Transcript (9)AUTACOIDS

Histamine
Serotonin
Polypeptides
Eicosanoids
Pharmacology
Dr.Sanjib Das
MD
WHAT ARE AUTACOIDS?
 Name derived from two Greek words: autos = ‘self’ and akos =
‘remedy’ combined to mean “self-remedy’
 Includes many endogenous substances normally present or formed in
the body as:
•
•
•
•
Histamine
Serotonin
Polypeptides (angiotensin, bradykinin)
Eicosanoids (prostaglandins, thromboxanes, leukotrienes)
 Autacoids are mostly local hormones with two main characteristics:
[1] Short duration of action
[2] Act locally near sites of synthesis or formation
 Most autacoids are not used clinically as drugs or therapeutic agents,
but often participate in causing various organ system disorders
 Most of the Autacoid antagonists & few agonists are used for treating
many diseases including: asthma, migraine, hypertension, and peptic
ulcer
II. Autacoids- Histamine
 A. Histamine
 Understand the following properties of histamine:
a. Distribution and storage
b. Synthesis and release
c. Metabolism and elimination
d. Receptor classification (H1 and H2)
e. Know the post-receptor second messengers which are
activated
f. Pharmacologic actions: airway smooth muscle, exocrine
glands cardiovascular (including the triple response),
sensory nerve endings
 Know the basic pharmacology of H1-receptor
antagonists
a. Actions related to H1 receptor blockade
b. Actions not caused by H1 receptor blockade
c. Pharmacokinetics
 Know the clinical uses and toxicity of H1-receptor
blockers, including the newer "non-sedating" H1
receptor blockers
 Know fexofenadine is the active metabolite of
terfenadine and is now available as a drug
 Know which histamine antagonists are used for
treatment of motion sickness and compare their
efficacy with other drugs used for this purpose.
 Know the basic pharmacology of H2-receptor
antagonists
 a. Actions related to H2 receptor blockade
b. Actions not caused H2 receptor blockade
c. Pharmacokinetics
 Know the clinical uses and toxicity of H2-receptor
blockers, including drug interactions.
1.Histamine and histamine releasers
HISTAMINE ,MORPHINE ,CURARE
2.H1-Antagonists
older generation
BROMPHENIRAMINE ,CHLORPHENIRAMINE ,CYCLIZINE
,CYPROHEPTADINE ,MECLIZINE ,DIPHENHYDRAMINE
,DIMENHYDRINATE ,PROMETHAZINE ,PYRILAMINE
,TRIPELENNAMINE
non-sedating (2 nd generation)
CETRIZINE ,FEXOFENADINE ,LORATIDINE ,DESLOARATIDINE
3.H2-Antagonists
 CIMETIDINE ,FAMOTIDINE ,NIZATIDINE ,RANITIDINE
4.Anti-motion Sickness
 CYCLIZINE ,MECLIZINE ,PROMETHAZINE ,DIMENHYDRINATE
,DIPHENHYDRAMINE
HISTAMINE: Synthesis, Storage, and Distribution
 Histamine found in many plants and animal tissues is:
• Formed by decarboxylation of L-histidine
• Then either stored or rapidly inactivated
 It occurs in most tissues but is unevenly distributed
 It is mostly bound in granules in mast cells or basophils
• Mast cell sites include nose, mouth, feet, blood vessels, GIT
• Two important non-mast cell sites are:


Brain where histamine acts as a neurotransmitter
Enterochromaffin-like cells (ELC) in the stomach release histamine
to stimulate acid secretion from parietal cells
 Bound histamine is inactive but is released by many stimuli to act on
surrounding tissues
 Histamine can be released by immunologic, chemical, or mechanical
mechanisms
Type I Hypersensitivity
 Immunologic Release - upon
exposure to antigens, plasma cells
secrete IgE which
• Binds to IgE receptors on
mast cells or basophils
antibodies which
• Are degranulated to release
histamine, ATP, etc
 Histamine thus released :
• Mediates type I allergic
reactions
• Modulates acute inflammation
 Chemical or Mechanical Release histamine is also released from mast
cells by:
• Drugs like morphine and
tubocurarine (which displace
histamine from cell binding
sites without mast cell injury)
• Chemical injury
• Mechanical injury
Types of Histamine Receptors
Receptor
Tissue Sites
antagonists
Type
H1
H2
Smooth muscle,
endothelium,
brain
First- & secondgeneration H1
blockers
Gastric mucosa,
mast cells,
cardiac muscle,
brain
H2 blockers:
Cimetidine
Famotidine
Nizatidine
Ranitidine
 H1 receptor
activation
increases
intracellular
calcium
 H2 receptor
activation
increases
intracellular
cAMP
Histamine effects due to H1 receptors
 Sensory nerve ending  pain and itching of urticaria
 Arterioles and precapillary sphincters  vasodilation 
lowers BP  reflex tachycardia
 Histamine may cause flushing, warm sensation, and
headache
 Histamine causes dilation of precapillary vessels 
increased permeability  edema
 Histamine causes contraction of bronchial smooth muscles
 bronchoconstriction
 Histamine affects GI smooth muscles  GIT contraction 
diarrhea
Histamine effects due to H2 receptors
Gastric parietal and intestinal cells 
increased GIT secretion
Cardiac muscle  increased heart rate and
contractility
Heart rate is increased by two mechanisms:
• Indirectly by H1 thru reflex tachycardia and
• Directly by stimulating cardiac H2 receptors
• Direct cardiac stimulation is minimal and H2
antagonists have little or no effect on heart rate
Histamine Antagonists
Physiological Antagonism- Epinephrine
(Anaphylactic shock)
Histamine receptor antagonists =
• H1 antagonists
• H2 antagonists
 Histamine release inhibitors - used as
prophylactics to protect against allergic rhinitis or
bronchoconstriction related to exercise, antigen
inhalation, aspirin, or occupational asthma
• Cromolyn
• Nedocromil
Clinical Uses of H1 antagonists






