapeutic
index, difficult to define therapeutic endpoints, inter and intra-
patient variability, and varying effects of pathological states
and drugs on digoxin's disposition.
In sum, there exists significant variability as far as a given
dose and concentration produced in a given patient. It is
important to be able to determine various patient attributes
that may help predict drug concentrations for any given
patient. There are several known attributes that have a direct
correlation with the eventual therapeutic dose.
Variables such as ideal body weight, serum creatinine, age,
concomitant drug therapy all have great influence on the
eventual therapeutic dosing regimen.
51.
52. Rapid digitalizing (loading dose) regimen
IV: 8-12 mcg/kg (0.0080.012 mg/kg) total loading dose;
administer 50% initially; then may cautiously give 1/4 the
loading dose q68hr twice; perform careful assessment of
clinical response and toxicity before each dose
PO: 1015 mcg/kg total loading dose; administer 50% initially;
then may cautiously give 1/4 the loading dose q68hr twice;
peform careful assessment of clinical response and toxicity
before each dose
Maintenance PO: 3.4-5.1 mcg/kg/day or 0.1250.5 mg/day
PO; may increase dose every 2 weeks based on clinical
response, serum drug levels, and toxicity
IV/IM: 0.10.4 mg qDay; IM route not preferred due to severe
injection site reaction
53. As per ACCF/AHA guidelines, a loading dose
to initiate digoxin therapy in patients with heart
failure is not necessary
0.125-0.25 mg PO/IV qDay;
higher doses including 0.375-0.5 mg/day
rarely needed
Use lower end of dosing (0.125 mg/day) in
patients with impaired renal function or low
lean body mass
54. Dosing Modifications
Adjust maintenance dose by estimating CrCl
and measuring serum levels
In heart failure, higher dosages have no
additional benefit and may increase toxicity;
decreased renal clearance may lead to
increased toxicity
In geriatric patients, use lean body weight to
calculate dose
58. Incidence and Causes
Incidence is decreasing
1970s – Upto 25-30% of all treated patients
1980s and 1990s – 4-5% of all treated patients
DIG trial – probable digoxin toxicity in about 12%
in digoxin group and about 8% in placebo group –
actual incidence about 4%
2000s – Reported incidence < 0.1%
59. Causes
Suicide gestures/purposeful overdoses
Incorrect Dosage
Risk factors
Renal dysfunction (Moderate to severe renal
failure – CrCl <60 ml/min in Males in <50 ml/min
in Females)
Elderly
Females
Concomitant drug interactions
60. Mechanisms
Most of digoxin effect in HF patients is thought to
be due to ANS modulation. But Toxic effects are
explained mainly by excessive Na-K pump
inhibition.
Toxic effects of digoxin (ie, arrhythmias) occur
when the cytoplasmic [Ca] increases to
concentrations exceeding the storage capacity of
the sarcoplasmic reticulum. As a consequence of
this internal [Ca] overload, several cycles of Ca
release–reuptake are required to restore the Ca
equilibrium between sarcoplasmic reticulum and
cytoplasm.
61. In addition, high internal concentrations of Ca
activate a depolarizing (inward) current
corresponding to the forward mode of the
electrogenic Na–Ca exchanger (3Na/2Ca).
This current generates delayed after-
depolarizations that give rise to extra-systoles
and sustained ventricular arrhythmias in vivo.
The toxicity of digoxin could also be amplified
in human heart failure, because the Naþ–Ca2þ
exchanger is upregulated in HF.
62. The pharmacological properties of the three main
human cardiac Na/K-ATPase isoforms explain the role
of hypokalemia in the toxic effects of digoxin.
The functional Na/K-ATPase is a heterodimer of alpha
and beta subunits. The alpha subunit bears the
catalytic site and binds digoxin, ATP, Na, and K. The
three isoforms have the same apparent affinity for
digoxin; however, their apparent affinities vary
according to the concentration of potassium.
