Mohamed helmy, MD
National heart institute

 65 years old male patient presented in the ER
by attack of hypertensive crisis with BLP
:260/120 resistant to medications including
IV nitrate and iv Frusamid…….Whats your
Next option ???????

 50 y male patient known to have uncontrolled
hypertension presented in the ER by sever
agonizing chest pain radiating to the back ,
unequal radial pulse , blp 179/100 in the
rightarm, TTE revealed aortic regurge with
suspected flap in the ascending aorta whats
your first chiose drug ?????????

 During PPCI for 45 female patient presented
in the ER by extensive anterior MI , CA
revealed big thrombus in the proximal LAD
and after stenting there is noreflow , whats
your prefered medication ?????????

 Sodium nitroprusside (Abbreviated SNP, brand name: Nitropress)
has potent vasodilating effects in arterioles and venules (venules
more than arterioles, but this selectivity is much less marked
than that of nitroglycerin)[6]. It is administered intravenously in
cases of acute hypertensive emergency. SNP breaks down in
circulation to release nitric oxide (NO). NO activates guanylate
cyclase in vascular smooth muscle and increases intracellular
production of cGMP. cGMP activates Protein Kinase G which
activates phosphatases which inactivate Myosin light chains.
Myosin light chains are involved in muscle contraction. The end
result is vascular smooth muscle relaxation, which allow vessels
to dilate.
 In the human heart, nitric oxide reduces both total peripheral
resistance as well as venous return, thus decreasing both preload
and afterload. For this reason, it can be used in severe
cardiogenic heart failure where this combination of effects can
act to increase cardiac output. In situations where cardiac output
is normal, the effect is to reduce blood pressure.

 Sodium nitroprusside slowly breaks down to release 5
cyanide ions, especially upon exposure to UV light.
Despite the toxic potential of cyanide, nitroprusside
remains an effective drug in certain clinical
circumstances such as malignant hypertension or for
rapid control of blood pressure during vascular
surgery and neurosurgery. The cyanide can be
detoxified by reaction with a sulfur-donor such as
thiosulfate, catalysed by the enzyme rhodanese. In
the absence of sufficient thiosulfate, cyanide ions can
quickly reach toxic levels.[7] The half-life of
nitroprusside is 1–2 minutes, but the metabolite
thiocyanate has an excretion half-life of several days.

 Sodium nitroprusside is appropriate for the acute
treatment of congestive heart failure. The
starting dose is 0.3 to 0.5 μg/kg/min titrated to
goal attainment of desired hemodynamics but
usually not beyond 5 μg/kg/min. Doses of 10
µg/kg/min or sustained administration will result
in excessive cyanide production, which may
occasionally lead to cyanide poisoning and may
rarely lead to the development of
methemoglobinemia. Both conditions require
immediate intervention with cessation of the
infusion and/or initiation of hemodialysis and
possibly administration of thiosulfate or
methylene blue

DRUG DOSAGE ONSET/DUR ADV.EFFE
Nitroprusside 0.25-
10mcg/kg/min
Instant/1-2min. Thiocyanate,cyani
de poisoning
Nitroglycerine 5-100mcg/min 1-5min/3-5min Flushing,headach
e,methemoglobin
Nicardipine 5-15mg/hr 5-10min/1-4hr Tachycardia,flushing
.avoid-heart failure
Hydralazine 10-20mg 5-15min/3-8hr Flushing,tachy,avoid
-A.diss,MI
Enalapril 10-40mg IM,1.25-
5MG1Vq6hr
20-30min/6hr Hypotension,renal
failure,hyperkalemia
Fenoldopam 0.1-
0.3mcg/kg/min
5min/10-15min Flushing,headache,t
achy