Allergic reactions: hay fever, allergic rhinitis, and urticaria
Motion sickness: more effective for prevention than for treatment; most
effective ones have sedative activity:
•
Marked as in dimenhydrinate or diphenhydramine
•
Slight as cyclizine or meclizine
Local anesthetic activity: (Non H1 receptor mediated)
diphenhydramine and promethazine are more potent than procaine as local
anesthetics
Additionally, they also have antiparkinsonian, anticholinergic, adrenergicblocking, and serotonin-blocking activity ((All are Non H1 receptor
mediated)
Most common adverse effects are:
(a) Sedation
(b) Antimuscarinic activity  urinary retention, blurred vision
Less common adverse effects are: postural hypotension, drug allergy, and
excitation and convulsions in children
Classes of H1 Antagonists
 First-generation H1 antagonists are sedative and
include:
• Brompheniramine
• Chlorpheniramine
• Cyclizine
• Cyproheptadine  also blocks serotonin receptors
• Dimenhydrinate
• Diphenhydramine
• Doxylamine
• Hydroxyzine
• Meclizine
• Promethazine ( phenothiazine structure)
• Pyrilamine
• Tripelennamine
Classes of H1 Antagonists
 Second-generation H1 antagonists are non-sedating and less lipid soluble
include:
•
•
•
•
•
Azelastine
Cetirizine
Fexofenadine
Loratadine
Desloratidine
 Used mainly for hay fever, allergic rhinitis, and urticaria
 Less likely to block autonomic receptors
 Minimal effect on heart, BP, motion sickness, or nausea
 Less CNS effects because they don’t cross the blood-brain barrier
 Sedation incidence 7% versus 50% for first-generation
 Astemizole and terfenadine were withdrawn because they block potassium
channels to produce a lethal arrhythmia (torsade de pointes) in patients taking
ketoconazole or erythromycin
H2 antagonists
 Cimetidine, ranitidine, famotidine, nizatidine
 Mainly for blocking H2 receptors to reduce gastric acid secretion
 Clinically used to suppress gastric acid secretion in peptic ulcer, GERD,
and other GIT hypersecretory disorders
 Doses that suppress gastric secretion have little or no effect on intestinal
secretions, heart, or blood vessels
 Adverse effects are infrequent and usually minor
 Most common adverse effects include
•
•
•
•
Diarrhea
Dizziness
Drowsiness
Skin rash
 Headaches may occur with famotidine and ranitidine
 Nizatidine has the fewest adverse effects
Now answer following Qs before you practice MCQs
 A. Histamine
 Understand the following properties of histamine:
a. Distribution and storage
b. Synthesis and release
c. Metabolism and elimination
d. Receptor classification (H1 and H2)
e. Know the post-receptor second messengers which are
activated
f. Pharmacologic actions: airway smooth muscle, exocrine
glands cardiovascular (including the triple response),
sensory nerve endings
 Know the basic pharmacology of H1-receptor
antagonists
a. Actions related to H1 receptor blockade
b. Actions not caused by H1 receptor blockade
c. Pharmacokinetics
 Know the clinical uses and toxicity of H1-receptor
blockers, including the newer "non-sedating" H1
receptor blockers
 Know fexofenadine is the active metabolite of
terfenadine and is now available as a drug (Why?)
 Know which histamine antagonists are used for
treatment of motion sickness and compare their
efficacy with other drugs used for this purpose.
 Know the basic pharmacology of H2-receptor
antagonists
 a. Actions related to H2 receptor blockade
b. Actions not caused H2 receptor blockade
c. Pharmacokinetics
 Know the clinical uses and toxicity of H2-receptor
blockers, including drug interactions.
B. Serotonin
 Understand the following properties of serotonin:
 a. Distribution and storage
b. Synthesis and release
c. Metabolism and elimination
d. Receptor classification (5HT-1a, 1c, 1d, 2, 3, 4)
e. Pharmacologic actions: cardiovascular,
gastrointestinal, respiratory, nervous system
 Know the clinical use of serotonin receptor
antagonists
 1. Serotonin agonists
 BUSPERONE
 FENFLURAMINE
 DEXFENFLURAMINE
 CISAPRIDE
 SUMATRIPTAN
 Several TRIPTANs
 TEGASEROD
 2. 5HT-Antagonists
 CYPROHEPTADINE
 ONDANSETRON
 Several SETRONs
SEROTONIN (5-hydroxytryptamine or 5-HT)
 Widely distributed in plant and animal tissues, venoms, and stings
 Formed from the amino acid L-tryptophan, then stored or inactivated
 90% of body 5-HT is in GIT enterochromaffin cells; also found in blood
platelets and raphe nuclei of the brain stem
 It is the precursor of melatonin in the pineal gland
 5-HT acts on seven receptor subtypes identified by subscripts 1 through 7
(i.e., 5-HT1A, 5-HT2A, 5-HT7, etc)
 Many 5-HT receptors (brain 5-HT1A or 5-HT2A receptors) have no peripheral
physiologic function
 Main 5-HT functions are
• Regulation of GIT motility
• CNS neurotransmitter
5-HT effects
 Nervous system - as a CNS neurotransmitter affecting:
• Sleep
• Sensory perception
• Motor activity
• Temperature regulation
• Appetite
• Sexual behavior
• Hormone secretion
 5-HT also stimulates:
• 5-HT3 receptors on afferent vagal nerve endings  Bezold-Jarisch
reflex  bradycardia and hypotension
• 5-HT3 receptors in GIT and medulla  vomiting reflex triggered by
cancer chemotherapy drugs
 Bronchial smooth muscles - contract  bronchoconstriction
5-HT effects
Cardiovascular system - generally causes
vasoconstriction by stimulating vascular 5-HT2
receptors except in heart and skeletal muscles
where vessels are dilated
• Coronary vessels with endothelial damage are constricted
• BP effect is triphasic (decrease, increase, decrease)
• Constricts veins  increased capillary filling  skin flush
• Causes platelet aggregation thru platelet 5-HT2 receptors
GIT contractions result from stimulation of 5-HT2
receptors on GI smooth muscles causing increased
tone and peristalsis
• 5-HT overproduction in carcinoid tumor  severe diarrhea
Clinical Uses of 5-HT agonists
 Buspirone a 5-HT1A agonist used as an anxiolytic
 Fenfluramine and dexfenfluramine (Redux; or combined with
phenteramine in Fen-Phen) are 5-HT agonists that were widely used
as appetite suppressants but later withdrawn when serious adverse
effects of pulmonary hypertension and valvular lesions occurred in
young women using them
