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PHL 313 315 VASODILATORS Autacoids
ALHARBI, Ph.D.
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AutacoidsTEXTBOOKBasic and Clinical
Pharmacology12th edition Author
Katzung, B. Publisher Lang
Medical Books.
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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., alpha-adrenoceptor antagonists, angiotensin
converting enzyme inhibitors).
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Therapeutic Uses of VASODILATORS1-
Hypertension2- Congestive heart failure3-
Coronary artery insufficiency4- HemostasisSlow
bleeding into surgical field5-
ImpotenceIncreased erectile function 6-
Peripheral vascular disease
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Common Side-Effects of Vasodilators 1-
Systemic vasodilation and arterial pressure
reduction can lead to a baroreceptor-mediated
reflex stimulation of the heart LEADING TO2-
TACHYCARDIA This increases oxygen demand, which
is undesirable if the patient also has coronary
artery disease.
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Common Side-Effects of Vasodilators3-
OROTHSTATIC HYPOTENSIONVasodilators 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 WATERVasodilators 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.
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Common Side-Effects of Vasodilators5-
HEADACHEDue to Vasodilation of cerebral blood
vessel6- Cutaneous FlushingDue to
vasodilation of skin blood vessels.
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MAJOR DRUG CLASSES OF VASODILATORS  1-
Nitrodilators2- potassium-channel openers3-
direct acting vasodilators (multiple actions)
only Hydralazine4- calcium channel blockers
(CCBs)5- Endothelin receptor antagonist6-
Renin inhibitors7- Angiotensin converting
enzyme inhibitors (ACE-I)8- Angiotensin-ii
receptor blockers (ARBs)9- Phosphodiestrase-type
5 inhibitors10- Activation of dopamine
receptors (D1-receptors) -
Fenoldopam
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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
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1- Examples of NitrodilatorsNitrogly
cerin Isosorbide dinitrate (Isordil,
Sorbitrate, Dilatrate)Isosorbide Mononitrate
Sodium nitroprusside (Nitropress)Hydralazine
(Apresoline) (actually its action is not through
nitric oxide)
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ORGANIC NITRATES1- 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.

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NONPROPRIETARY NAMES AND TRADE NAMES CHEMICAL STRUCTURE PREPARATIONS, USUAL DOSES, AND ROUTES OF ADMINISTRATIONa
Nitroglycerin (glyceryl trinitrate NITRO-BID, NITROSTAT, NITROL, NITRO-DUR, others)  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  g/min
Isosorbide dinitrate (ISORDIL, SORBITRATE, DILATRATE-SR, others)  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
Isosorbide-5-mononitrate (IMDUR, ISMO, others)   T 10-40 mg twice daily C 60-120 mg daily
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• Cardiovascular Effects
• 1- Low concentrations of nitroglycerin preferentia
  lly dilate veins more than arterioles.
• 2- This venodilation decreases venous return,
  leading to a fall in left and right ventricular
  chamber size and end-diastolic 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.

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• 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 life-threatening hypotension and even
  aggravating angina.

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• 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.

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• 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

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• 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

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• 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.

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• 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.

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• Therapeutic Uses
• 1- ANGINA
• 2- CONGESTIVE HEART FAILURE
• 3- UNSTABLE ANGINA PECTORIS AND
  NON-ST-SEGMENTELEVATION 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.

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Mechanism Vessels Affected Uses
Direct effect, conversion to NO, increase cGMP Venous Angina pectoris (coronary artery disease), CHF,
Direct effect, conversion to NO, increase cGMP Arteriolar and venous Hypertensive emergencies, acute CHF
Direct effect, partially EDRF-dependent formation of NO, increase cGMP possible K channel agonist inhibition of inositol triphosphate-induced Ca release Arteriolar Hypertension, CHF (with nitrate)
Drug
Nitroglycerin and nitrates
Sodium nitroprusside
Hydralazine
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Hydralazine Hydralazine dilates arterioles but
not veins. Hydralazine may be used more
effectively, particularly in severe hypertension.
The combination of Hydralazine with nitrates
is effective in heart failure and should be
considered in patients with both hypertension and
heart failure, especially in African-American
patients
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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.
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• 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.
• .