 Labetalol
 - alpha-1 and non-selective beta blocker
- beta blockade predominates during IV administration (3-7 times alpha blockade)
- beta blockade prevents reflex increase in heart rate, cardiac output and
myocardial oxygen consumption
- in pre-eclampsia rapidly reduces BP without decreasing uteroplacental blood
flow
- crosses placenta but neonatal bradycardia and hypoglycaemia rarely seen
- disadvantages in pre-eclampsia include interpatient variability in dose
requirement and variable duration of action
 Dose
 For acute hypertension
 bolus of 1-2 mg/kg over 10 min
 OR mini-boluses of 20 mg followed by 20-80 mg every 10 min
 OR incremental infusion of 0.5-4 mg /min. This method is least likely to cause
hypotension and bradycardia
 For pre-eclampsia
 10 mg IV initially
 double dose every 10 min as necessary to a maximum of 300 mg
 alternatively: 1-2 mg/min IVI reducing to 0.5 mg/min or less after arterial

 Pharmacodynamics
 - direct arteriodilator with little venodilator action
- reduces diastolic pressure more than systolic
- may induce reflex tachycardia and increased cardiac output which may blunt its hypotensive
effect. Combination with a central alpha-2 agonist or a beta blocker decreases this reflex
sympathetic activity
- improves renal and uteroplacental blood flow in pre-eclampsia
- onset time 10-20 min. Duration of action 6-8 h
 Adverse effects
 - reflex tachycardia
- headaches,
- nausea & vomiting
- flushing
- skin rash
- lupus syndrome: more likely to develop after prolonged therapy, in slow acetylators and in
patients with renal failure
- infusions may be difficult to titrate in pre-eclampsia and may be associated with a higher
incidence of fetal distress
- in presence of hypovolaemia may result in hypotension and fetal distress
- neonatal thrombocytopenia (rare)
 Dose
 - in hypertensive emergencies: IV boluses of 10-20 mg, repeated as necessary at 15 min
intervals, to a maximum of 50 mg. Can also be given as an infusion: 0.5-1 mg/min
- in pre-ecplamsia for control of BP: 5 m

46 y male patient known to have CHF (EF:28%),
presented in the ER by attack of acute sever
dyspnea, pulmonary congesion with increase
in CVP , poor response to max doses of
dpopamin and dobuamine
Whats your next option

 Mode of action
 vasodilatory, natriuretic and diuretic effects
 primarily mediated via natriuretic peptide receptor A on vascular smooth muscle,
endothelium, kidneys and adrenals
 no direct inotropic effect
 ± reduces aldosterone and inhibits plasma renin activity
 Pharmacokinetics
 administration: IV infusion
 distribution
◦ distribution t1/2 ~2 mins
◦ mean volume of distribution at steady state 0.19 l/kg
 elimination by multiple routes:
◦ after binding to cell surface natriuretic peptide receptor C nesiritide is internalized and
degraded
◦ hydrolysis by endopeptidase
◦ renal filtration
 elimination t1/2 ~18 mins
 clearance proportional to body weight (~0.55 l/h/kg)
 dosage adjustment not required in patients with renal dysfuncti

 Dosage and Administration
 AdultsIV Recommended dose is 2 mcg/kg IV bolus over 60 sec followed by
continuous infusion at a dose of 0.01 mcg/kg/min. If hypotension occurs during
administration, reduce or discontinue the dose and start other measures to
support BP.
 General Advice
 For IV administration only. Not for intradermal, IM, subcutaneous, or intra-arterial
administration.
 Follow manufacturer's instructions for reconstitution of powder and final dilution
for infusion solution.
 Do not shake or agitate vials during reconstitution or dilution. Do not use filter
needles during preparation of infusion.
 Do not administer if solution is cloudy, discolored, or contains particulate matter.
 Prime IV tubing with infusion solution prior to connecting to patient's vascular
access port and prior to administering bolus dose and starting infusion.
 Infusion rate may be increased by 0.005 mcg/kg/min, no more often than every 3
h up to a max of 0.03 mcg/kg/min. Increases in infusion rate should be preceded
by a bolus dose of 1 mcg/kg.
 Do not administer through a central heparin-coated catheter.
 Flush catheter between administration of nesiritide and any incompatible
injectable medication.