In the presence of physiological [K] concentrations,
the alpha 1 and alpha 3 isoforms exhibit 3–5-fold
lower sensitivities to digoxin; potassium exerts a
protective effect. In contrast, the alpha 2 isoform
remains highly sensitive to cardiac glycosides.
63. Furthermore, the alpha 2 isoform very rapidly
binds and releases digoxin (within a few minutes),
whereas the half-times for the dissociation of
digoxin from alpha 1 and alpha 3 are 80 and 30
min, respectively.
Thus, under physiological conditions, the alpha 2
isoform could be effectively inhibited at low
concentrations of digoxin.
Also, It has been assumed that, in the presence of
high concentrations of digoxin, alpha 1 and alpha
2 isoforms are inhibited and induce toxic effects.
64. Manifestations
Traditionally divided into extra cardiac and
cardiac
‘Definite’ Toxicity defined as
Nausea/Vomiting with
Cardiac effects with
Resolution of side effects on discontinuation
SDC not a necessary criterion – but SDC > 2.0
ng/ml helpful
65. Extracardiac SEs
Nonspecific but more common
Gastrointestinal (60-80%)
Nausea / Vomiting
Anorexia, Abdominal Pain, Diarrhoea
Malaise (30-40%)
Lethargy, Fatigue
Neurological (20-30%)
Dizziness, Confusion
Headache
Visual changes (flashing lights, halos, colour
disturbances in green – yellow spectrum, blurred
vision)
66. Cardiac SEs
More specific but less common
Almost any permutations and combinations of
heart block, brady- and tachydysrhythmias are
possible.
The only dysrhythmia not assumed to be due
to Digoxin toxicity – Mobitz Type 2 Heart block
69. Digoxin toxicity signs
Inverse check mark
with proximal ST segment depressed
In leads other than those with tall R waves
With T wave not rising above baseline (Inverted T)
With shortened Qtc
70.
71. Note that
Digoxin does not affect the QRS
Maximal therapeautic effect of digoxin is usually
present befoe the ECG effects appear
72. Management
If the evidence of toxicity is relatively minor
with, for example, symptoms of nausea,
withdrawal of the drug is often the only specific
treatment required.
If there is no evidence of serious cardiac
problems, such as heart block or significant
dysrhythmias, then following the withdrawal of
the drug and the correction of electrolyte
imbalance, symptomatic measures will usually
suffice.
73. More serious evidence of toxicity, particularly
with cardiac involvement, dysrhythmias, is
potentially life threatening, and requires
admission to hospital.
Measures
Hypokalemia correction - intravenous
supplementation of no more than 20 mmol/h of
potassium, to reduce digitalis binding to Na/K
ATPase. More rapid infusion may lead to
asystole.
Heart blocks – Atropine and Temporary cardiac
pacing
74. Malignant ventricular arrhythmias
Phenytoin (100 mg intravenously, repeated after
5 minutes if required) is a useful
antidysrhythmic as it opposes digitalis binding
and may improve atrioventricular conduction by
its anticholinergic properties.‘
Ultrashort acting beta blockers – Esmolol
Cardioversion should be avoided wherever
possible, due to the risk of precipitating
asystole, and when necessary should be
attempted using the lowest energy possible.
75. Digoxin-specific antibody fragments
Digoxin-specific fab antibody fragments (Digibind) are
the most effective treatment available. However, this
therapy is expensive and therefore should be reserved
for treatment of serious toxicity, especially in the
presence of malignant cardiac dysrhythmias.
These antibodies have a high affinity and specificity
for cardiac glycosides and have been shown to
reverse digoxin toxicity and reduce the risk of death.
In several large studies, approximately 80% of
patients had complete resolution of all evidence of
toxicity, 10% improved whilst 0% showed no
response.
They appear effective for all age groups and also in
patients with poor renal reserve (despite eventual
76. Pharmacokinetics
Half life 12-20 hrs
Vd 0.4 L/kg
After administration, SDC cannot be measured
without complete elimination from the body