Download cardiovascular drugs and autacoids

PHL 313 & 315
VASODILATORS
Autacoids
ALHARBI, Ph.D.
Autacoids
TEXTBOOK
Basic and Clinical
Pharmacology
12th edition
Author: Katzung, B.
Publisher: Lang
Medical Books.
GENERAL PROPERTIES OF VASODILATORS
1- Vasodilator drugs can be classified based on their site of
action (arterial versus venous)
3- Some drugs primarily dilate resistance vessels (arterial
dilators; e.g., hydralazine)
4- while others primarily affect venous capacitance vessels
(venous dilators; e.g., nitroglycerine).
5- Most vasodilator drugs have mixed arterial and venous
dilator properties (mixed dilators; e.g., alphaadrenoceptor antagonists, angiotensin converting enzyme
inhibitors).
Therapeutic Uses of VASODILATORS
1- Hypertension
2- Congestive heart failure
3- Coronary artery insufficiency
4- Hemostasis
Slow bleeding into surgical field
5- Impotence
Increased erectile function
6- Peripheral vascular disease
Common Side-Effects of Vasodilators
1- Systemic vasodilation
and arterial pressure reduction can lead to a baroreceptormediated reflex stimulation of the heart LEADING TO
2- TACHYCARDIA
This increases oxygen demand, which is undesirable if the patient
also has coronary artery disease.
Common Side-Effects of Vasodilators
3- OROTHSTATIC HYPOTENSION
Vasodilators can impair normal baroreceptor-mediated reflex
vasoconstriction when a person stands up, which can lead to
orthostatic hypotension and syncope upon standing.
4- RENAL RETENTION Of SODIUM AND WATER
Vasodilators can lead to renal retention of sodium and
water, which increases blood volume and cardiac output
and thereby compensates for the reduced systemic
vascular resistance.
Common Side-Effects of Vasodilators
5- HEADACHE
Due to Vasodilation of cerebral blood vessel
6- Cutaneous Flushing
Due to vasodilation of skin blood vessels.
MAJOR DRUG CLASSES OF VASODILATORS
1- Nitrodilators
2- potassium-channel openers
3- direct acting vasodilators (multiple actions) only Hydralazine
4- calcium channel blockers (CCBs)
5- Endothelin receptor antagonist
6- Renin inhibitors
7- Angiotensin converting enzyme inhibitors (ACE-I)
8- Angiotensin-ii receptor blockers (ARBs)
9- Phosphodiestrase-type 5 inhibitors
10- Activation of dopamine receptors (D1-receptors)
- Fenoldopam
1- Nitrodilators
There are two basic types of nitrodilators:
1- Release NO spontaneously (e.g., sodium nitroprusside)
2- organic nitrates that require an enzymatic process to form NO.
- Organic nitrates do not directly release NO
- nitrate groups interact with enzymes and
intracellular sulfhydryl groups that reduce
the nitrate groups to NO or to S-nitrosothiol,
- which then is reduced to NO.
- Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form
cGMP.
- Increased intracellular cGMP inhibits calcium entry into the cell, thereby
decreasing intracellular calcium concentrations and causing smooth muscle
relaxation
1- Examples of Nitrodilators
Nitroglycerin
Isosorbide dinitrate (Isordil, Sorbitrate, Dilatrate)
Isosorbide Mononitrate
Sodium nitroprusside (Nitropress)
Hydralazine (Apresoline) (actually its action is not
through nitric oxide)
ORGANIC NITRATES
1- These agents are prodrugs that are sources of nitric
oxide (NO).
2- NO activates the soluble isoform of guanylyl cyclase,
thereby increasing intracellular levels of cyclic GMP.
3- In turn, cyclic GMP promotes the dephosphorylation of
the myosin light chain and the reduction of cystolic
Ca2+ and leads to the relaxation of smooth muscle cells in a
broad range of tissues.
NONPROPRIETARY NAMES AND
TRADE NAMES
Nitroglycerin (glyceryl
trinitrate; NITRO-BID,
NITROSTAT, NITROL,
NITRO-DUR, others)
CHEMICAL STRUCTURE
PREPARATIONS, USUAL DOSES, AND
ROUTES OF ADMINISTRATIONa
T: 0.3-0.6 mg as needed
S: 0.4 mg per spray as needed
C: 2.5-9 mg 2-4 times daily
B: 1 mg every 3-5 h
O: 2.5-5 cm, topically to skin every 4-8 h
D: 1 disc (2.5-15 mg) for 12-16 h per day
IV: 10-20 g/min; increments of 10 g/min to a
maximum of 400
Isosorbide
dinitrate (ISORDIL,
SORBITRATE, DILATRATESR, others)
Isosorbide-5-mononitrate
(IMDUR, ISMO, others)
g/min
T: 2.5-10 mg every 2-3 h
T(C): 5-10 mg every 2-3 h
T(O): 5-40 mg every 8 h
C: 40-80 mg every 12 h
T: 10-40 mg twice daily
C: 60-120 mg daily

Cardiovascular Effects

1- Low concentrations of nitroglycerin preferentially
dilate veins more than arterioles.

2- This venodilation decreases venous return, leading to
a fall in left and right ventricular chamber size and enddiastolic pressures

3- Systemic arterial pressure may fall slightly, and heart
rate is unchanged or may increase slightly in response to
a decrease in blood pressure.

4- Doses of nitroglycerin that do not alter systemic
arterial pressure may still produce arteriolar dilation in
the face and neck, resulting in a facial flush, or dilation
of meningeal arterial vessels, causing headache.

Cardiovascular Effects

1- Higher doses of organic nitrates cause further venous pooling and may
decrease arteriolar resistance as well

2- thereby decreasing systolic and diastolic blood pressure and cardiac output
and causing pallor, weakness, dizziness, and activation of compensatory
sympathetic reflexes.

3- The reflex tachycardia and peripheral arteriolar vasoconstriction tend to
restore systemic vascular resistance; this is superimposed on sustained venous
pooling.

4- Coronary blood flow may increase transiently as a result of coronary
vasodilation but may decrease subsequently if cardiac output and blood
pressure decrease sufficiently.

5- In diabetic patient with neuropathy, nitrates may reduce arterial pressure
and coronary perfusion pressure significantly, producing potentially lifethreatening hypotension and even aggravating angina.

Cardiovascular Effects

organic nitrates cause dilation and prevent vasoconstriction of large epicardial
vessels without impairing autoregulation in the small vessels, which are responsible
for ~90% of the overall coronary vascular resistance.

sublingual nitroglycerin can dilate epicardial stenoses and reduce the resistance to
flow

In patients with angina owing to coronary artery spasm, the ability of organic
nitrates to dilate epicardial coronary arteries, and particularly regions affected by
spasm, may be the primary mechanism by which they are of benefit.

Cardiovascular Effects

Mechanism of Relief of Symptoms of Angina Pectoris

The ability of nitrates to dilate epicardial coronary
arteries, even in areas of atherosclerotic stenosis, is
modest

The main action is reduction in myocardial work leading
to decrease in myocardial O2 demand, as their primary
effect in chronic stable angina.

This accomplish by decrease preload

Tolerance

1- repeated or continuous exposure to high doses of
organic nitrates leads to a marked attenuation in the
magnitude of most of their pharmacological effects.

2- The magnitude of tolerance is a function of dosage
and frequency of use.

3- Tolerance may result from a reduced capacity of the
vascular smooth muscle to convert nitroglycerin to NO,

4- Multiple mechanisms have been proposed to account
for nitrate tolerance, including volume expansion,
neurohumoral activation, cellular depletion of
sulfhydryl groups, and the generation of free radicals

Tolerance

5- associated with oxidative stress that is why hydralazine (anti-oxidant)
decreases organic nitrate tolerance

6- A more effective approach to restoring responsiveness is to interrupt therapy
for 8-12 hours each day, which allows the return of efficacy.

It is usually most convenient to omit dosing at night in patients with
exertional angina either by adjusting dosing intervals of oral or buccal
preparations or by removing cutaneous nitroglycerin

7- Coronary and digital arteriospasm during withdrawal and its relaxation by
nitroglycerin also have been demonstrated radiographically.

Because of the potential problem of nitrate dependence, it seems prudent not to
withdraw nitrates abruptly from a patient who has received such therapy
chronically.

Interaction of Nitrates with PDE5 Inhibitors

1- Erectile dysfunction is a frequently encountered
problem whose risk factors parallel those of coronary
artery disease.

2- Thus many men desiring therapy for erectile
dysfunction already may be receiving (or may require,
especially if they increase physical activity) anti-anginal
therapy.

3- The combination of sildenafil and other
phosphodiesterase 5 (PDE5) inhibitors with organic
nitrate vasodilators can cause extreme hypotension.
 Therapeutic
Uses

1- ANGINA

2- CONGESTIVE HEART FAILURE


3- UNSTABLE ANGINA PECTORIS AND NON-ST-SEGMENT–
ELEVATION MYOCARDIAL INFARCTION
Should include antiplatelets

4- ACUTE MYOCARDIAL INFARCTION

5- VARIANT (PRINZMETAL) ANGINA

6- Diffuse Esophageal Spasm
In a limited number of patients with diffuse esophageal spasm without
gastroesophageal reflux†, isosorbide dinitrate has been used effectively to relieve
pain, dysphagia, and spasm.