 Clinical indications
 acute decompensated heart failure with dyspnoea on minimal exertion or at rest
◦ reduces preload. Rapid reduction in pulmonary capillary wedge pressure (faster than glyceryl trinitrate) and
right atrial pressure
◦ reduces afterload resulting in increase in cardiac output
◦ diuresis & natriuresis
◦ 6 month mortality similar to patients treated with nitrate but lower than those treated with dobutamine
 contraindicated in cardiogenic shock or in patients with systolic BP <90 mmHg
 Adverse effects
 Cardiovascular
 Similar incidence to patients treated with nitrate.
 hypotension
◦ usually resolves spontaneously or responds to fluid challenge of 250 ml or less
◦ duration of episode longer than hypotensive episodes associated with glyceryl trinitrate
 not proarrhythmic
 Non-cardiovascular
 Less common than with glyceryl trinitrate
 general pain
 abdominal pain
 catheter-related pain
 headache
 nausea

 Adverse effects
 Cardiovascular
 Similar incidence to patients treated with nitrate.
 hypotension
◦ usually resolves spontaneously or responds to fluid challenge of 250 ml or less
◦ duration of episode longer than hypotensive episodes associated with glyceryl trinitrate
 not proarrhythmic
 Non-cardiovascular
 Less common than with glyceryl trinitrate
 general pain
 abdominal pain
 catheter-related pain
 headache
 nausea
 Drug interactions
 does not interact with enalapril
 interactions with IV vasodilators (including IV ACE inhibitors) and other cardiovascular drugs have not been
formally studied
 Dosage & administration
 bolus of 2 mcg/kg followed by infusion of 0.01 mcg/kg/min
 reduce dose/discontinue if hypotension occurs
 should only be used in pregancy if potential benefit to mother outweighs potential risk to fetus
 administer with caution to breastfeeding mot

 Clinical Results
 Natrecor has been evaluated in 10 trials that included 941 subjects with
congestive heart failure.
 The randomized, double-blind VMAC (Vasodilation in the Management of Acute
Congestive Heart Failure) trial included 489 subjects who required hospitalization
for management of shortness of breath at rest due to acutely decompensated CHF.
The trial compared the effects of Natrecor, placebo and intravenous nitroglycerin
when added to background therapy. Among other measures, the trial was
designed to evaluate the change from baseline in pulmonary capillary wedge
pressure (PCWP) and the change from baseline in subjects' dyspnea (abnormal
breathing), evaluated after three hours.
 Results demonstrated that subjects receiving Natrecor reported greater
improvement in their dyspnea at three hours than subjects receiving placebo.
Additionally, there was a greater reduction in mean PCWP for the Natrecor-treated
group compared to placebo- and nitroglycerin-treated subjects.
 In a second double-blind trial, 127 subjects requiring hospitalization for
symptomatic CHF were randomized to receive placebo or one of two doses of
Natrecor. Results demonstrated that subjects receiving both doses of Natrecor
reported greater improvement in dyspnea at six hours compared to subjects
receiving placebo.

 28 Y female patient presented to you in the
ER by attack of repeated palpitation,
presyncope , no PH of RHD, IHD, and she was
hemodynamicaly stable , normal echodoppler
study
 ECG revealed the following strip :

 Supports SVT
◦ Slowing or termination by
vagal tone
◦ Onset with premature P
wave
◦ RP interval <100mS
◦ P & QRS rate & rhythm
linked to suggest ventricular
activation depends on atrial
discharge
◦ Long-short cycle sequence
 Supports VT
◦ Fusion beats
◦ Capture beats
◦ AV dissociation
◦ P & QRS rate & rhythm
linked to suggest that atrial
activation depends on
ventricular discharge
◦ “compensatory” pause
◦ L axis deviation
◦ QRS duration >140mS

 The administration of adenosine during SVT may be a useful
diagnostic as well as therapeutic intervention.
 Adenosine may unmask atrial flutter when the diagnosis is not
readily apparent from the ECG.
 It is particularly effective for treatment of arrhythmias that depend
on the AV node, such as AV node re-entry or orthodromic AV re-
entry. The response of atrial tachycardias is variable. Sometimes
adenosine terminates these arrhythmias and other times it reveals
the P-wave morphology by creating AV block.
 It is also used to differentiate VT from SVT with aberrant conduction.
VT is rarely affected by adenosine, but SVT will either terminate or
be exposed by transient AV block. Adenosine may not have any
effect if it is administered slowly through a peripheral vein or if the
patient has consumed caffeine.