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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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Inhibitors of AngiotensinMechanism Sites
of Action1- Renin release from the kidney
cortex is stimulated bya- reduced renal
arterial pressureb- sympathetic neural
stimulationc- 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

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Inhibitors of AngiotensinMechanism 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

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Inhibitors of Angiotensin Mechanism Sites
of Action

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Inhibitors of Angiotensin Mechanism Sites
of Action

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. The converting enzyme involved in tissue
angiotensin II synthesis is also inhibited by ACE
inhibitors.Three classes of drugs act
specifically on the renin-angiotensin
system1- ACE inhibitors2- 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)

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Angiotensin-Converting Enzyme (ACE)
Inhibitors1- 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
renin-angiotensin 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 captopril2-
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.

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Angiotensin-Converting Enzyme (ACE)
Inhibitors3- Lisinopril is a lysine
derivative of enalaprilat.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.. .


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Angiotensin-Converting
Enzyme (ACE) Inhibitors8- 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 .

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Adverse effects of
angiotensin-Converting Enzyme (ACE)
Inhibitors1- 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
wheezing5- 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.

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Adverse
effects of angiotensin-Converting Enzyme (ACE)

Inhibitors7- 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
taste10- 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. .

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Angiotensin II Receptor Antagonists


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The AngII receptor blockers 1-
Candesartan2- olmesartan 3- irbesartan 4-
eprosartan5- telmisartan 6- valsartan (the
active metabolite of losartan) 7-
losartan.
Angiotensin II Receptor Antagonists

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• 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 gt irbesartan
• eprosartan gt telmisartan valsartan
• (the active metabolite of losartan) gt losartan.

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• 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
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• 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
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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 4- 32 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. The
recommended dosage of eprosartan is 400-800
mg/day in one or two doses.
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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.
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. 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
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• . 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.

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• 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
  40-80 mg once daily.

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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. .
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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..
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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
pressureindependent 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,
long-standing 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...
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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. .
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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
pressurelowering effects similar to those of ACE
inhibitors and ARBs. .
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Direct Renin Inhibitors   .
63

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 dose-dependent 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
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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. .
65

Adverse Aliskiren 1- hyperkalemia in diabetics
on combination therapy, 2- Angioedem. 3-
Like other RAS inhibitors, aliskiren is not
recommended in pregnancy. . .
66
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 Clevidipine (I.V. Only) 5 1 1 0
Diltiazem 3 2 5 4
Verapamil 4 4 5 5
67

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
68

DRUGS USED IN HEART FAILURE
Class Group Commonly Used Agent(s)
Diuretics Thiazide diuretics HCTZ
  Loop diuretics Furosemide
  Potassium sparing diuretics Spironolactone
Cardiac glycosides Digitalis preparations Digoxin
Inotropic drugs   Dobutamine
Vasoactive drugs Vasodilators Hydralazine
    Isosorbide
  ACE inhibitors Enalapril
  Captopril
  Angiotensin II receptor blockers  
    Losartan
  Angiotensin II receptor blockers  
69

DRUGS USED IN HEART FAILURE
Class Group Commonly Used Agent(s)

-Blockers  Metoprolol CR/XL
  Carvedilol
Antiarrhythmic drugs   Amiodarone
    Dofetilide
Aldosterone receptor antagonists   Spironolactone
    Eplerenone
Natriuretic peptides   Nesiritide
Vasopressin receptor antagonists   Tolvaptan
70
Autacoids
71

• 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
  EicosanoidsLipoxygenase 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.

72
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

73
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 agentsNO
(gas) ET (peptide)
74
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 N-methylhistamine
• It increases mastocytosis

75

• 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.

76
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 plasma expanders also may elicit the
response.
77
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
78
PHARMACOLOGY OF HISTAMINE
79
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
80

• 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

81

• 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.

82

• 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

83
(No Transcript)
84

• 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

85

• 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-depen
  dent dilation that is relatively rapid in onset
  and short-lived.
• Increase calcium which lead to release Nitric
  oxide
• .

86

• 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

87

• Histamine-induces Vasodilation

88

• Increased "Capillary" Permeability
• Causes edema formation.
• H1 receptors on endothelial cells are the major
  mediators of this response
• Role of H2 receptors is uncertain.

89

• 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

90

• 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

91

• 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).

92

• CLINICAL USES OF HISTAMINE
• HISTAMINE ANALOQUE
• BetaSERC 16 tabletsCOMPOSITION
• Each tablet contains betahistine dihydrochloride
  16 mg.

93

• CLINICAL USES OF HISTAMINE
• SERC 16 tabletsPHARMACOLOGICAL
  ACTIONBetahistine 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.

94

• CLINICAL USES OF HISTAMINE
• SERC 16 tabletsIn 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 Ménières syndrome or vestibular vertigo,
  however, remains unclear.