Drug
Uses
Nitroglyce Angina pectoris
rin and
(coronary artery
nitrates disease), CHF,
Vessels
Affected
Mechanism
Venous Direct effect, conversion to
NO, increase cGMP
Sodium
nitroprusside
Arteriolar Direct effect, conversion to
Hypertensive
and
emergencies, acute
NO,* increase cGMP
venous
CHF
Hydralazine Hypertension, CHF Arteriolar Direct effect, partially EDRF-dependent
formation of NO,* increase cGMP; possible K
(with nitrate)
channel agonist; inhibition of inositol
triphosphate-induced Ca++
release
+
Hydralazine
Hydralazine dilates
arterioles but not veins.
Hydralazine may be used more effectively, particularly in severe hypertension.
The combination of
heart failure
Hydralazine with nitrates is effective in
and should be considered in patients with both hypertension and heart failure,
especially in African-American patients
Hydralazine
Hydralazine has been shown to prevent tolerance toward organic
nitrate
This is due to antioxidant properties
hydralazine is a highly potent radical scavenger.
Thus, the combination
with isosorbide dinitrate (ISDN) will favorably
influence the nitroso-redox balance in the cardiovascular system in
patients with congestive heart failure
Thus explain at least in part the improvement of prognosis in
patients with chronic congestive heart failure.
Adverse Effects Hydralazine
-The most common adverse effects of hydralazine are:
-In patients with ischemic heart disease, reflex tachycardia and
sympathetic stimulation may provoke angina or ischemic
arrhythmias.
dizziness, drowsiness, headache.
CV: tachycardia, angina, arrhythmias, edema, orthostatic
hypotension.
sodium retention.
drug-induced lupus syndrome.
-.
Minoxidil
1- Minoxidil is a very efficacious orally active vasodilator.
2- The effect results from the opening of potassium channels in
smooth muscle membranes by minoxidil sulfate, the active
metabolite.
3- Increased potassium permeability stabilizes the membrane at its
resting potential and makes contraction less likely.
4- Like hydralazine, minoxidil dilates arterioles but not veins.
Because of its greater potential antihypertensive effect, minoxidil
should replace hydralazine when maximal doses of the latter are not
effective or in patients with renal failure and severe hypertension,
USE IN PATIENTS who do not respond well to hydralazine
.
Minoxidil
ADVESRSE EFFECTS:
1- Tachycardia, palpitations, angina, and edema are observed when
doses of CARDIAC DEPRESSANTS blockers and diuretics are
inadequate.
2- Headache, sweating WHY ?
3- Hypertrichosis (GROWTH OF HAIR), which is particularly
bothersome in women, are relatively common.
4- Minoxidil illustrates how one person's toxicity may become
another person's therapy. Topical minoxidil (as Rogaine) is used as a
stimulant to hair growth for correction of baldness.
Sodium Nitroprusside
1- Sodium nitroprusside is a powerful parenterally
administered vasodilator
2- It is used in treating hypertensive emergencies as well as severe
heart failure.
3- Nitroprusside dilates both arterial and venous vessels, resulting in
reduced peripheral vascular resistance and venous return.
4- The action occurs as a result of activation of guanylyl cyclase,
either via release of nitric oxide or by direct stimulation of the
enzyme.
5- The result is increased intracellular cGMP, which relaxes vascular
smooth muscle.
Sodium Nitroprusside
1- Nitroprusside is a complex of iron, cyanide groups,
and a nitroso moiety.
2- It is rapidly metabolized by uptake into red blood
cells with liberation of cyanide.
3- Cyanide in turn is metabolized by the mitochondrial
enzyme rhodanase, in the presence of a sulfur donor, to
the less toxic thiocyanate.
4- Thiocyanate is distributed in extracellular fluid and
slowly eliminated by the kidney.
Sodium Nitroprusside
ADVERSE EFFECTS:
1- the most serious toxicity is related to accumulation of
cyanide
2- metabolic acidosis
3- arrhythmias
4- excessive hypotension
2-. Methemoglobinemia during infusion of nitroprusside has
also been reported.
Diazoxide
1- Diazoxide is an effective and relatively long-acting parenterally
administered arteriolar dilator
2- Diminishing usage suggests that it may be withdrawn.
3- Injection of diazoxide results in a rapid fall in systemic vascular
resistance and mean arterial blood pressure.
4- its mechanism suggest that it prevents vascular smooth muscle
contraction by opening potassium channels and stabilizing the
membrane potential
at the resting level.
Use
Hypoglycemia related to islet cell adenoma, carcinoma, hyperplasia, or
adenomatosis; nesidioblastosis; leucine sensitivity; extrapancreatic malignancy
Diazoxide
ADVERSE EFFECTS:
1- hypotension
2- The reflex sympathetic response can provoke angina
2- in patients with ischemic heart disease, and diazoxide
should be avoided in this
situation.
3- Diazoxide inhibits insulin release from the pancreas
(probably by opening potassium channels in the beta cell
membrane) and is used to treat hypoglycemia secondary to
insulinoma
Fenoldopam
1- Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies
And postoperative hypertension with renal compromised function.
2- Mechanism of Action
A selective postsynaptic dopamine agonist (D1-receptors) which exerts hypotensive
effects by decreasing peripheral vasculature resistance with increased renal blood
flow leading to diuresis, and natriuresis
3- It is 6 times as potent as dopamine in producing renal vasodilatation and has
minimal adrenergic effects
4- Fenoldopam is administered by continuous intravenous infusion.
5-As with other direct vasodilators, the major toxicities are reflex tachycardia,
headache, and flushing.
5- Fenoldopam also increases intraocular pressure and should be avoided in
patients with
glaucoma.
Inhibitors of Angiotensin
Mechanism & Sites of Action
1- Renin release from the kidney cortex is stimulated by:
a- reduced renal arterial pressure
b- sympathetic neural stimulation
c- reduced sodium delivery
d- increased sodium concentration at the distal renal tubule
* Renin acts upon angiotensinogen to split off the inactive precursor
decapeptide angiotensin I.
* Angiotensin I is then converted, primarily by endothelial ACE, to
the arterial vasoconstrictor octapeptide angiotensin II
Inhibitors of Angiotensin
Mechanism & Sites of Action
* Angiotensin-ii is in turn converted in the adrenal gland to
angiotensin III.
* Angiotensin II has vasoconstrictor and sodium-retaining activity.
* Angiotensin II and III both stimulate aldosterone release
* Angiotensin may contribute to maintaining high vascular
resistance in hypertensive states associated with high plasma renin
activity,
* renal arterial stenosis has high renin level
- Angiotensin system also induce cardiac hypertrophy
Inhibitors of Angiotensin
Action
Mechanism & Sites of
Inhibitors of Angiotensin
Action
Mechanism & Sites of
.
The converting enzyme involved in tissue angiotensin II
synthesis is also inhibited by ACE inhibitors.
Three classes of drugs act specifically on the reninangiotensin system:
1- ACE inhibitors
2- the competitive inhibitors of angiotensin at its receptors
(antagonist), including losartan
3- aliskiren, an orally active renin antagonist
4- aldosterone receptor inhibitors (eg, spironolactone, eplerenone)
Angiotensin-Converting Enzyme (ACE) Inhibitors
1- Captopril
- drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes
angiotensin I to angiotensin II
- (under the name plasma kininase) inactivates bradykinin, a potent vasodilator,
which works by stimulating release of nitric oxide and prostacyclin
The hypotensive activity of captopril results both from an inhibitory action on the reninangiotensin system
and a stimulating action on the kallikrein-kinin system
The latter mechanism has been demonstrated by showing that a bradykinin receptor
antagonist blunts the blood pressure-lowering effect of captopril
2- Enalapril is an oral prodrug that is converted by hydrolysis to a
converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril.
Enalaprilat itself is available only for intravenous use, primarily for hypertensive
emergencies.
4- Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril,
and trandolapril are other long-acting members of the class.
All are prodrugs, like enalapril, and are converted to the active
agents by hydrolysis, primarily in the liver.
5- Angiotensin II inhibitors lower blood pressure principally by
decreasing peripheral vascular resistance. Cardiac output and heart
rate are not significantly changed.
6- Unlike direct vasodilators, these agents do not result in reflex
sympathetic activation and can be used safely in persons with
ischemic heart disease.
7- The absence of reflex tachycardia may be due to downward
resetting of the baroreceptors
or to enhanced parasympathetic activity.
Angiotensin-Converting Enzyme (ACE) Inhibitors
8- ACE inhibitors have a particularly useful role in treating patients with chronic
kidney disease because they diminish proteinuria and stabilize renal function
(even in the absence of lowering of blood pressure).
9- This effect is particularly valuable in diabetes, and these drugs are now
recommended in diabetes even in the absence of hypertension.
10- These benefits probably result from improved intrarenal hemodynamics, with
decreased glomerular efferent arteriolar resistance and a resulting reduction of
intraglomerular capillary pressure.
10 - ACE inhibitors have also proved to be extremely useful in the treatment of
heart failure, and after myocardial infarction, and there is recent evidence
that ACE inhibitors reduce the incidence of diabetes in patients with high
cardiovascular risk
Adverse effects of angiotensin-Converting Enzyme (ACE)
Inhibitors
1- Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are
hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss.
2- Other adverse effects common to all ACE inhibitors include acute renal failure
(particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of
a solitary kidney)
3- hyperkalemia
Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes
4- dry cough sometimes accompanied by wheezing
5- Angioedema.. Bradykinin and substance P seem to be responsible for the cough and
angioedema seen with ACE inhibition.
6- ACE inhibitors are contraindicated during the second and third trimesters of pregnancy
because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated
with fetal malformations or death.
Adverse effects of angiotensin-Converting Enzyme (ACE)
Inhibitors
7- recent evidence also implicates first-trimester exposure to ACE inhibitors in
increased teratogenic risk.
8- Captopril, particularly when given in high doses to patients with renal
insufficiency, may cause neutropenia or proteinuria.
9- Minor toxic effects seen more typically include altered sense of taste
10- allergic skin rashes, and drug fever, which may occur in up to 10% of
patients.
11- Important drug interactions include those with potassium supplements or
potassium-sparing diuretics, which can result in hyperkalemia.
12- Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of
ACE inhibitors by blocking bradykinin-mediated vasodilation, which is at least in
part, prostaglandin mediated.
ANGIOTENSIN II RECEPTOR ANTAGONISTS
ANGIOTENSIN II RECEPTOR ANTAGONISTS
1- Candesartan
2- olmesartan
3- irbesartan
4- eprosartan
5- telmisartan
6- valsartan (the active metabolite of losartan)
7- losartan.
ANGIOTENSIN II RECEPTOR ANTAGONISTS
The AngII receptor blockers bind to the AT1 receptor with •
high affinity and are more than 10,000-fold selective for
the AT1 receptor over the AT2 receptor.
The rank-order affinity of the AT1 receptor for ARBs is:
* candesartan = olmesartan > irbesartan =
eprosartan > telmisartan = valsartan = •
(the active metabolite of losartan) > losartan. •
ANGIOTENSIN II RECEPTOR ANTAGONISTS
* Do ARBs have therapeutic efficacy equivalent to that of ACE
inhibitors?