 Cisapride a 5-HT4 agonist used for GERD and GI motility disorders
(only available for compassionate use)
The -triptansare selective
 Sumatriptan, naratriptan, rizatriptan, and zolmitriptan
agonists for 5-HT1D and 5-HT1B receptors
• Constrict cerebral and meningeal vessels in treatment of acute
migraine headaches
• Efficacy against migraine equal to or greater than other drugs
• Adverse effects include: tingling or warmth sensations, dizziness,
muscle weakness, neck pain, chest discomfort
• May cause coronary vasospasm and angina
Clinical Uses of 5-HT antagonists
Many 5-HT antagonists are relatively unspecific
because they usually block other receptors too and
thus are not used clinically.
Cyproheptadine blocks 5-HT2 and H1 receptors in
treatment of carcinoid tumors, postgastrectomy
dumping syndrome, and cold-induced urticaria
Ondansetron, granisetron, and dolasetron block
5-HT3 receptors; used for treatment of nausea and
vomiting during cancer chemotherapy
The -setrons
C. Ergot Alkaloids
 Know the natural source of ergot alkaloids and the
clinical conditions associated with ergot poisoning
 Know the clinical uses of ergot alkaloids, including uses
and toxicity
 Ergot alkaloids
 BROMOCRIPTINE
 DIHYDROERGOTAMINE
 ERGONOVINE
 ERGOTAMINE
 METHYLERGONOVINE
 LYSERGIC ACID DIETHYLAMIDE (LSD)
Ergot Alkaloids
 Preparations include:
•
•
•
•
•
Dihydroergotamine
Ergotamine mixtures
Ergotamine tartrate
Ergonovine
Methylergonovine
Migraine
Uterus
 Alkaloids are produced by Claviceps purpurea, a fungus that infects grain,
especially rye, under damp storage
 In ancient times, ingestion of contaminated grain resulted in epidemics of
ergotism characterized by:
•
•
•
Hallucinations, convulsions
Prolonged vasospasm  gangrene and fiery pain
Uterine contractions resulting in abortion
 Called St. Anthony's fire in medieval ages after the saint who provided relief
from the burning pain caused by vasospasm
 Last known epidemic in 1951 occurred in France from eating bread made
from contaminated flour
 Severe symptoms occasionally produced by excessive use of medical ergot
preparations
Chemistry and Mechanism of Action
 Two families of alkaloids:
• Amine alkaloids – ergonovine, lysergic acid diethylamine (LSD)
• Peptide alkaloids - ergotamine, ergocryptine, and bromocriptine
 Ergots are variably absorbed and extensively metabolized
 Because gastrointestinal absorption is erratic, patient
responses vary widely and widely variable central and
peripheral effects can occur
 Ergots act as partial agonists or antagonists on several
receptor types:
• 5-HT1A and 5-HT1D
• CNS dopamine receptors
• a-adrenergic
 They may act on presynaptic or postsynaptic sites
Ergot Alkaloid Effects - 1
 CNS: are powerful hallucinogens as shown by LSD which acts as an agonist
on pre- or post-junctional 5-HT2 receptors on CNS neurons
• Produce somatic, perceptual, and psychologic effects, dizziness, weakness,
tremors, nausea, paresthesias, blurred vision, visual illusions, distorted
perspective, impaired memory, thinking difficulty, poor judgment, altered mood,
sympathetic overactivity, etc
• LSD is effective in very small doses (1-2 mg/kg), very rapid onset, and variable
duration (usually hours)
• Excessive doses  'bad trips' or panic reactions
 Vascular smooth muscle contraction  vasoconstriction
• Due to stimulation of a-adrenergic and 5-HT receptors
• Sensitivity varies with the vascular bed; cerebral vessels are very sensitive to
vasoconstriction by ergotamine, dihydroergotamine, and sumatriptan which
are often used for migraine therapy
• Cerebral vasoconstriction has been attributed to partial agonist effects on
neuronal or vascular 5-HT1D receptors
Ergot Alkaloid Effects - 2
 Uterus: small doses evoke rhythmic contraction and
relaxation; higher doses cause powerful and prolonged
contracture due to stimulation of a-adrenergic and 5-HT
receptors
• As pregnancy progresses a1-adrenergic receptors
become more dominant and uterine sensitivity to ergot
alkaloids increases
• In stimulating uterine contractions ergonovine &
methylergonovine are much stronger than other ergot
alkaloids
 Bronchial smooth muscles are unaffected but GIT is
very sensitive
Toxicity
 Most common adverse effects are
GI disturbances like nausea,
vomiting, and diarrhea due to
increased GIT motility resulting
from activation of 5-HT receptors in
the CNS and GIT
 Most serious toxic effect is
prolonged vasospasm in the arms
and legs  gangrene and may
require amputation
 Drowsiness and hallucinations
occur occasionally
Clinical Uses of Ergot Alkaloids
 Treatment of migraine: pathophysiology is still poorly understood, but
pain onset and relief seem related to vasomotor changes that depend on
changes in platelet or neuronal 5-HT
• Relief with ergot derivatives is so specific to be almost diagnostic
• Vasoconstriction produced by ergotamine is long lasting and
cumulative
• To minimize cumulative toxicity, ergotamine doses should not exceed
10 mg/week
• Dihydroergotamine and selective agonists for 5-HT1D and 5-HT1B
receptors like sumatriptan, naratriptan, rizatriptan, and
zolmitriptan are used to constrict cerebral and meningeal vessels but
not in patients with coronary artery diseases as they may constrict
coronary blood vessels
 Drugs used for migraine prophylaxis
•
•
•
•
•
Amitriptyline
Propranolol
Topiramate
Valproic acid
Verapamil
Clinical Uses of Ergot Alkaloids & Related
Compounds
Ergot alkaloids are also used for treatment of:
 Postpartum hemorrhage: ergonovine produces a powerful and prolonged
uterine spasm useful for control of late uterine bleeding
• Maternal and fetal deaths may increase when ergonovine is given before
delivery
 Hyperprolactinemia: bromocriptine and cabergoline are ergot alkaloids with
high affinity for pituitary dopamine D2 receptors
• Have been used to reduce high prolactin levels produced by pituitary tumors
 Gastrointestinal disorders:
• Cisapride is a 5HT4 agonist used for treatment of GERD and motility
disorders (only available for compassionate use in USA)
• Tegaserod is a partial 5HT4 agonist used for treatment of irritable bowel
syndrome