 Receptors
 3 types of receptors. A1 and A2 receptors are subtypes of P1 class of receptors
 A1 or A2 agonist-receptor complex is responsible for inhibition or stimulation of adenylate
cyclase and a decrease or increase in intracellular cAMP respectively.
 adenosine also has actions which are not mediated via cAMP
 both cAMP mediated effects and other actions appear to be mediated by G proteins
 A1 and A2 receptors blocked by methylxanthines such as theophylline
 A3 receptor has recently been characterized. It is resistant to blockade by methylxanthines but
may be stimulated by both A1 and A2 agonists
 Cardiac electrophysiological effects
 mostly mediated by A1 receptor
 depression of sinus node automaticity and AVN conduction. Associated with an increase in PR
and AV intervals but not in HV interval, suggesting a site of action proximal to bundle of His.
Mediated by:
 activation of a specific outward K current which is independent of adenylate cyclase. Results in
shortening of the atrial action potential, hyperpolarisation of the SAN cells and depression of
the amplitude, duration and rate of rise of action potential in AVN cells.
 attenuation of effects of catecholamines by inhibiting adenylate cyclase stimulation of the
inward calcium current in atrial and ventricular myocytes. Greater inhibition of this current
occurs after previous stimulation by beta agonists
 stimulation of presynaptic adrenergic receptors on adrenergic nerves which decreases the
amount of norepinephrine released for any given level of sympathetic stimulation

 Drug interactions
 dipyridamole potentiates action by inhibiting uptake
 methylxanthines are competitive antagonists and may necessitate larger doses
 can be safely administered to patients taking digoxin, quinidine, beta blockers, calcium
blockers, ACE inhibitors
 Adverse effects
 occur in approx 20% but are brief (<1 min)
 include:
◦ facial flushing
◦ SOB
◦ chest tightness
◦ asystole
 Contraindications
 not recommended in patients with sick sinus syndrome due to possibility of prolonged heart
block
 bronchospasm
 © Charles Gomersall December 1999
 ©Charles Gomersall, September, 2012 unless otherwise stated. The author, editor and The
Chinese University of Hong Kong take no responsibility for any adverse event resulting from
the use of this webpage.
Copyright policy Contributors

 30 male patient presented in the ER by
attack of unstble angina and he developed
rapid palpitation , ECG revealed Atrial flutter ,
he was hemodynamicaly stable
 Whats your drug of choice???

Indication Peak Effect
(min) T1/2 Duration Receptor HR  BP
Esmolol Yes Yes 2 9 min 10-20
min
1
Atenolol No Yes 2 6-7 h 12 h 1
Labetalol No Yes 5 5.5 h 3-5 h 1,1&2
Metoprolol No Yes 20 3-7 h 5-8 h 1
Propranolol Yes No <10 4 h Variable 1&2
Diltiazem Yes No 2-5 3.4 h 1-3 h Ca2+
Verapamil Yes No 3-5 2-5 h 1-2 h Ca2+

 Brevibloc (Esmolol Hcl)
 Bristol-Myers Squibb Company
 Ultrashort-acting, Cardioselective (ß1) Beta blocker(IV)
 Indication:
--- Supraventricular Tachycardia
--- Atrial Fibrillation
--- Atrial Flutter ---
Peri-OP, Post-OP Tachycardia / Hypertension
--- Acute Myocardial Ischemia