Although both classes of drugs block the RAS
they differ in several important aspects:
•ARBs reduce activation of AT1 receptors more effectively than do ACE
inhibitors.
• ACE inhibitors reduce the biosynthesis of AngII by the action of
ACE, but do not inhibit alternative non-ACE AngII-generating
pathways.
•ARBs block the actions of AngII via the AT1 receptor regardless of
the biochemical pathway leading to AngII formation.
ANGIOTENSIN II RECEPTOR ANTAGONISTS
•In contrast to ACE inhibitors, ARBs permit activation of AT2
receptors.
• Because ARBs block AT1 receptors, this increased level of AngII is
available to activate AT2 receptors.
•ACE inhibitors increase the levels of a number of ACE substrates,
including bradykinin and Ac-SDKP.
Whether the pharmacological differences between ARBs and ACE
inhibitors result in significant differences in therapeutic outcomes is
an open question.
ANGIOTENSIN II RECEPTOR ANTAGONISTS
Candesartan Cilexetil (Atacand)
Candesartan cilexetil is an inactive ester prodrug that is completely
hydrolyzed to the active form, candesartan,
The plasma clearance of candesartan is affected by renal
insufficiency but not by mild-to-moderate hepatic insufficiency.
Candesartan cilexetil should be administered orally once or twice
daily for a total daily dose of 432 mg.
Eprosartan (Teveten)
. Clearance is by renal elimination and biliary excretion.
The plasma clearance of eprosartan is affected by both renal
insufficiency and hepatic insufficiency.
Irbesartan (Avapro)
.
cleared by renal elimination (20%) and biliary
excretion (80%).
The plasma clearance of irbesartan is unaffected
by either renal or mild-to-moderate hepatic
insufficiency.
The oral dosage of irbesartan is 150-300 mg once
daily.
. Losartan (Cozaar)
* Losartan is converted to the 5-carboxylic acid metabolite EXP
3174, which is more potent than losartan as an AT1 receptor
antagonist.
The plasma clearances of losartan and EXP 3174 are due to renal
clearance and hepatic clearance (metabolism and biliary excretion).
The plasma clearance of losartan and EXP 3174 is affected by
hepatic but not renal insufficiency
Losartan should be administered orally once or twice daily for a
total daily dose of 25-100 mg.
In addition to being an ARB, losartan is a competitive antagonist of
the thromboxane A2 receptor and attenuates platelet aggregation
. Olmesartan Medoxomil (Benicar)
Olmesartan medoxomil is an inactive ester prodrug that is •
completely hydrolyzed to the active form, olmesartan
* Plasma clearance of olmesartan is due to both renal •
elimination and biliary excretion.
Although renal impairment and hepatic disease decrease the •
plasma clearance of olmesartan
* no dose adjustment is required in patients with mild-to-•
moderate renal or hepatic impairment.
The oral dosage of olmesartan medoxomil is 20-40 mg once daily.•
Telmisartan (Micardis)
Telmisartan is cleared from the circulation mainly •
by biliary secretion of intact drug.
•
The plasma clearance of telmisartan is affected by
hepatic
but not renal insufficiency.
The recommended oral dosage of telmisartan is 4080 mg once daily.
Valsartan (Diovan)
Valsartan is cleared from the circulation by
the liver (~70% of total clearance).
The plasma clearance of valsartan is affected
by hepatic but not renal insufficiency.
The oral dosage of valsartan is 80-320 mg
once daily.
.
Therapeutic Uses of AngII Receptor Antagonists
1- All ARBs are approved for the treatment of hypertension.
2- In addition, irbesartan and losartan are approved for diabetic
nephropathy
3- losartan is approved for stroke prophylaxis
4- and valsartan is approved for heart failure and to reduce
cardiovascular mortality in clinically stable patients with left
ventricular failure or left ventricular dysfunction following
myocardial infarction.
5- The efficacy of ARBs in lowering blood pressure is comparable
with that of ACE inhibitors and other established antihypertensive
drugs, with a favorable adverse-effect profile..
Current recommendations are to use ACE inhibitors as first-line agents for the
treatment of heart failure and to reserve ARBs for treatment of heart failure in
patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors.
ARBs are renoprotective in type 2 diabetes mellitus, in part via blood pressure–
independent mechanisms
Based on these results, many experts now consider them the drugs of choice for
renoprotection in diabetic patients.
Losartan is superiority of an ARB compared with alpha 1 adrenergic receptor
antagonist with regard to reducing stroke in hypertensive patients with left
ventricular hypertrophy).
irebesartan appears to maintain sinus rhythm in patients with persistent, longstanding atrial fibrillation.
Losartan is reported to be safe and highly effective in the treatment of portal
hypertension in patients withcirrhosis and portal hypertension without
compromising renal function...
Adverse Effects of ARBs
1- The incidence of angioedema and cough with ARBs is less than
that with ACE inhibitors.
2- ARBs have teratogenic potential and should be discontinued in
pregnancy.
3- In patients whose arterial blood pressure or renal function is
highly dependent on the RAS (e.g., renal artery stenosis), ARBs can
cause hypotension, oliguria, progressive azotemia, or acute renal
failure.
4- ARBs may cause hyperkalemia in patients with renal disease or in
patients taking K+ supplements or K+-sparing diuretics.
5- There are rare postmarketing reports of anaphylaxis, abnormal hepatic
function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria,
hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.
DIRECT RENIN INHIBITORS
DRIs are a novel class of antihypertensive drugs that inhibit the
RAS at its origin.
Angiotensinogen is the only specific substrate for renin, and its
conversion to AngI presents a rate-limiting step for the generation of
downstream components of the RAS.
Aliskiren (TEKTURNA) is the only DRI approved
for clinical use.
Aliskiren, a second-generation renin inhibitor that was approved by
the U.S. FDA in 2007 for the treatment of hypertension.
Aliskiren has blood pressure–lowering effects similar to those of
ACE inhibitors and ARBs.
DIRECT RENIN INHIBITORS
.
Aliskiren
Aliskiren is a potent competitive inhibitor of renin.
It binds the active site of renin to block conversion of
angiotensinogen to AngI,
thus reducing the consequent production of AngII.
In healthy volunteers, aliskiren (40-640 mg/day) induces a dosedependent decrease in blood pressure,
aliskiren is similar to the high dose of valsartan in lowering blood
pressure, reducing albuminuria, normalizing serum creatinine, and
protecting against end-organ damage
Therapeutic Uses of Aliskiren
1- Aliskiren is an effective antihypertensive agent that is
well tolerated in monotherapy and combination therapy.
2- It has cardioprotective and renoprotective effects in
combination therapy
3- Aliskiren is recommended in patients who are intolerant
to other antihypertensive therapies or for use in
combination with
other drugs for further blood pressure control.
Adverse Aliskiren
1- hyperkalemia in diabetics on combination
therapy,
2- Angioedem.
3- Like other RAS inhibitors, aliskiren is not
recommended in pregnancy.
CA2+ CHANNEL ANTAGONISTS
DRUGS
VASODILATION
(CORONARY
FLOW)
SUPPRESSION OF
CARDIAC
CONTRACTILITY
SUPPRESSION OF
AUTOMATICITY
(SA NODE)
SUPPRESSION OF
CONDUCTION (AV
NODE)
Amlodipine
5
1
1
0
felodipine
5
1
1
0
Isradipine
NR
NR
NR
NR
Nicardipine
5
0
1
0
Nifedipine
5
1
1
0
Diltiazem
3
2
5
4
Verapamil
4
4
5
5
Clevidipine
(I.V. Only)
DRUGS USED IN DIASTOLIC HEART FAILURE
1- BETA BLOCKER
2- CALCIUM CHANNEL BLOCKER
3- ACE INHIBITORS OR ARB
4- Ranolazine
a novel anti anginal drug known to inhibit late sodium current (INaL)
Ranolazine Prevents Heart Failure with Preserved Ejection Fractionuggested
that Ranolazine (RAN), a novel anti anginal drug known to inhibit late sodium current
(INaL) may improve diastolic dysfunction (DD) caused by HTN induced oxidative
stress. By improving diastolic dysfunction RAN can improve Heart Failure with
Preserved Ejection Fraction (HFPEF). Methods: A mouse model
DRUGS USED IN HEART FAILURE
Commonly Used
Agent(s)
Group
Class
HCTZ
Thiazide diuretics
Diuretics
Furosemide
Loop diuretics
Spironolactone
Potassium sparing diuretics
Digoxin
Digitalis preparations
Dobutamine
Hydralazine
Inotropic drugs
Vasodilators
Isosorbide
Enalapril
Cardiac glycosides
ACE inhibitors
Captopril
Angiotensin II receptor
blockers
Losartan
Angiotensin II receptor
blockers
Vasoactive drugs
DRUGS USED IN HEART FAILURE
Commonly Used
Agent(s)
Metoprolol CR/XL
Carvedilol
Amiodarone
Dofetilide
Spironolactone
Eplerenone
Nesiritide
Tolvaptan
Group
Class
-Blockers
Antiarrhythmic
drugs
Aldosterone
receptor antagonists
Natriuretic peptides
Vasopressin receptor
antagonists
Autacoids
TOPICS WILL BE COVERED
1- Pharmacology of Histamine and its analogues
2- Pharmacology of Antihistamines(H1 &H2) &
mast cell sabilizers
3- Pharmacology of The Eicosanoids:Products of Cyclooxygenases
- Prostaglandins, Thromboxanes, & Related Compounds
- Analogues of Cyclooxygenases Products and their inhibitors
Second Assessment Test
4- Autacoids: Pharmacology of The Eicosanoids:Lipoxygenase products and their
blockers
5- Pharmacology of Serotonin, agonists and antagonists & the Ergot
AlkaloidsAutacoids
6- Pharmacology of Nitric oxide and Vasoactive Peptides and their blockers such
as endothelins, angiotensin, neurotensin, substance P.
AUTACOIDS
Introduction
• Means self remedy
• Naturally occurring substances
• Localized in tissues
• Do not normally circulate
• Diverse physiological and pharmacological activities
• Differ from hormones and neurotransmitters
• Short duration of action
• Usually involved in a response to injury
• Sites of action restricted to the synthesis area
CLASSIFICATION
1. Biogenic amines: Histamine, 5-hydroxytryptamine
2. Biogenic Peptides: Angiotensin and kinins
3. Small Proteins: cytokineins
4. Membrane derived lipids: LTs, PGs, TxA2 & PAF
5. Endothelium-derived agents:NO (gas); ET (peptide)
Histamine
1- Synthesis
2- Histamine Storage
- mast
cell
3- DISTRIBUTION OF HISTAMINE
4- Metabolism Histamine
•
The more important of these involves ring methylation to form Nmethylhistamine
It increases mastocytosis
Release Histamine
unexpected anaphylactoid reactions
As a result of the interaction of antigen with
immunoglobulin E (IgE) antibodies on the mast cell
surface
•
Histamine Release by Drugs, Peptides, Venoms, and
Other Agents.
•
These drugs stimulate the release of histamine from
mast cells directly and without prior sensitization.
Examples of Agents Release Histamine
1-amides, amidines, quaternary ammonium compounds,
pyridinium compounds, piperidines, and alkaloids
(Tubocurarine, succinylcholine, morphine
2- radiocontrast media
3- certain carbohydrate
elicit the response.
plasma expanders also may
Release Histamine
4- some antibiotics,
Vancomycin-induced "red-man syndrome" involving upper body
and facial flushing and hypotension may be mediated
through histamine release.
Beta-lactam antibiotics such amoxil as well as cephalosporin
Polymyxin B is also very active.
5- food
PHARMACOLOGY
OF
HISTAMINE
Histamine receptors
1- H1 receptor
- Smooth muscle
- brain
2- H2 receptor
- Gastric mucosa
3- H3 receptor
- Presynaptic: brain, myenteric plexus
4- H4 receptor
- Eosinophils, neutrophils, CD4 T cells
1- Central Nervous System
•
Histamine increases wakefulness via H1
receptors
•
explaining the potential for sedation by classical
antihistamines
• Histamine is a powerful stimulant of sensory
nerve endings, especially those mediating pain
and itching via H1
Gastric Acid Secretion
•
Acting at H2 receptors, histamine is a
powerful gastric secretagogue
•
and evokes a copious secretion of acid
from parietal CELL
• it also increases the output of pepsin and
intrinsic factor.
IMMUNE SYSTEM