Only available for emergency treatment of irritable bowel syndrome with
constipation (IBS-C) and chronic idiopathic constipation (CIC) in women (<55 years
of age) in which no alternative therapy exists.
• Selective 5HT3 antagonists dolasetron, grandisetron, and ondansetron
are used as antiemetics
A 40-year-old man working as a school bus driver
has a long history of seasonal allergic rhinitis and
complains of postnasal drainage, coughing, and
throat irritation. Which of the following would you
use for treatment of this patient?
A) Brompheniramine
B) Cyclizine
C) Fexofenadine
D) Meclizine
E) Tripelennamine
Ans = C
2nd generation
has less CNS
effects
In a 26-year-old woman with a history of recurrent
left-sided pulsatile head pain, prolonged chronic
treatment with dihydroergotamine may produce
which of the following in this patient?
A) Bronchoconstriction
B) Cerebral vasodilation
C) Decreased GIT motility
D) Gangrene
E) Uterine bleeding
ANS = D
Most severe
effect of
ergot alkaloids
Drugs related to histamine
Histamine
Antihistamines
Histamine releasers
Morphine
Tubocurarine
Vancomycin
Histamine release
inhibitors
Cromolyn sodium
Nedocromil
H1 antagonists
First generation
Chlorpheniramine
Hydroxyzine
Meclizine
Diphenhydramine
 Dimenhydrinate
Promethazine
Second generation
(non-sedating)
Cetirizine
Fexofenadine
Loratadine
Deslortadine
H2 antagonists
Cimetidine  Cyp450
Famotidine
Nizatidine
Ranitidine
H-1 = PI
H-2 = cAMP
Which of the following medications would be
preferred to treat seasonal allergy in 32-yearold man who is a heavy-machine operator?
A. Bromocriptine
B. Cetirizine
C. Cimetidine
D. Diphenhydramine
E. Granisetron
Answer: B
2nd generation
Which of the following mechanism is
associated with the use of ranitidine to treat
peptic ulcers in a 49-year-old man?
A. Decreased cAMP in parietal cells
B. Decreased channel opening in enteric
nerves
C. Decreased IP3 in gastric mucosa
D. Increased IP3 in gastric mucosa
E. Increased IP3 in smooth muscle
Answer: A
H2 signal via
Gs