 ß1-selective Adrenergic Receptor Blocker,
ß1:ß2 = 40:1 (highly cardioselective)
 Very Soluble in Water
 No Intrinsic Sympathomimetic Activity
 No Membrane Stabilizing Activity
 No Significant Drug Interaction
 Rapid Onset: 2 mins
 Ultra-short Action: 10-20 mins

 Decrease in
--- heart rate (peak effect in 60 sec)
--- blood pressure (peak effect in 2 min)
--- cardiac index
--- rate pressure product (RPP)
--- left and right ventricular ejection fraction
 Prolongation of
--- sinus cycle length
--- decrease AV node conduction velocity
--- decrease the rate of SA node activity
--- antegrade Wenckebach cycle length
--- the sinus node recovery time
--- increase AV nodal refractoriness interval

 A Selective Approach:
◦ Targeted to the Heart
◦ Little effect on Bronchial Smooth Muscle
◦ Maybe used with caution in p'ts with asthma, COPD
 A Flexible Approach:
◦ Administer as long as indicated…..
◦ Maintenance infusions up to 48 hrs or short as you want;
rapid reversal of effect within minutes

 A Confident Approach:
◦ Easy to titrate upward or downward to desired heart
rate
◦ Allows maximum beta blockade while still maintaining
ventricular function
 An Effective Approach:
◦ Rapid control of atrial fibrillation,atrial flutter and sinus
tachycardia

The Advantage of Brevibloc  III

 Indication
- Supraventricular tachycardia (SVT)
- Peri-OP, post-OP Tachycardia /
Hypertension
- Acute Myocardial Ischemia
 Dosage
Loading: 0.5 mg/kg, over 1 min
Maintenance: 0.05-0.2 mg/kg/min; *0.2
mg/kg/min --- average effective dosage: 0.1 mg/kg/min

Dosage Guideline

 A “less toxic” amiodarone
 Half-life: 13-19 hours
 Only FDA-approved for atrial
fibrillation/flutter
◦ Not as effective as amiodarone

 GI irritation
 Prolongs QT interval
 Negative inotrope
◦ Contraindicated in:
 NYHA IV
 Acute CHF exacerbations

 Metabolized by CYP 3A4
 Inhibits CYPs 3A4 & 2D6 and P-gp
 Increases digoxin levels
 Dosing: 400 mg BID

 Pharmacology
◦ Type III antiarrhythmic
◦ Indicated for acute conversion of atrial
flutter a/o fibrillation
◦ Proarrhythmic
More so in patients w/ CHF
If ibutilide fails to convert, it may at
least enhance the response to
electrocardioversion

 Monitor for proarrhythmias, including
torsade de pointes, for 4-6 hours after
dosing and until QT is not prolonged
 Hepatically cleared
◦ Half-life: ~6 hours

 Approved Dosing
◦ 1 mg (0.01 mg/kg < 60 kg) over 10 min; repeat,
if needed, after 10 min
◦ Preload with magnesium (?)
 Alternative Method of Dosing
◦ 2 mg (placed in 50 cc D5W) over 30 minutes
◦ Stop infusion when patient converts
◦ Preload with magnesium (?)

 Prasugrel
• Developed by Lilly and Sankyo
• Drug belongs to the same class as clopidogrel—
thienopyridine P2Y12 receptor antagonists
• Acts directly on the receptor
Heartbeat – November 2005

• Data reported from a pooled analysis of three
early-phase studies
• In total, 112 healthy volunteers were
randomized to receive either a 60-mg
loading dose of prasugrel or a 300-mg
loading dose of clopidogrel in a two-way
crossover design
• ADP-induced platelet aggregation was
measured in blood samples at four to five
hours and 24 hours after the medications
were administered
Heartbeat – November 2005

 All subjects responded effectively to prasugrel, but
when the same subjects were given clopidogrel,
between 22% and 43% were classed as
nonresponders, depending on the definition of
nonresponder used
Heartbeat – November 2005