H4 receptors are on immune active cells such as
eosinophils and neutrophils

Activation of H4 receptors on eosinophils induces:
- H4 antagonists may be useful inhibitors of
allergic and inflammatory responses
IMMUNE SYSTEM

- suggesting that the histamine released from mast
cells acts at H4 receptors to recruit eosinophils.
- H4 antagonists may be useful inhibitors of
allergic and inflammatory responses
Histamine-induces Vasodilation
Vasodilation involves both H1 and H2 receptors distributed
throughout the resistance vessels in most vascular beds
1- Activation H1 receptors
Medaites its action via endothelium-NO-dependent
dilation that is relatively rapid in onset and short-lived.
Increase calcium which lead to release Nitric oxide
.
Histamine-induces Vasodilation
2- activation of H2 receptors
H2 receptors couple via GS to the activation of
adenylyl cyclase
- (stimulating the cyclic AMP-PKA
pathway in smooth muscle)
- causes dilation that develops more slowly
and is more sustained
Histamine-induces Vasodilation
Increased "Capillary" Permeability
•
Causes edema formation.
•
H1 receptors on endothelial cells are the major
mediators of this response
•
Role of H2 receptors is uncertain.
Triple Response of Lewis
it elicits a characteristic phenomenon known as the
triple response (Lewis, 1927).
(1) a localized red spot
-
The initial red spot results
from the direct vasodilating effect of histamine
(H1-receptor-mediated NO production)
extending for a few millimeters around the site of
injection
that appears within a few seconds
and reaches a maximum in about a minute
Triple Response of Lewis
2) a brighter red flush, or "flare,"
-
the flare is due to histamine-induced stimulation of
axon reflexes
-
that cause vasodilation indirectly
- extending about 1 cm or so beyond the original
red spot
- and developing more slowly
Triple Response of Lewis
(3) a wheal that is discernible in 1 to 2 minutes
- and occupies the same area as the original
small red spot at the injection site.
- the wheal reflects histamine's capacity to
increase capillary permeability (edema formation).
CLINICAL USES OF HISTAMINE
HISTAMINE ANALOQUE
•
BetaSERC® 16 tablets
COMPOSITION:
•
Each tablet contains betahistine dihydrochloride
16 mg.
CLINICAL USES OF HISTAMINE
•
SERC® 16 tablets
PHARMACOLOGICAL ACTION:
Betahistine
The mechanism of action:
•
•
Pharmacological testing in animals has shown that:
- the blood circulation in the striae vascularis of the
inner ear improves
• - probably by means of a relaxation of the precapillary
sphincters of the microcirculation of the inner ear.
CLINICAL USES OF HISTAMINE
•
SERC® 16 tablets
In pharmacological studies, betahistine was found to
have weak H1 receptor agonistic
• - and considerable H3 antagonistic properties in the
CNS and autonomic nervous system.
•
- Betahistine was also found to have a dose dependent
inhibiting effect on spike generation of neurons in
lateral and medial vestibular nuclei.
• The importance of this observation in the action
against Ménière’s syndrome or vestibular vertigo,
however, remains unclear.
CLINICAL USES OF HISTAMINE
•
SERC® 16 tablets
INDICATIONS:
Symptomatic treatment of the vertigo associated with
Ménière’s Syndrome.
CONTRA-INDICATIONS:
- Patients with active peptic ulcer.
- Patients with phaeochromocytoma.
DOSAGE AND DIRECTIONS FOR USE:
Adult dosage
The usual initial dose is 8 to 16 mg three times daily
to be taken preferably with meals. Maintenance doses
of up to 48 mg daily have been recommended.
CLINICAL USES OF HISTAMINE
•
SERC® 16 tablets
SIDE-EFFECTS AND SPECIAL
PRECAUTIONS:
Gastro-intestinal disturbances, headache and skin
rashes have been reported.
•
Special precautions
Caution should be exercised when betahistine
dihydrochloride is given to patients with a history of
peptic ulcer or asthmatic patients.
Concomitant use with antihistamines should be
avoided.
ANTIHISTAMINES
H1-RECEPTOR
BLOCKERS
FIRST GENERATION ANTIHISTAMINES
(H1 BLOCKERS)SEDATING
1- Ethanolamines
- Carbinoxamine maleate
- Clemastine fumarate
- Diphenhydramine HCl
- Dimenhydrinate (DIZINIL)-ANTIMOTION SICKNESS)
2- Ethylenediamines
- Pyrilamine maleate
- Tripelennamine HCl
- Tripelennamine citrate
3- Alkylamines
- Chlorpheniramine maleate
- Brompheniramine maleate
4- Piperazines
- Hydroxyzine HCl
- Hydroxyzine pamoate
- Cyclizine HCl
- Cyclizine lactate
- Meclizine HCl
5- Phenothiazines
- Promethazine HCl
6- Piperidines
- Cyproheptadine HCl(periactin)
- Phenindamine tartrate
7-OTHERS
- ketotifen and olopatadine
- effective in allergic conjunctivitis and rhinitis.
Nasal sprays or topical ophthalmic preparations
Second-Generation H1 blockers
(non-sedating H1 blockers)
1- Alkylamines
- Acrivastine
2- Piperazines
- Cetirizine hydrochloride(ZYRTEC)
3- Phthalazinones
- Azelastine hydrochloride
4- Piperidines
- Levocabastine hydrochloride
-
Loratadine
- Desloratadine
- Ebastine
- Mizolastine
- Fexofenadine
PHARMACOLOGY OF ANT-IHISTAMINES(H1)
1- Competitive antagonism for the same receptor
2- do not prevent histamine release
3- do not cause physiological antagonism (smooth muscle
dilatation)
- NOT SUITABLE FOR ACUTE BRONCHIAL
ASTHMA

