Drug type
example
Mechanism action
Nitrates and nitrites
Amyl nitrite 3-5 min
1-decrease cardiac demand
Nitroglycerine From 10 mins to
2-decrease preload
10 hours(Depending upon
route of administration)
3-increase cardiac delivery by remove coronary spasm
Isosorbide mononitrate 6-10 h
IS LONG ACTION AND TACK BY
ORALLY
Beta Blockers
Propranolol
1-decrease cardiac demand
Metoprolol
2-decrease afterload
Atenolol
3- increase cardiac delivery by remove coronary spasm
4-decrease cardiac contractility and rate
Calcium Channel
Blockers
Nifedipine
1-decrease cardiac demand
Nicardipine
4-decrease cardiac contractility and rate
Diltiazem
Verapamil
‫االلية المفصلة لعمل دواء النترات هي كالتالي‬
) glutathione S-transferase( ‫) حصل بواسطة‬denitrated (‫ تصبح‬Nitrates -1
)SH GROUB (‫) عبر وجود مجموعة‬NO ( ‫بعد ذلك سوف يتحرر عندنا‬
‫ ) هذه التحوالت كلها ال تتم اال بوجود‬guanylyl-cyclase ( ‫) تفعل دورة‬NO( ‫لما يتحرر‬
. ‫ بدونها لن تكمل العملية‬SH GROUB ‫مجموعة‬
‫) العضالت الملساء‬cGMP( ‫ سوف يتم زيادة توليف مركب‬-2
protein kinase G ‫ سوف يؤدي الى تنشيط مركب‬cGMP ‫ لما يتم صناعة هذا المركب‬-3
‫) بعد ما حصل هذه‬dephosphorylation of myosin light chain‫وهذا يؤدي الى‬
. ‫العمليات كلها سوف ينتج بالنهاية ارتخاء في العضالت الملساء‬
: ‫نتائج هذه العملية كلها باختصار كالتالي‬
1-NO stimulates guanylyl-cyclase in platelets as in smooth muscle.
2- A decreased availability of tissue -SH groups reduces the action of
nitrates
‫) سوف تقل من تنشيط النترات‬SH groups( ‫عندما تقل مجموعة‬
Cardiovascular actions After therapeutic doses :
1- Marked relaxation of large veins
‫ بيكون من المنطق ان يحصل‬..‫ تخيل ماذا يحصل بالجسم‬..‫لما االوردة الكبيرة بالجسم تتوسع‬
: ‫مايلي‬
a. Decreased preload and cardiac output
b. Decreased blood pressure (slightly) ‫الن االوردة اصبحت واسعة والضغط بيقل‬
c. Improved perfusion of subendocardial regions (due to the lowering of
left ventricular end-diastolic pressure, which reduces subendocardial
compression
‫التروية في طبقة تحت شغاف القلب سوف تتحسن بسبب انخفاض الضغط البطيني في نهاية‬
. ‫االنبساط لمن انخفض الضغط هذا ادت الى تقليل الضغط على منطقة تحت شغاف القلب‬
2- Relaxation of large arteries (less pronounced than vein relaxation)
‫الشراين الكبيرة بالجسم ترتخي لكن بنسبة اقل من ارتخاء االوردة من المنطق لمن الشرايين‬
:‫ترتخي ماذا يحصل ؟ سوف يزيد تدفق الدم في اماكن معينة بالجسم وهي‬
Relaxation of large arteries which leads to increased blood flow in :
a. The skin in (face and thorax) and the brain.
b. Large epicardial vessels .
c. Large collateral vessels perfusion of ischemic regions is increased)
‫اذا تم اخذ الدواء بجرعات عالية ماذا سوف يحصل ؟‬
After higher doses:
(Relaxation of all segment of the vascular system) which leads to:
1- Reflex tachycardia.
2- reflex increase in cardiac contractility.
3- Postural hypotension.
Other actions in this drug :
1-Relaxation of smooth muscle of:
a)
b)
c)
d)
the bronchi (small effect)
the biliary system (rapid reduction of biliary pressure)
the gastrointestinal tract (sphincteral and non sphincteral)
the genitourinary tract (small effect)
2-Decreased platelet aggregation
3-Increased methemoglobin formation
with nitrites, not with therapeutic doses of nitrates) due to the
formation of nitrite ion that can oxidize the ferrous ion of hemoglobin
to the ferric state.