D. Angiotensin II
Understand the following properties of angiotensins I, II
and III:
a. Pathway of synthesis and metabolism, including
enzymes and localization
b. Know that Ang I is a decapeptide, Ang II is octapeptide
and Ang III is heptapeptide
c. Physiological and pharmacological control of renin and
angiotensinogen
d. Receptor classification (AT1 and AT2)
e. Know the post-receptor second messengers which are
activated
f. Pharmacologic actions: cardiovascular, adrenal cortex,
adrenal medulla, CNS, kidney
Know the pharmacologic methods for inhibiting the reninangiotensin system
a. Renin inhibitors
b. Angiotensin converting enzyme inhibitors (ACEI)
c. Angiotensin receptor antagonists: (ARBs)
d. Know the clinical uses of these classes of agents
1.Angiotensin
 ANGIOTENSIN II
2.Angiotensin Antagonists
 Several SARTANs
 LOSARTAN
3. Converting Enzyme Inhibitors
 CAPTOPRIL
 ENALAPRIL
 FOSINOPRIL
 LISINOPRIL
 RAMIPRIL
Renin-Angiotensin System
 Angiotensinogen synthesized in
the liver is the substrate acted on by
 Renin secreted from kidneys to
form
 Angiotensin I (decapeptide)
which has little or no biological
activity and is acted on by
Angiotensin converting enzyme
(ACE) from lungs to form
Angiotensin II (octapeptide)
which is responsible for most of the
system’s biologic activity
The Juxtaglomerular Apparatus
Location of macula densa beside
renin secreting JG cells in the
afferent arteriole places the
macula densa in an ideal position
for regulating renin secretion.
Renin secretion can be inhibited
by 4 mechanisms:
[1] Chemoreceptors in macula
densa: increased NaCl flux
[2] Baroreceptors in afferent
arteriole wall: increased BP
[3] Blockade of sympathetic
stimulation of b1 adrenergic
receptors via renal nerve
activity
[4] Angiotensin II also produces
a negative feed back on renin
secretion
Signaling Pathways in Renin Secretion
Beta blockers
 renin secretion
Vasodilators
 renin secretion
Ang II
renin secretion;
Blocked by –prils & sartans
Diuretics
 renin secretion
Major Effects of Angiotensin II
Angiotensin II will
•  peripheral
resistance to 
afterload, and
•  aldosterone
secretion to  fluid
volume and 
preload.
 ACE inhibitors will
act oppositely to
decrease both preload
and afterload!
 ACE inhibitors also
protect against
subsequent failure by
slowing remodeling
after myocardial
infarcts
ACE Inhibitors
 Currently available preparations include:
benazepril, captopril, enalapril, fosinopril,
lisinopril, moexipril, quinapril, perindopril,
ramipril, or trandolapril
The –pril drugs
 Captopril is an active drug but all others are
prodrugs that have to be converted to the
corresponding di-acid as enalapril to enalaprilat
Because all ACE inhibitors:
• Are equally effective in blocking conversion of angiotensin
I to angiotensin II
• They have the same clinical uses and adverse effects
• There is no compelling reason to favor one over another
Actions and Effects of ACE Inhibitors
Inhibit ACE  reduce angiotensin II formation and lower
BP & cardiovascular disease through 4 mechanisms:

1)
2)
3)
4)

Elevated bradykinin levels
•
•

Reduced angiotensin vasoconstriction  vasodilation lowers BP
by reducing peripheral vascular resistance, but unlike other
vasodilators, ACE inhibitors do not elicit reflex tachycardia
Reduced angiotensin II will decrease aldosterone release from
adrenal medulla, decrease fluid volume, and decrease cardiac
output
Reduced destruction of bradykinin  increase bradykinin levels 
vasodilation to enhance BP lowering
Decrease vascular and cardiac hypertrophy & remodeling
Explain the BP lowering in hypertensives whose renin levels are low
or normal (i.e., the BP lowering is not due to reduced AII formation)
Cause adverse effects of coughing and angioneurotic edema
Renal renin secretion may increase because of reduction in
negative feed-back inhibition by angiotensin II
Therapeutic Characteristics of ACE Inhibitors
 ACE inhibitors lower BP without compromising blood
supply to the heart, brain, or kidneys
 Are most effective in hypertensives with elevated plasma
renin levels, but will still lower BP (bradykinin effect) even
when renin levels are not high
 Compared with other antihypertensive drugs like diuretics
or b-adrenergic blockers, ACE inhibitors have milder and
fewer adverse effects, without changing blood lipids or
glucose
 Unlike direct vasodilators, ACE inhibitors do not cause
reflex sympathetic activation (or reflex tachycardia)
because of concurrent baroreceptor resetting or
parasympathetic activation
Clinical Uses of ACE Inhibitors
 All ACE inhibitors are effective orally for monotherapy and
will lower BP in about 50% of patients with mild to moderate
hypertension
 They are most effective in young and middle-aged
Caucasians, but less effective in elderly and AfricanAmericans
 ACE inhibitors are first choice antihypertensive drugs for
treatment of hypertensives with:
• Diabetes
• Chronic renal disease
• Left ventricular hypertrophy
 Additionally, ACE inhibitors enhance the antihypertensive
efficacy of diuretic drugs by attenuating aldosterone
secretion (i.e., natriuresis induced by the diuretic is
unopposed)
Toxicity of ACE Inhibitors
 Adverse effects are milder and fewer than those of
diuretics or b-blockers
 Common adverse effects include:
• Dry, hacking, non-productive cough in 5-20% of patients
• Angioedema and anaphylaxis in 0.1-0.2%
• Hyperkalemia due to inhibited aldosterone secretion especially in
patients with renal insufficiency
• Taste disturbances that interfere with nutrition
• Nonallergic, pruritic maculopapular rash
• Leukopenia in patients with renal insufficiency
 ACE inhibitors are contraindicated during last two
trimesters of pregnancy because of fetal risks of
hypotension, renal failure, malformations, or death
Angiotensin II Antagonists

Currently available preparations include: candesartan, eprosartan,
irvesartan, losartan, olmisartan, telmisartan, or valsartan
Known as ARBs or -sartans

Two types of angiotensin II receptors are: AT1 and AT2 whose relative
proportions vary in different tissues

AT1 receptors predominate in vascular smooth muscle and cause
most of the known actions of angiotensin II

AT2 receptors occur mainly in fetal tissues and their function is still
uncertain

All the currently available angiotensin II antagonists act by blocking
AT1 receptors selectively without affecting AT2 receptors

May cause hyperkalemia especially in patients with renal
insufficiency

Compared with ACE inhibitors, angiotensin II antagonists are more
specific in blocking angiotensin effects because they do not affect
bradykinin metabolism (i.e., no coughing or angioneurotic edema)
Renin Inhibitor
Aliskiren
• Pharmacokinetics
 Poor oral absorption
 Decreased by high-fat meal
 Aliskiren is a substrate of P-glycoprotein
 Concurrent use of P-glycoprotein inhibitors may increase
absorption.
• Mechanism of action
 A direct renin inhibitor
• Use
 Treatment of hypertension, alone or in combination with other
antihypertensive agents
 Similar to ARBs
Clinical Uses of AII Antagonists
 Uses and hypotensive efficacy similar to ACE inhibitors
 No adverse effects of coughing or angioneurotic
edema because they do not affect bradykinin
 Used mainly to lower BP in hypertensive patients
 Also used to slow morphologic changes (remodeling)
after myocardial infarction and thus protect against
subsequent development of heart failure
E. Kinins
 Know the enzymes and substrates involved in
synthesis and metabolism of kinins
 Know that bradykinin is a nine-amino-acid
peptide; the others are 10 and 11
 Know that there are at least two types of
bradykinin receptors (B1 and B2)
 Know that kinin effects may be mediated by
generation of prostaglandins, as well as changes
in cellular calcium or cyclic nucleotides
 Know how converting enzyme inhibitors may
influence the actions of kinins
Bradykinin: The Kallikrein-Kinin System
 Kinins are potent arteriodilators formed by
enzymes called kallikreins acting on protein
substrates called kininogens
Two kinin receptors, B1 and B2:
• B1 receptors have limited tissue distribution and function
• B2 receptors are widely distributed and cause the biologic
effects noted for bradykinin