Do not block gastric acid production
(blocked by H2)
PHARMACOLOGY OF ANTIHISTAMINES(H1)
4- Protect against shock and allergic reactions
5- CNS depression, a side effect first generation
WHILE SECOND GENERATION DO NOT)
6- ANTICHOLINERGIC ACTIVITY (mainly
sedating H1-blockers)
the principle of antimotion sickness
- dimenhydrinate
PHARMACOLOGY OF ANTI-HISTAMINES(H1)
6- Local anesthetic effect suh as promethazine
7- Adrenoceptor-blocking actions such as
promethazine
8- Serotonin-blocking action such as
cyproheptadine
Therapeutic uses of H1 BLOCKERS
1-allergic reactions such as hay fever
2- motion sickness, verigo
3- NAUSEA AND VOMITING OF
PREGNANCY
4- sedation
5-common cold
Common Adverse Effects of H1 blockers
1- The most frequent side effect in the first-generation H1
antagonists is
sedation.
- Concurrent ingestion of alcohol or other CNS depressants
produces an additive effect that impairs motor skills.
2- dizziness, tinnitus, lassitude, incoordination, fatigue
3- blurred vision, diplopia (due to atropine like action)
4- Tachycardia
Common Adverse Effects
5- some H1 antagonists increase appetite such as cyproheptadine
due to serotonin blocking activity
6- antimuscarinic actions of some of the first-generation H1receptor antagonists include:
- dryness of the mouth and respiratory passages (sometimes
inducing cough)
- urinary retention or frequency, and dysuria.
These effects are not observed with second-generation H1
antagonists
Common Adverse Effects
OF SECOND GENERATION
H1-BLOCKERS
1- Lethal ventricular arrhythmias
in early second-generation agents
1- terfenadine
2- or astemizole
Common Adverse Effects
OF SECOND GENERATION H1-BLOCKERS
3- The mechanism of this toxicity involves blockade of
potassium channels in the heart
4- The result is prolongation of the action potential
5- excessive prolongation leads to arrhythmias.
6- Both terfenadine and astemizole were withdrawn
from the United States market in recognition of these
problems.
H1 blockers-Drug Interactions
- Drugs inhibit CYP3A4 such as:
- ketoconazole
- itraconazole
- macrolide antibiotics such as erythromycin
OR CLARITHROMYCIN.
These antimicrobial drugs cause significant
increases in blood concentrations of the
antihistamines(SECOND GENERATION).
H1 blockers-Drug Interactions

7- Terfenadine and astemizole should be considered
to be contraindicated in patients taking:
- ketoconazole
- itraconazole
- macrolides
- and in patients with liver disease.

8- Grapefruit juice also inhibits CYP3A4 and has been shown to
increase terfenadine's blood levels significantly as well as other drugs.
MAST

CELL STABILIZERS
Mechanism of Action
inhibits mast cell degranulation
CROMOLYN
& NEDOCROMIL

Cromolyn sodium (disodium cromoglycate)
and nedocromil sodium)

they effectively inhibit both antigen- and
exercise-induced asthma,
CROMOLYN & NEDOCROMIL
have no effect on
1- airway smooth muscle tone
2- and are ineffective in reversing
asthmatic bronchospasm
3-they are only of value when taken
prophylactically
 CLINICAL
USE OF CROMOLYN &
NEDOCROMIL
1-allergen inhalation,

by sulfur dioxide

and by a variety of causes of
occupational asthma.

2- Cromolyn solution is also useful in reducing
symptoms of allergic rhinoconjunctivitis.(EYE
DROP)
ADVERSE EFFECTS
Because the drugs are so poorly absorbed, adverse
effects of cromolyn and nedocromil are minor and
are localized to the sites of deposition.
 These include such minor symptoms as:
throat irritation,
 cough,
mouth dryness,

H2 Antagonists
Effect: Block all phases of gastric acid
secretion due to histamine.

proton pump inhibitors (NEXIUM OR LOSEC,
OMEPRAZOLE) are steadily replacing H2
antagonists for most clinical indications.
H2 Antagonists
1- Cimetidine
2- Ranitidine
3- Nizatidine
4- Famotidine
CLINICAL USES OF H2 ANATGONIST
1- GASTROESOPHAGEAL REFLUX DISEASE
(GERD)
2- PEPTIC ULCER DISEASE
ranitidine, 150 mg; famotidine, 20 mg
3- PREVENTION OF BLEEDING FROM
STRESS-RELATED GASTRITIS
ADVERSE EFFECTS OF H2 ANATGONIST
1- CENTRAL NERVOUS SYSTEM
- confusion, hallucinations, agitation)
given I.V.
These events may be more common with
cimetidine.
- rarely occur in ambulatory patients.
If
ADVERSE EFFECTS OF H2 ANATGONIST
2- ENDOCRINE EFFECTS
- Cimetidine inhibits binding of dihydrotestosterone to androgen
receptors
- inhibits metabolism of estradiol
- and increases serum prolactin levels.
When used long-term or in high doses
- it may cause gynecomastia
- impotence in men and galactorrhea in women.
These effects are specific to cimetidine and do not occur with the other H2
antagonists.
ADVERSE EFFECTS OF H2 ANATGONIST
3- Increases liver enzymes BUT reversible
H2 blockers-Drug Interactions
1- Cimetidine interferes with several
important hepatic cytochrome P450 drug
metabolism pathways,
- including those catalyzed by CYP1A2, CYP2C9,
CYP2D6, and CYP3A4
- Half-lives of drugs metabolized by these pathways
may be prolonged.
SEROTONIN (5-HT)
1- It formed from L-tryptophan
2-
In the pineal gland, serotonin serves as a precursor of
melatonin, a melanocyte-stimulating hormone.
3- over 90% of the serotonin in the body is found in
enterochromaffin cells in the gastrointestinal tract.

Physiological role of SEROTONIN (5-HT)
1- Brain serotonergic neurons are involved in numerous
diffuse functions such as
- mood
- sleep
- appetite
- temperature regulation
Physiological role of
SEROTONIN (5-HT)
2- the perception of pain
3- the regulation of blood pressure, and vomiting
4- Serotonin also appears to be involved in clinical
conditions such as depression, anxiety, and
migraine(blood vessels).
5- Serotonergic neurons are also found in the
enteric nervous system of the gastrointestinal
tract and around carcinoid tumor.
PHARMACOLOGY
OF
SEROTONIN (5-HT)
1- Cardiovascular system
* 5-HT2
-
Serotonin directly causes the contraction of vascular
smooth muscle, mainly through 5-HT2 receptors.
- In humans, serotonin is a powerful vasoconstrictor
(AGONIST MAY PRECIPITATE ANGINA AND
HEART ATTACK )
- Serotonin can also elicit reflex bradycardia by activation
of 5-HT3 receptors on chemoreceptor nerve endings.
Cardiovascular system
- Serotonin also constricts veins
venoconstriction with a resulting increased capillary filling appears
to be responsible for the flush that is observed following release
from a carcinoid tumor.
2- Gastrointestinal tract
5-HT2
Serotonin is a powerful stimulant of gastrointestinal smooth muscle
increasing tone and facilitating peristalsis.
This action is caused by the direct action of serotonin on 5-HT2
smooth muscle receptors
5-HT4
Activation of 5-HT4 receptors in the enteric nervous system causes
increased acetylcholine release
increase motility or "prokinetic" effect of partial serotonin agonists
such as Tegaserod
Overproduction of serotonin in carcinoid tumor is associated with
severe diarrhea.
2- Gastrointestinal tract

Zelnorm®
 (tegaserod maleate)

INDICATIONS AND USAGE
 IBS with Constipation
 Zelnorm® (tegaserod maleate) is indicated for the short-term
treatment of women with irritable bowel
 syndrome (IBS) whose primary bowel symptom is constipation.
 lished.
 Chronic Idiopathic Constipation
 Zelnorm® (tegaserod maleate) is indicated for the treatment of
patients less than 65 years of age with
 chronic idiopathic constipation.
2- Gastrointestinal tract

Zelnorm®
 (tegaserod maleate)

Post Marketing Experience
 Voluntary reports of adverse events occurring with the use of Zelnorm
include the following: ischemic
 Colitis
 1- mesenteric ischemia, gangrenous bowel,
 2- electrolyte disorders
 3- suspected sphincter of Oddi spasm, bile duct stone,
 cholecystitis with elevated transaminases,
5-HT1D/1B Agonists & Migraine Headache
The 5-HT1D/1B agonists (triptans) are used almost exclusively in
migraine headache.
Migraine in its "classic" form is characterized by an aura of variable
duration
that may involve nausea, vomiting, and visual scotomas
or even hemianopsia and speech abnormalities; followed by a severe
throbbing unilateral headache that lasts for a few hours to 1-2 days
. "Common" migraine lacks the aura phase, but the headache is similar.
Although the symptom pattern varies among patients,
the severity of migraine headache justifies vigorous therapy in the great
majority of cases.
5-HT1D/1B Agonists
Almotriptan
Eletriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan
The efficacy of triptan 5-HT1 agonists in migraine is
equal to or greater than that of other acute drug
treatments, eg, parenteral, oral, or rectal ergot
alkaloids.