Methemoglobin is mean :
‫تعني تحول الحديد( فيروس ايون) الموجود في الهيموجلوبين الى ( فيريك) وبالتالي تقل قدرته على‬
.. ‫حمل االكسجين ولذلك نالحظ جلد الشخص يكون ازرق‬
……………………………………………………
*ABSORPTION the drug*:
• Bioavailability:
o Oral: generally low but isosorbide mononitrate > 95%)
o Sublingual: 10-60 %
o Transdermal 50-90 %
‫‪ DISTRIBUTION:‬‬
‫‪In all body tissues including brain.‬‬
‫‪ BIOTRANSFORMATION:‬‬
‫‪• > 99%, mainly in liver (by a high capacity nitrate-reductase).‬‬
‫‪Half-life: very variable‬‬
‫‪• Sublingual nitroglycerin: 2-3 min‬‬
‫‪• Oral isosorbide mononitrate: 4-5 hours‬‬
‫‪…………………………………………………………………………………………..‬‬
‫))‪(( Nitrates Tolerance and Dependence‬‬
‫ناخذ فكرة عامة عن معنى )‪: )Nitrates Tolerance‬‬
‫لما يفرز الجسم ‪ NO‬عبر ‪ endothelium‬يعمل ارتخاء للعضالت الملساء‬
‫ويعمل ‪ vasodilation‬حتى يفرز الجسم ال ‪ NO‬الزم يكون عندنا مجموعة‬
‫‪ SH‬الن هي مفتاح خروج ال ‪ NO‬هذه المجموعة ‪ SH‬تكون موجدودة بكميات‬
‫محددة في الخلية يعني مثال الجسم يفرزها وممكن تخلص ويفرزها مرة اخرى‬
‫عندنا الحاجة وتخلص الكمية تكون كمية محدودة بالخلية فاذا خلصت مجموعة‬
‫ال ‪ SH‬لن يتكون عندنا ‪ NO‬لذلك معنى كلمة ‪ Nitrates Tolerance‬هو ان‬
‫الشخص لما ياخذ العالج اول مرة ياتي معه فائدة ولكن لما ياخذه مرة ثانية‬
‫يشتكي ويقول الدواء ماله فايدة ولم يعالج االلم لماذا؟ الن مجموعة ال ‪ SH‬في‬
‫الجسم تكون استنفذت وحتى نعالج هذه المشكلة ننصح المرضى اما ان يقلل من‬
‫جرعة الدواء الن كلما اكثر من الدواء سوف تقل ال ‪ SH‬وبالتالي الدواء لن‬
‫يساعده وتستنفذ هذه المجموعة او نقول للشخص خذ الدواء مرة الفجر ومرة‬
‫المغرب حتى يسمح للجسم ويعطي وقت للجسم ان يصنع مرة اخرى هذه‬
‫المجموعة ال ‪...SH‬‬
‫‪• Frequently repeated exposures to nitrates leads to a decrease‬‬
‫‪in most of their pharmacological effects.‬‬
‫‪• Tolerance to a nitrate results in tolerance (at least partial) to‬‬
‫‪all other compounds of the class.‬‬
• The amount of tolerance is a function of the dosage and the
frequency of administration, and it exhibits a very high
individual variability.
• Since tolerance appears rapidly (24 hours) and disappears
rapidly (6-10 hours), brief periods of no therapy (hours of
overnight) can be sufficient to permit recovery.
‫ تذهب الن يكون‬،‫ ساعات‬6 ‫ ساعة وتختفي بسرعة بعد‬22 ‫المقاومة تظهر خالل‬
‫الجسم كون عندنا االس اتش‬
Nitrate can cause dependence. In fact sudden death or myocardial
infarction have occurred after a few days' break in long-term
exposure to an organic nitrate
‫الننترات ممكن تسبب مثل االدمان عليه يعني نعتمد عليه بقوة الن الموت بسبب احتشاء القلب يحصل بعد‬
. ‫ايام قليلة من اخذ الدواء لفترة طويلة ثم قطعه وعدم اخذ الدواء‬
Adverse effects of Nitrates
1-Central nervous system:
• Throbbing headache…… 50%, can be severe
• Dizziness, vertigo, lightheadedness
• Syncope
2- Cardiovascular system
•
•
•
•
Flushing of the face .
Palpitations
Postural hypotension
Profound hypotension (if taken concomitantly with sildenafil,
a specific cGMP phosphodiesterase-5 inhibitor. The inteaction
can be life-threatening).
Other systems:
• Skin rashes, contact dermatitis
• Methemoglobinemia (with nitrite, or with toxic doses of
nitrates)
• Withdrawal reactions (digital vasospasm, coronary spasms,
myocardial ischemia, myocardial infarction)
• Drug abuse (with amyl nitrite)
Contraindications and Precautions:
•
•
•
•
•
•
•
Angina due to hypertrophic Cardiomyopathy
Constrictive pericarditis
Increased intracranial pressure
Severe hypotension (systolic < 90 mm Hg)
Hypovolemic states
Hyperthyroidism
Severe hepatic disease
Therapeutic uses of nitrates
1- Angina pectoris
2. Heart failure
3. Myocardial infarction
4. Cyanide poisoning
1. Angina pectoris:
1-Treatment (or prevention) of the acute attack:
Nitroglycerin (sublingual route) or amyl nitrite (inhalant
route). [pain is relieved; protection lasts 30-40 min].