95

• CLINICAL USES OF HISTAMINE
• SERC 16 tabletsINDICATIONSSymptomatic
  treatment of the vertigo associated with
  Ménières Syndrome.CONTRA-INDICATIONS-
  Patients with active peptic ulcer.- Patients
  with phaeochromocytoma.DOSAGE AND DIRECTIONS
  FOR USEAdult dosageThe 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.

96

• CLINICAL USES OF HISTAMINE
• SERC 16 tabletsSIDE-EFFECTS AND SPECIAL
  PRECAUTIONSGastro-intestinal disturbances,
  headache and skin rashes have been reported.
• Special precautionsCaution 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.

97
ANTIHISTAMINESH1-RECEPTOR
BLOCKERS

98

• FIRST GENERATION ANTIHISTAMINES (H1
  BLOCKERS)SEDATING
• 1- Ethanolamines
• - Carbinoxamine maleate
• - Clemastine fumarate
• - Diphenhydramine HCl
• - Dimenhydrinate (DIZINIL)-ANTI-MOTION
  SICKNESS)
• 2- Ethylenediamines
• - Pyrilamine maleate
• - Tripelennamine HCl
• - Tripelennamine citrate

99

• 3- Alkylamines
• - Chlorpheniramine maleate 
• - Brompheniramine maleate  
• 4- Piperazines
• - Hydroxyzine HCl
• - Hydroxyzine pamoate
• - Cyclizine HCl
• - Cyclizine lactate
• - Meclizine HCl

100

• 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

101

• Second-Generation H1 blockers
• (non-sedating H1 blockers)
• 1- Alkylamines
• - Acrivastine
• 2- Piperazines
• - Cetirizine hydrochloride(ZYRTEC)
• 3- Phthalazinones
• - Azelastine hydrochloride

102

• 4- Piperidines
• - Levocabastine hydrochloride
• - Loratadine
• - Desloratadine
• - Ebastine
• - Mizolastine
• - Fexofenadine

103

• 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)

104

• PHARMACOLOGY OF ANTI-HISTAMINES(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

105

• 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

106
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

107
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

108
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 H1-receptor 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

109
Common Adverse Effects OF SECOND GENERATION
H1-BLOCKERS 1- Lethal ventricular arrhythmias
in early second-generation agents 1- terfenadine
2- or astemizole

110
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.

111
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(SECO
ND GENERATION).

112

• 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.

113

• MAST CELL STABILIZERS
• Mechanism of Actioninhibits mast cell
  degranulation
• CROMOLYN NEDOCROMIL
• Cromolyn sodium (disodium cromoglycate) and
  nedocromil sodium)
• they effectively inhibit both antigen- and
  exercise-induced asthma,

114

• 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

115

• CLINICAL USE OF CROMOLYN NEDOCROMIL1-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)

116

• 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,

117
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.

118
H2 Antagonists

• 1- Cimetidine
• 2- Ranitidine
• 3- Nizatidine
• 4- Famotidine

119

• 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

120

• ADVERSE EFFECTS OF H2 ANATGONIST
• 1- CENTRAL NERVOUS SYSTEM
• - confusion, hallucinations, agitation)
  If given I.V.
• These events may be more common with
  cimetidine.
• - rarely occur in ambulatory patients.

121

• 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.

122

• ADVERSE EFFECTS OF H2 ANATGONIST
• 3- Increases liver enzymes BUT reversible

123

• 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.

124
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.

125
Physiological role of SEROTONIN (5-HT)

• 1- Brain serotonergic neurons are involved in
  numerous diffuse functions such as
• - mood
• - sleep
• - appetite
• - temperature regulation

126
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.

127

• PHARMACOLOGY
• OF
• SEROTONIN (5-HT)

128

• 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.

129

• 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.

130

• 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.

131

• 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.

132

• 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,

133

• 5-HT1D/1B Agonists Migraine HeadacheThe
  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.

134

• 5-HT1D/1B Agonists
• Almotriptan
• Eletriptan
• Frovatriptan
• Naratriptan
• Rizatriptan
• Sumatriptan
• Zolmitriptan

135

• 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

136

• 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.

137

• 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)

138

• 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

139

• 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
  

140

• 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
  

141

• 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

142

• 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 gt 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

143

• ADVERSE EFFECTS OF
• 5-HT3 ANTAGONISTS
• 1- All three agents cause a small but
  statistically significant prolongation of the QT
  interva