Most adverse effects are mild and include

altered sensations (tingling, warmth, etc),

dizziness, muscle weakness, neck pain,

for parenteral sumatriptan

chest pain has been reported,

probably because of the ability of these drugs to cause
coronary vasospasm.

They are therefore contraindicated in patients with
coronary artery disease and in patients with angina.

Another disadvantage is the fact that their duration of effect
(especially that of almotriptan, sumatriptan, rizatriptan, and
zolmitriptan is often shorter than the duration of the
headache.
zolmitriptan
Contraindications
 Known or suspected ischemic heart disease (e.g., angina pectoris,
myocardial infarction, silent ischemia)

coronary vasospasm (e.g., Prinzmetal variant anginaother serious
underlying cardiovascular disease (e.g., uncontrolled hypertension),

or cerebrovascular syndromes (e.g., stroke syndromes, transient
ischemic attacks).

Treatment within the previous 24 hours with another 5-HT1 receptor
agonist or with an ergot alkaloid (e.g., ergotamine,
dihydroergotamine, methysergide).

Concurrent or recent (within 2 weeks) treatment with a monoamine
oxidase-A (MAO-A)(stop here)

As a result, several doses may be required during a
prolonged migraine attack, but their adverse effects
limit the maximum safe daily dosage.

Naratriptan and eletriptan are contraindicated in
patients with severe hepatic or renal impairment or
peripheral vascular syndromes;

frovatriptan is contraindicated in patients with
peripheral vascular disease

zolmitriptan is contraindicated in patients with
Wolff-Parkinson-White syndrome
SEROTONIN-RECEPTOR
ANTAGONISTS
1- Cyproheptadine
- 5-HT2-blocker (STIMULATE APPETITE & CARCINOID
SYNDROME)
- H1-receptor-blocker
- causes sedation
- antimuscarinic effects
- use in carcinoid tumor in GIT
- serotonin syndrome
5-HT3 ANTAGONISTS
1- Selective 5-HT3-receptor antagonists have potent
antiemetic
2- mediated mainly through central 5-HT3-receptor blockade in
the vomiting center and chemoreceptor trigger zone
3- blockade of peripheral 5-HT3 receptors on extrinsic intestinal
vagal and spinal afferent nerves.
4- The antiemetic action of these agents is restricted to
emesis attributable to vagal stimulation (eg,
postoperative) and chemotherapy
5-HT3 ANTAGONISTS
1- ondansetron
2- granisetron
3- dolasetron (prolong QT interval)
These three drug used once daily by oral or intravenous routes. .
4- palonosetron.
It is a newer intravenous agent that has greater affinity for the 5-HT3 receptor
and a long serum half-life of 40 hours.
- All of them do not inhibit dopamine or muscarinic receptors
- They do not have effects on esophageal or gastric motility
Therapeutic uses 5-HT3 ANTAGONISTS
1- CHEMOTHERAPY-INDUCED NAUSEA AND
VOMITING
•
5-HT3-receptor antagonists prevent of acute chemotherapy-induced nausea
and emesis
•
The drugs are most effective when given as a single dose by intravenous
injection 30 minutes prior to administration of chemotherapy
•
Or oral dose given 1 hour before chemotherapy
•
When used alone, these drugs have little or no efficacy for the prevention of
delayed nausea and vomiting (ie, occurring > 24 hours after chemotherapy
•
the efficacy is enhanced by combination therapy with a corticosteroid
(dexamethasone) and Neurokinin-1 receptor antagonist (Aprepitant ).
2- POSTOPERATIVE AND POSTRADIATION NAUSEA
AND VOMITING
ADVERSE EFFECTS OF
5-HT3 ANTAGONISTS
1- All three agents cause a small but statistically
significant prolongation of the QT interval, but this is most
pronounced with dolasetron.
it should not be administered to patients with prolonged
QT or in conjunction with other medications that may
prolong the QT interval.
THE ERGOT ALKALOIDS
1- Ergot alkaloids are produced by Claviceps purpurea, a fungus
that infects storage conditions.
2- The accidental ingestion of ergot alkaloids in contaminated
grain lead to :
- dementia with florid hallucinations
- prolonged vasospasm, which may
result in gangrene
- stimulation of uterine smooth muscle,
which in pregnancy may result in abortion.
1- Bromocriptine dopamine agonist
2- Ergonovine (uterine contraction)
3- Ergotamine (MIGRAINE)
4- Lysergic acid diethylamide (LSD) dopamine agonist
5- Methysergide
2- Ergonovine
(uterine contraction)
Ergonovine is more selective than other ergot alkaloids in
affecting the uterus and is the agent of choice in
obstetric (prevent bleeding after delivery)
MECHANISM OF ACTIONS
1-
5-HT2 partial agonist
(Vasoconstriction)
2- α1- Adrenoceptor Agonist.
(vasoconstriction)
In very small doses, ergot preparations can evoke
rhythmic contraction and relaxation of the uterus.
3- Ergotamine

Ergotamine and related compounds potently
constrict blood vessels for prolonged period
- USE IN MIGRAINE HEADACHE
4- Lysergic acid diethylamide (LSD) dopamine agonist
5- Methysergide (mixed actions on the previous
receptors
CLINICAL USES OF ERGOTAMINE
1- MIGRAINE
- Triptan drugs are preferred by most clinicians and
patients,
- traditional therapy with ergotamine can also be
quite effective when given during the prodrome of an
attack
it becomes progressively less effective if delayed.
Ergotamine tartrate is combined with caffeine (100 mg
caffeine for each 1 mg ergotamine tartrate) to facilitate
absorption of the ergot alkaloid
CLINICAL USES OF ERGOTAMINE
- The vasoconstriction induced by ergotamine is
long-lasting and cumulative when the drug is
taken repeatedly
- Therefore, patients must be carefully informed
that no more than 6 mg of the oral preparation
may be taken for each attack and no more than
10 mg per week.
- Dihydroergotamine, 0.5-1 mg intravenously, is
favored by some clinicians for treatment of
intractable migraine.
CLINICAL USES OF ERGONOVINE
POSTPARTUM HEMORRHAGE
Oxytocin is the preferred agent for control of postpartum
hemorrhage
- but if OXYTOCIN agent is ineffective, ergonovine
maleate, 0.2 mg usually given intramuscularly
It is usually effective within 1-5 minutes and is less toxic
than other ergot derivatives for this application.
It is given at the time of delivery of the placenta or
immediately afterward if bleeding is significant
CLINICAL USES OF BROMOCRIPTINE
HYPERPROLACTINEMIA
- Increased serum levels of the anterior pituitary hormone prolactin are
associated with:
* secreting tumors of the gland
* with the use of centrally acting dopamine antagonists, especially the D2blocking antipsychotic drugs
Because of negative feedback effects, hyperprolactinemia is associated with
amenorrhea and infertility in women
as well as galactorrhea in both sexes.
Bromocriptine is extremely effective in reducing the high levels of prolactin
that result from pituitary tumors and has even been associated with regression
of the tumor in some cases
The usual dosage of bromocriptine is 2.5 mg two or three times daily.
Eicosanoids: Prostaglandins, Thromboxanes,
Leukotrienes, & Related Compounds
Eicosanoids: Prostaglandins, Thromboxanes,

SYNTHESIS OF EICOSANOIDS
 Products of Prostaglandin Endoperoxide
Synthases (Cyclooxygenases)

Two unique COX isozymes convert arachidonic
acid into prostaglandin endoperoxide.

PGH synthase-1 (COX-1) is expressed
constitutively in most cells.
Eicosanoids: Prostaglandins, Thromboxanes,
 In contrast, PGH synthase-2 (COX-2) is
inducible

its expression varies markedly depending on the
stimulus.

COX-2 is an immediate early-response gene
product that is

markedly up-regulated by shear stress, growth
factors, tumor promoters, and cytokines
Eicosanoids: Prostaglandins, Thromboxanes,
Physiological role

COX-1 generates prostanoids

such as gastric epithelial cytoprotection

whereas COX-2 is the major source of prostanoids in
inflammation and cancer.

For example, endothelial COX-2 is the primary source
of vascular prostacyclin

whereas renal COX-2-derived prostanoids are
important for normal renal development and
maintenance of function. (maintain blood flow)
Eicosanoids: Prostaglandins, Thromboxanes,
Physiological role
 COX-3

Mainly centrally FEVER AND PAIN and can be
inhibited by

PARACETAMOL
prostaglandins and
prostaglandin analogs
currently in clinical use.
PHARMACOLOGY OF EICOSANOIDS

Effects of Prostaglandins & Thromboxanes

The prostaglandins and thromboxanes have major effects on four types of smooth
muscle:
1- vascular
2- gastrointestinal
3- airway
4- eye ( smooth muscle)
5- reproductive
PHARMACOLOGY OF EICOSANOIDS

Effects of Prostaglandins & Thromboxanes
1- platelets and monocytes
2- kidneys
3- the central nervous system, autonomic presynaptic
nerve terminals
4- sensory nerve endings
5- endocrine organs
PHARMACOLOGY OF EICOSANOIDS
 A. SMOOTH MUSCLE
 1. Vascular TXA2 is a potent vasoconstrictor


TXA2 is a smooth muscle cell mitogen
The mitogenic effect is potentiated by exposure of
smooth muscle cells to testosterone
PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza®
USES
 Lubiprostone is a PGE1 derivative used for the
 Tretament of chronic idiopathic constipation and
irritable bowel syndrome with constipation.
PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza®
 Mechanism of action:
 Lubiprostone stimulates chloride channels
 (ClC-2) in the luminal cells of the intestinal
epithelium, thereby
 increasing intestinal fluid secretion.