2-Chronic prophylaxis:
• Nitroglycerin (oral, transdermal), other nitrates (oral) [attacks
are reduced or eliminated].
Main mechanisms of antianginal effects:
A. In exertional angina: decreased myocardial O2 demand
B. In variant angina: increased myocardial O2 supply (they are
not the treatment of choice)
C. In unstable angina: (decreased myocardial O2 demand,
increased myocardial O2 supply, and decreased platelet
aggregation, all might contribute to the therapeutic efficacy).
High doses may cause undesirable effects due to:
A. reflex tachycardia
B. reflex increase in cardiac contractility
2- Heart failure
• nitrates can increase stroke volume and cardiac output in patients
with systolic heart failure (the decreased preload lowers the
ventricular filling pressure, so allowing a more efficient ventricular
contraction).
They are not used routinely in heart failure but can be used when:
1- symptoms of pulmonary congestion predominate (redistribution
of blood volume away from the chest relieves the congestion. This
improves exercise tolerance even when cardiac output is not
increased)
2- pulmonary edema occurs or is impending.
3- . Myocardial infarction
• minor reduction in short-term mortality
.‫انخفاض طفيف في معدل الوفيات على المدى القصير‬
• not recommended for routine use,
• but it is reasonable to use IV nitroglycerin in more complicated
patients, such as those with impending heart failure or hypertension.
‫ مثل تلك التي‬،‫ولكن من المعقول أن استخدام النتروجليسرين الرابع في المرضى أكثر تعقيدا‬
‫مع فشل القلب أو ارتفاع ضغط الدم وشيك‬
.
4. Cyanide poisoning
• Amyl nitrite and sodium nitrite are sometimes used to produce
methemoglobin which can complex cyanide ion to form
cyanomethemoglobin.
• Then IV sodium thiosulphate is used to convert cyanomethemoglobin
to thiocyanate and methemoglobin.
Beta blockers
Beta-blockers in Angina:
They decrease cardiac O2 demand by:
• Reducing heart rate
• Reducing cardiac contractility
• Lowering blood pressure
b) They increase myocardial perfusion in certain parts of the heart >>>>
subendocardial regions.
Effective the Beta blockers:
1234-
effective in chronic prophylaxis of exertional angina
acute treatment of unstable angina.
not effective in variant angina.
High doses may cause undesirable effects due to:
increased end diastolic volume
increased ejection time
Beta-blockers in Myocardial Infarction:
Is reduce mortality in myocardial infarction. They should be given early
and continued indefinitely.
The mortality reduction is likely due to the following reasons:
1) They decrease myocardial oxygen demand
2) They decrease the risk of ventricular fibrillation
3) They limit the infarct size (so decreasing the risk of myocardial
rupture)
4) They reduce myocardial remodeling ‫اعادة ظهور‬
Warning! withdrawal effects after chronic use of beta blockers in ischemic
heart disease are well documented. In risk patients abrupt withdrawal
may cause hypertension, angina, myocardial infarction, and sudden death
Calcium Channels
There are two types of calcium channels:
1- Ligand-gated (or "receptor-operated
2-Voltage-gated (or "potential-operated"): they open when the cell is
depolarized.
Voltage Gated Calcium Channels
Type
Location
Properties of Ca++ current
L (long-lasting)
Smooth muscle, heart, neurons
Long, high threshold
T (Transiently
opening)
Heart, neurons
Short, low threshold
N
Neurons
Short, high threshold
P
Purkinje
Long, high threshold
Classification of Ca++ Channel Blocking Drugs
Others
Dihydropyridines
Drug
Vascular Selectivity
Drug
Vascular Selectiv
Nifedipine
High
Verapamil
Low
Nicardipine
Very High
Diltiazem
Low
Bepridil
Absent
Mechanism of action:
• Calcium channel blockers bind to the voltage-gated Ca++ channel of Ltype .
• Verapamil and diltiazem block Ca++ channels both in the heart and in
the vessels.
• Dihydropyridines block Ca++ channels in the vessels only.
• Blockade can be reversed by drugs that increase transmembrane flux
of Ca++, such as beta-1 agonists.
Cardiac actions:
•
•
•
•
(Only verapamil and diltiazem can cause these effects)
Decreased conduction (in "slow fibers").
Decreased automaticity .
Increased refractoriness (markedly, but only in "slow fibers" or in
fibers that fire frequently and are incompletely polarized at rest).
Dose-dependent decrease of cardiac contractility.