 Agent metabolized differently, and more rapidly,
than clopidogrel
• Issue of no-response or low response shifted
upward with prasugrel
"Is more platelet inhibition better for improving
outcomes, as we've seen with clopidogrel vs just
aspirin alone?"
- Cannon
Heartbeat – November 2005

 The Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet
Inhibition with Prasugrel–Thrombolysis in
Myocardial Infarction 38 (TRITON-TIMI 38)
randomized 13 608 ACS patients undergoing
PCI to prasugrel or standard dose
clopidogrel,20 and showed that prasugrel
therapy was associated with significantly
reduced rates of ischaemic events, including
stent thrombosis, but with an increased risk
of major bleeding

 The presently described TRITON-TIMI 38
substudy was not powered to show a
significant difference in clinical outcomes
between patients on prasugrel and those on
clopidogrel. However, this substudy was
designed and sufficiently powered to show
differences in platelet function between
patients on prasugrel and those on
clopidogrel. Previous studies have shown that
such differences in platelet function affect
clinical outcome.7–

 45 female patient addmitted in the ER with
ACS, on iv nitrare , heparin , ASA, clopidogrel
at fifth day she start to complain from sever
dyspnea , tachpnea , Po2 65, , with
hematemsis and then developed DVT, CT
angio revealed PE, after 2days she developed
acute ischemia in right leg ,lab revealed plat
count 53000, mild anaemia
 Whats your possible diagnosis and
management???

 Venous thromboembolism
 Arterial thrombosis
 Skin lesions at heparin injection site
 Acute platelet activation syndromes
10/98medslides.com 54

 a rapid drop in platelets may also be
indicative of HIT, particularly if the
patients received heparin within the
previous 3 months
 a fall in platelet count of >50% that
begins after 5 days of heparin therapy,
but with the platelet count > 150 x
109/L, should also raise the suspicion
of HIT
10/98medslides.com 55

 Lower limb involvement
 Stroke
 Myocardial infarction
 Other
10/98medslides.com 56
AM J Med 1996;101:502-507
Venous thrombotic events predominate over arterial
events by 4:1 ratio. Usually involving large vessels.

 HIT-associated mortality is high (about
18%)
 5% of affected patients require limb
amputation
 Overt bleeding or bruising is rare even
with severe thrombocytopenia
 Appropriate management can limit
morbidity and mortality
10/98medslides.com 57

Test Advantages Disadvantages
PAA Rapid and simple Low sensitivity - not suitable for
testing multiple samples
SRA Sensitivity >90% Washed platelet (technically
demanding), needs radiolabeled
material 14C
HIPA Rapid, sensitivity >90% Washed platelets
ELISA High sensitivity, High cost, lower specificity
for
detects IgA and IgM clinically significant HIT
10/98medslides.com 58
Thromb Haemost 1998;79:1-7

 Ancrod
◦ a defibrinogenating snake venom
◦ slow onset of action (must be given over 12 to
24 hours)
◦ does not  thrombin generation which is
important in the pathogenesis of HIT
◦ HIT and DIC patients may already be
hypofibrinogenemic
10/98medslides.com 59
Blood 1996;88(Suppl 1):626a

 The only direct thrombin inhibitor
approved for use and for treatment of
HIT in the U.S.
 German trial of 200 patients with HIT
◦ 75% to 81% effectively anticoagulated
◦ significant reduction in composite endpoints
(death, limb amputation, new thrombotic
complications) compared with historical
control
7 day 10% vs 23%
35 day 25% vs 52%
10/98medslides.com 60
Blood 1996;88(suppl):281a

 a small synthetic non-polypeptide molecule
 a direct thrombin inhibitor
 FDA approved June30, 2000
 has the same theoretical advantages of lepirudin
◦ short half-life (< 1hr)
◦ lack of cross-reactivity for HIT antibodies
◦ potent antithrombin activity
 metabolized predominantly by the liver, may
require dose adjustment
 excreted normally even in severe renal failure
Update 10/00medslides.com 61