The increased chloride concentration within the
intestinal lumen softens the stool and increases
intestinal motility.
PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza®
 b. Side eff ects:
 Nausea is the most common side eff ect of
lubiprostone which can be decreased if taken with
food.

diarrhea is the second most reported adverse

reaction, followed by headache and abdominal pain.
PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza®
 Pharmacokinetics
 Absorption: Minimal absorption, action is primarily
in GI tract.
 Distribution: Minimal systemic distribution.

Contraindicated :
 Mechanical gastrointestinal obstruction
PHARMACOLOGY OF EICOSANOIDS
 INTESTINE
 Lubiprostone: Amitiza®
 Pharmacokinetics
 Absorption: Minimal absorption, action is primarily
in GI tract.
 Distribution: Minimal systemic distribution.

Contraindicated :
 Mechanical gastrointestinal obstruction
PHARMACOLOGY OF EICOSANOIDS
 A. SMOOTH MUSCLE
 2. PGF2a is also a vasoconstrictor but is not a mitogen for
smooth muscle cells.

the isoprostane 8-iso-PGF2a (iPF2aIII) which is also a
vasoconstrictor may act via the TP receptor.

In patients with cirrhosis

8-iso-PGF2a is produced in large amounts in the liver

and is thought to play a pathophysiologic role as an
important vasoconstrictor substance in the hepatorenal
syndrome.
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
1- PGI2 and PGE2, promote vasodilation by
increasing cAMP and decreasing smooth muscle
intracellular calcium
2- Vascular prostacyclin is synthesized by both
smooth muscle and endothelial cells,
3- In the microcirculation, PGE2 is a vasodilator
produced by endothelial cells.
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)



ILOPROST, a synthetic analog of prostacyclin
(PGI2), is a vasodilating agent and a plateletaggregation inhibitor.
Indications
 Pulmonary arterial hypertension leading to
Improved exercise capacity
 USE BY INHALATION
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)

MECHANISM OG ACTION


Dilates pulmonary and arterial vasculature.

These actions are mediated through activation of
the IP receptors (prostacyclin receptors)

Leading to an increase in the production of
intracellular cyclic adenosine monophosphate
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)
 TXA2 production is also inhibited


Contraindicated in:
 Hypersensitivity
 Systolic BP <85 mm Hg
 Lactation: Lactation.
 Use Cautiously in:
•
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)



Contraindicated in:
 Systolic BP <85 mm Hg
 lactation
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS)
 Use Cautiously in:
 Concurrent use of drugs or coexisting medical
conditions that may risk of syncope

COPD, asthma, or acute pulmonary infection (may risk
of bronchospasm)

Hepatic impairment (may need to dosing interval)

OB: Use only if maternal benefit outweighs fetal risk.
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS) •.
 Common

Adverse Effects
Cough
 headache
 vasodilation (flushing)
 Hypotension, syncope and palpitations
 hemoptysis due to thrombaxe-A2 inhibition
PHARMACOLOGY OF EICOSANOIDS
Vasodilator prostaglandins
 ILOPROST (VENTAVIS) •..
 Interactions

risk of hypotension with other vasodilators or diuretics


Risk of bleeding may be by anticoagulant
PHARMACOLOGY OF EICOSANOIDS
2. . Airways Respiratory smooth muscle
-
The cysteinyl leukotrienes are bronchoconstrictors.
They act principally on smooth muscle in peripheral
airways and are a thousand times more potent than
histamine both in vitro and in vivo.
-
They also stimulate bronchial mucus secretion and
cause mucosal edema.
-
Bronchospasm occurs in about 10% of people taking
NSAIDs, probably because of a shift in arachidonate
metabolism from COX-1 metabolism to
leukotriene formation
PHARMACOLOGY OF EICOSANOIDS
PLATELETS

Both PGD2 and PGI2 inhibit aggregation.

TXA2 is the major product of platelet COX-1, is a platelet
aggregator

and amplifies the effects of other more potent platelet
agonists such as thrombin.

The platelet actions of TXA2 are restrained in vivo by PGI2

which inhibits platelet aggregation by all recognized
agonists.
PHARMACOLOGY OF EICOSANOIDS
PLATELETS
Platelets release TXA2 during activation and aggregation.

Urinary metabolites of TXA2 increase in patients
experiencing a myocardial infarction

this Platelet COX-1-derived thromboxane synthesis is
irreversibly inhibited by chronic dosing with aspirin in
low doses.

Macrophage COX-2 appears to contribute roughly 10%
of the increment in TX biosynthesis observed in
smokers, while the rest is derived from platelets.
PHARMACOLOGY OF EICOSANOIDS
 KIDNEY


Both the medulla and the cortex of the kidney synthesize
prostaglandins
the medulla substantially more than the cortex.

The kidney also synthesizes several
hydroxyeicosatetraenoic acids, leukotrienes, cytochrome
P450 products, and epoxides.

These compounds play important autoregulatory roles
in renal function
PHARMACOLOGY OF EICOSANOIDS
 KIDNEY
by modifying renal hemodynamics and glomerular
and tubular function.


This regulatory role is especially important in
marginally functioning kidneys, as shown by the
decline in kidney function caused by COX inhibitors
in elderly patients and those with renal disease.
 The major eicosanoid products of the renal cortex
are PGE2 and PGI2
PHARMACOLOGY OF EICOSANOIDS
 KIDNEY
 PGE2
and PGI2 increase glomerular
filtration through their vasodilating
effects.
 These
prostaglandins also increase
water and sodium excretion.
PHARMACOLOGY OF EICOSANOIDS
KIDNEY
Loop diuretics, eg, furosemide, produce some of their
effect by stimulating COX activity.

In the normal kidney, this increases the synthesis of
the vasodilator prostaglandins.

Therefore, patient response to a loop
diuretic is diminished if a COX
inhibitor is administered concurrently
PHARMACOLOGY OF EICOSANOIDS
KIDNEY
The normal kidney synthesizes only small amounts of
TXA2.
 However, in renal conditions involving
inflammatory cell infiltration (such as
glomerulonephritis and renal transplant rejection)

the inflammatory cells (monocytemacrophages) release substantial
amounts of TXA2
PHARMACOLOGY OF EICOSANOIDS

REPRODUCTIVE ORGANS
 1. Female reproductive organs
 PGF2-alpha, together with oxytocin, is essential
for the onset of parturition
- Uterine muscle is contracted by PGF2a, TXA2
PHARMACOLOGY OF EICOSANOIDS
 CENTRAL AND PERIPHERAL NERVOUS SYSTEMS
 1. Fever

PGE2 increases body temperature

Exogenous PGF2a and PGI2 induce fever

pyrogens release interleukin-1, which in turn
promotes the synthesis and release of PGE2. This
synthesis is blocked by paracetamol and other
antipyretic compounds
PHARMACOLOGY OF EICOSANOIDS
EYE

PGE and PGF derivatives lower intraocular
pressure. (eye drops in glaucoma)

The mechanism of this action is unclear but
probably involves increased outflow of aqueous
humor from the anterior chamber via the uveoscleral
pathway
PHARMACOLOGY OF EICOSANOIDS
Glaucoma
Latanoprost
bimatoprost, travaprost, and unoprostone
1- a stable long-acting PGF2a derivatives
2- first prostanoid used for glaucoma
4- administered as drops into the conjunctival sac once or
twice daily.
5- Adverse effects include irreversible brown pigmentation of
the iris and eyelashes, drying of the eyes, and conjunctivitis
PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE MUCOSAL DEFENSE
Misoprostol
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is
a synthetic analog of prostaglandin E1.
The degree of inhibition of gastric acid secretion by misoprostol is
directly related to dose; oral doses of 100 to 200 mg significantly
inhibit basal acid secretion (up to 85% to 95% inhibition) or foodstimulated acid secretion (up to 75% to 85% inhibition).
The usual recommended dose for ulcer prophylaxis is 200 mg four times
a day.
PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE gastric MUCOSAL
DEFENSE
Mechanism of Action; Pharmacology. Prostaglandin E2
(PGE2) and prostacyclin (PGI2) are the major
prostaglandins synthesized by the gastric mucosa.
- PGE2 also can prevent gastric injury by cytoprotective
effects that include stimulation of mucin and bicarbonate
secretion and increased mucosal blood flow.
Since NSAIDs diminish prostaglandin formation by inhibiting
cyclooxygenase, synthetic prostaglandin analogs offer a
logical approach to reducing NSAID-induced mucosal
damage
PHARMACOLOGY OF EICOSANOIDS
AGENTS THAT ENHANCE GASTRIC MUCOSAL DEFENSE
Analog of prostaglandin E1
Misoprostol
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is
a synthetic analog of prostaglandin E1.
The degree of inhibition of gastric acid secretion by misoprostol is
directly related to dose; oral doses of 100 to 200 mg significantly
inhibit basal acid secretion (up to 85% to 95% inhibition) or foodstimulated acid secretion (up to 75% to 85% inhibition).
The usual recommended dose for ulcer prophylaxis is 200 mg four times
a day.
CLINICAL OF EICOSANOIDS
analogues
1- Dinoprostone, a synthetic preparation
of PGE2

is administered vaginally for oxytocic use.

it is approved for inducing abortion in the second trimester of
pregnancy


for missed abortion,
and for ripening of the cervix for induction of labor in patients at
or near term
CLINICAL OF EICOSANOIDS analogues

Dinoprostone also directly affects the collagenase of the cervix,
resulting in softening
For abortifacient purposes, the recommended dosage is a 20-mg
dinoprostone vaginal suppository repeated at 3- to 5-hour
intervals depending on the response of the uterus.