Vascular actions
(All Ca++ channel blockers can cause these effects)
• Vasodilation (mainly in arterioles)
• Some dihydropyridines have a relative vascular selectivity
(nicardipine for cerebral and coronary vessels)
Other actions:
• Relaxation of bronchiolar, gastrointestinal and uterine smooth muscle
•
Inhibition of insulin release (verapamil, nifedipine, after very high doses)
• Inhibition of platelet aggregation (in vitro)
• Blockade of P-glycoprotein which is a multidrug transporter associated
with the development of drug resistance in cancer cells (verapamil).
ABSORPTION:
Oral bioavailability: variable (verapamil: 30% ) (amlodipine: 80%)
Oral Tmax (time to reach maximum concentration): 30-60 min.
DISTRIBUTION:
In all tissues including brain.
BIOTRANSFORMATION:
> 99% in liver and other organs. Some metabolites are active.
EXCRETION:
< 1 % excreted by the kidney.
Half-life: very variable
(Diltiazem: . 3 hours; amlodipine . 40 hours)
Adverse Effects:
•
•
•
•
•
•
•
•
•
•
Central Nervous System
Headache
Dizziness, lightheadedness weakness
Cardiovascular System
Flushing (nifedipine )
Peripheral edema (nifedipine)
Profound hypotension (mainly with immediate-release nifedipine)
Tachycardia, palpitations (nifedipine)
A-V block, bradycardia, arrhythmias (verapamil, diltiazem,)
Ventricular fibrillation (verapamil, diltiazem)
Aggravation of myocardial ischemia (nifedipine .)
Other systems
Constipation (verapamil ), gingival hyperplasia (verapamil ) nausea,
heart burn, abdominal pain.
• Contraindications and Precautions
• Hypotension
• Cardiogenic shock, systolic heart failure (verapamil, diltiazem)
• SA and AV block, sick sinus syndrome (verapamil, diltiazem)
• Arrhythmias associated with Wolff-Parkinson-White syndrome
(verapamil, diltiazem)
• Ventricular tachycardia (verapamil, diltiazem)
• Myocardial ischemia (dihydropyridines)
• Digoxin overdose
• GERD, constipation, fecal impaction, intestinal obstruction,
hemorrhoids
Therapeutic Uses
Angina pectoris:
a) Exertional angina mainly because they decrease myocardial O2
demand (due to decreased afterload, heart rate and contractility)
Verapamil and diltiazem are the preferred drugs.
High doses may cause undesirable effects due to:
increased end diastolic volume
the increased ejection time
b) Variant angina mainly because they increase myocardial O2
supply (due to coronary vasodilation)
All calcium channel blockers are considered drugs of choice:
High doses of dihydropyridines may cause undesirable effects due to:
reflex tachycardia
reflex increase in cardiac contractility
Unstable angina and myocardial infarction:
• During myocardial ischemia, an increase in Ca++ influx (due to
membrane depolarization) can trigger a secondary cellular
damage.
• A cytoprotective effect, due to a decrease in the amount of
necrosis in the heart tissue, has not been consistently supported
by clinical studies, but these drugs can reduce the rate of
reinfarction and death in patients without heart failure.
Cardiac arrhythmias
Hypertension
•
•
•
•
•
Hypertrophic cardiomyopathy and diastolic heart failure:
Diltiazem (alone or in combination with beta-blockers) improves
diastolic compliance by reducing myocardial contractility.
Subarachnoid hemorrhage
Dihydropyridines (especially nicardipine) dilate cerebral vessels at
doses that have little effects in the periphery. Therefore they
inhibit delayed reactive vasospasm arising from hemorrhage.
Raynaud's phenomenon
They are drugs of choice for relieving peripheral vasospasm.
Migraine
They are sometimes used for migraine prophylaxis (mechanism
not established).
Neuropsychiatric disorders
Various neuropsychiatric disorders (rapid-cycling bipolar disorder,
Tourette’s disease, Huntington’s disease). Long term-efficacy in
these disorders remains to be established.
Combination Therapy
1. Nitrates and B-blockers
Each blocks the adverse effect of the other
B-blockers – blocks the reflex tachycardia associated with nitrates
Nitrates – attenuate the increase in the left ventricular end
diastolic volume associated with B-lockers by increasing venous
capacitance
2. CCBs and B-blockers
-These two drugs produce decrease blood
pressure
-useful in the treatment of exertional angina that is not
controlled adequately with nitrates and B-blockers
-B-blockers – attenuate reflex tachycardia produce by nifedipine
3. Nitrates and CCB
• Useful in severe vasospastic or exertional angina (particularly in
patient with exertional angina with congestive heart failure and
sick sinus syndrome)
• Nitrates reduce preload
• CCBs reduces the after load
4. CCB, BB, nitrates
• Useful in patients with exertional angina not controlled by the
administration of two types of anti-anginal agent