For softening of the cervix at term, the preparations used are
either a single vaginal insert containing 10 mg PGE2

or a vaginal gel containing 0.5 mg PGE2 administered every 6
hours. The softening of the cervix for induction of labor
substantially shortens the time to onset of labor and the delivery
time.
CLINICAL OF EICOSANOIDS analogues
PGF2alpha
1- This drug, carboprost tromethamine (15-methyl-PGF2a;
the 15-methyl group prolongs the duration of action)
2-used to induce second-trimester abortions and to control
postpartum hemorrhage that is not responding to conventional
methods of management.
3- Vomiting and diarrhea occur commonly,
probably because of gastrointestinal smooth muscle stimulation.
Transient elevations in temperature are seen in approximately
one eighth of patients.
Modulators of the pathways

NSAID’s and Corticosteroids (COX
Inhibitors)
 Lipoxygenase Inhibitors (Zileuton)

TXA2 Synthase Inhibitors

LTD4 Receptor Antagonist (MontelukastSINGULAIR)
Pharmacological/Physiological
Effects
2. Platelets
ARACHIDONIC ACID
COX -1
Platelet
TXA2
Vasoconstriction
Platelet Aggregation
_
_
ASPIRIN
COX -2
Endothelial
PGI2
Vasodilation
Anti-Platelet Aggregation
Therapeutic Uses of
Modulators

NSAID’s

Corticosteroids: anti-inflammatory

analgesic, antipyretic.

Montelukast (LTD4 BLOCKER) in asthma
Mean %
of Days
33%
32%
19%
Placebo Montelukast Beclometh.
% of
patients
without
asthma
attacks
Montelukast in
Asthma
Mean % days
patients experienced
sustained asthma
control
Beclomethasone
NS
Montelukast
Placebo
Time after randomization (days)
Time to first
asthma attack
BIOGENIC PEPTIDES
ANGIOTENSIN
Synthesis & metabolism

Angiotensinogen (plasma substrate) to
angiotensin I, by renin that is released during
renal ischemia.
 Angiotensin I to II by angiotensin converting
enzyme (ACE, Kinase II) in the pulmonary
endothelium.
 Renin inhibited by propranolol
 Angiotensin II metabolized by angiotensinases
in plasma and tissues.
BIOGENIC PEPTIDES
ANGIOTENSIN
Effects
 Causes profound vasoconstriction

Increases peripheral vascular resistance
 Increases blood pressure
 Directly stimulates heart
 Facilitates epinephrine and aldosterone release
 Increases Na reabsorption in kidney tubules
 Releases ADH (vasopressin) to restore blood volume

Losartan and valsartan blocks angiotensin (AT1)

receptors
Captopril & enalapril inhibit ACE (congest. heart fail.).
BIOGENIC PEPTIDES
BRADYKININ
Actions
Comes under the group “kinins”
This mediates nociception (pain)
Regulates BP (vasodilator)
Increases capillary permeability
Balances electrolytes and fluid,
Contracts gut slowly and stimulates
prostaglandin synthesis
 Produced by tissue damage, viral infection,
allergic reaction & inflammation
 Contracts various other smooth muscles






BIOGENIC PEPTIDE
BRADYKININ
Synthesis
Prekallikrein
(Plasma)
1. Kininogen
(alpha-2 globulins
High and low m.w.
Kallikrein
Hagman factor
(activated by collagen)
(plasma & tissues)
Bradykinin, Kallidin
Kallikrein
(nonapeptide)(decapeptide)
(Activated by peptidases)
Kallidin, a decapeptide, with same actions is also
produced along with bradykinin. Both are
metabolized to inactive agents by kinases II and ACE
BIOGENIC PEPTIDES
BRADYKININ & KALLIDIN
Receptors

B1 mediates vasoconstriction, sensitive to
metabolites.
 B2 mediates vasodilatation, permeability,
smooth muscle contraction, pain
 B3 mediates guinea pig tracheal contraction,
not antagonized by B1 or B2 antagonists.
SMALL PROTEINS
CYTOKINES (TNFa, IL-1,IL-6)
1. TNF (Tumor Necrosis Factor )

A mediator of endotoxic shock

Released by macrophages when exposed to endotoxin

Triggers wide endotoxemic symptoms

Elicits production of other cytokines, eicosanoids &
humoral factors

Stimulates degradation and adherence of neutrophils
to endothelium

Symptoms of septicemia at high concentration

Can be neutralized by TNF  antiserum

Chronic exposure leads to cachexia (TNF was
formerly known as cachectin)
SMALL PROTEINS
CYTOKINES
2. Interleukin-1 (IL-1)
 Known as lymphocyte activating factor ( T-cell
responses)
 Activates endogenous pyrogen (induces fever)
 Interacts synergestically with TNF 
  synthesis & release of IL-2 by interacting with
antigen stimulated T-cells
 Activates B-cells and antibody synthesis
  arachidonic acid metabolism,  inflammatory
proteins
  neutrophil chemoattraction & fibroblast
proliferation
  PGI2 synthesis in endothelial cells
SMALL PROTEINS
CYTOKINES
3. Interleukin-6 (IL-6)






A phosphoglycoprotein
Produced and secreted by macrophates,
monocytes, fibroblasts
Inflammatory stimuli causes production by
endothelium, T lymphocytes, mast cells
IL-6 induces production of hepatic fibrinogen
for protection against microorganisms
Endotoxin, TNF alpha and IL-1 increase the
levels of IL-6
Does not cause tissue injury or vascular
thrombosis
Platelet Activating Factor (PAF)
General Information
• Hanson (1971) identified a platelet aggregating agent
• Same substance (BP) was found in adrenal medulla
• Phospholipase A2 releases AA & lysoPAF from
membrane
• LysoPAF is acetylated by acetyl coenzyme A to PAF
(catalyzed by acetyl transferase)
• Antigen-antibody reaction, chemotactic peptides,
thrombin, collagen and other autacoids  synthesis.
• Platelets, neutrophils, monocytes, mast cells, eosinophils,
renal medullary cells and endothelium synthesize
PAF
PLATELET ACTIVATING FACTOR
Physiological functions
•
•
PAF in amniotic fluid derived from fetal lung.
It is a potent bronchoconstrictor (long lasting) & causes
pulmonary edema
•
Simulates G proteins that are on the cell surface
•
This activates phospholipase C & A2
•
Forms inositol phosphate, diacylglycerol and arachidonates
•
Thus, PAF
and TXA
leads to the formation of PGs, LT
PAF
Pharmacological actions
• Increases platelet aggregation
• Potent vasodilator,  PVR and BP
• Constricts pulmonary vessels
• Microvascular permeability 
• Releases eicosanoids, generates superoxides
• Contracts nonvascular smooth muscles,
• Increases respiratory secretions, forms
•
pulmonary edema
Decreases renal flow
Nitric Oxide (NO)
Known as endothelium derived relaxing factor
(EDRF)
• Organic nitrates (amyl nitrate, nitroglycerin,
nitroprusside) release NO
• Nitric Oxide Synthase (NOS) antagonists
counteracts vascular relaxation
EFFECTS OF NO
• Physiological vasodilator
• eNOS blockers increase BP by vasoconstriction
• Macrophages kill microorganisms by NO
It causes: involved in penile erection
PHARMACOLOGIC MANIPULATION OF
NITRIC OXIDE
Inhibitors of Nitric Oxide Synthesis
•
•
In many disorders, such as inflammation and sepsis
inhibition of the iNOS isoform is NEEDED
SEPTIC SHOCK
increased urinary excretion of nitrate, the oxidative product of NO, is a feature of gramnegative bacterial infection.
•
•
•
•
Lipopolysaccharide components from the bacterial wall induce synthesis of iNOS,
resulting in exaggerated hypotension, shock, and, in some cases, death.
This hypotension is reversed by NOS inhibitors such as L-NMMA in humans
A similar reversal of hypotension is produced by compounds that prevent the action of
NO (such as methylene blue)
as well as by scavengers of NO (such as hemoglobin).
Nitric Oxide Donors
1. Organic nitrates Nitroglycerin
•
metabolized to NO by mitochondrial aldehyde reductase, an enzyme enriched
in venous smooth muscle,
.
2. Sodium nitroprusside
generates NO in response to light as well as chemical or enzymatic
mechanisms in cell membranes.
3. Hybrid NO donors
A new strategy involves the incorporation of NO-donating moieties onto currently
available cardiovascular drugs. captopril. SNOCap, which incorporates a
nitrosothiol moiety on captopril, is currently being examined for its efficacy in
cardiovascular disorders
• Nitric Oxide Donors
6. Alternate strategies
Sildenafil (VIAGRA)
- inhibitor of type 5 phosphodiesterase
- results in prolongation of the duration of NOinduced cGMP elevations in a variety of tissues
Endothelin
potent vasoconstrictor peptides that were first isolated
from aortic endothelial cells.
Receptors:
ETB causes transient drop in BP
ETA causes prolonged increases in BP
endothelin receptor antagonists
Bosentan is a nonselective antagonist
Endothelin ANTAGONIST
Bosentan
is currently approved for use in pulmonary hypertension
ADVERSE EFFECTS OF Bosentan
1-Bosentan has been associated with fatal hepatotoxicity
patients taking this drug must have monthly liver function tests.
2- Negative pregnancy test results are required for women of childbearing age to take this drug