Bradykinin activates B2 receptors on endothelial cells to produce
EDRF (NO) which stimulates guanylyl cyclase to produce cGMP
 vasodialtion
 F. Other Peptides
 1. Vasopressin
 Know that vasopressin is a nine-amino-acid peptide
 Know the cardiovascular actions of vasopressin at high and
low doses
 Know selective antidiuretic agonists of vasopressin: dDAVP
and dVDAVP
 Know that there are selective cardiovascular antagonists of
vasopressin
 2. Oxytocin
 Know the clinical uses of oxytocin
ADH (Vasopressin)
Vasopressin - 1
 Also known as antidiuretic hormone (ADH)
 Synthesized in the hypothalamus together with oxytocin and
then secreted or released from the posterior pituitary
 Produces antidiuretic and vasopressor effects by acting
on 3 receptors:
• V1a receptors in vascular smooth muscle cause
vasoconstriction  Gq pathway
• V1b receptors potentiate release of ACTH by pituitary
corticotropes  Gq pathway
• V2 receptors in renal cells produce antidiuresis by
increasing water permeability and reabsorption in
collecting tubules  Gs pathway
Vasopressin - 2
 Desmopressin is a long-acting analog with minimal V1
activity
• Its antidiuretic-to-pressor ratio is 4000 times that of
vasopressin
• Thus, it is much more potent than vasopressin for
producing antidiuresis
 ADH deficiency results in diabetes insipidus
 Vasopressin and desmopressin are used to treat
diabetes insipidus
 Vasopressin may constrict coronary blood vessels in
patients with CAD
G. Eicosinoids
 Know the main precursor of eicosanoids: arachidonic acid (20 carbon; 4









double bonds)
Know how arachidonic acid is released (PLA2 and PLC + diglyceride
lipase)
Know these classes of eicosanoids: prostaglandins, thromboxanes, &
leukotrienes
Know the pathways for prostacyclin (PGI2) and thromboxane (TXA2)
synthesis
Know the main pharmacologic actions of PGE2, PGF2-alpha, PGI2,
TXA2, leukotrienes: vascular, airway, uterine, GI smooth muscle,
microvascular permeability, platelet function, sensory nerve endings,
gastric and intestinal secretions, temperature regulating center
Know the mechanism of actions: second messenger systems (cAMP,
calcium, PI metabolites)
Know the ways to inhibit synthesis of eicosanoids
Know how aspirin and non-steroidal anti-inflammatory agents block
prostaglandin synthesis
Know the main clinical uses of eicosanoids and inhibitors of eicosanoid
synthesis, especially their use in obstetrics
Know the clinical features of misoprostol use for GI ulcers
 7. Eicosanoids and related agents
 ALPROSTADIL
 CARBOPROST TROMETHAMINE
 LATANOPROST
 DINOPROSTONE
 EPOPROSTENOL (PROSTACYCLIN, PGI2)
 MISOPROSTOL
NONSTEROIDAL ANTIINFLAMMATORY (NSAID)
AGENTS
 ASPIRIN
EICOSANOIDS
The name eicosanoid is derived from the Greek word eicosa
for twenty because all eicosanoids are synthesized from
fatty acids that are 20 carbon atoms in length
 Refers to a large family of oxygenation products of
polyunsaturated long chain fatty acids widely distributed in
many plants and animal tissues
 Highly potent with wide spectrum of biologic activity and
very short half-lives
 Are autacrine or local hormones secreted to act on
receptors on the cell surface to release second messengers
like cAMP (cause vasodilation) or IP3 (cause
vasoconstriction by increasing intracellular calcium) 
see 2 slides forward
 Most abundant and important precursor is arachidonic acid
which is mobilized from cell membrane phospholipids by
phospholipase A2
Arachidonic Acid Release and Metabolism
Arachidonic acid released by
phopholipase A2 is
oxygenated by four separate
routes:
 Cyclooxygenases, COX-1
and COX-2, to form
prostaglandins (PG) and
thromboxanes (TX)
 Lipogenases to form
leukotrienes
 Epoxygenases to form
epoxides
 Free radicals to form
isoprostanes or PG
stereoisomers
Important Eicosanoids
Effects
PGE2 PGF2α PGI2
TXA2
LTB4
LTC4
LTD4
Receptors
EP1-4
FPA,B
IP
TPα,β
BLT1,2
CysLT2
CysLT1
Vascular
tone
or
or 


?
 or 
 or 
Bronchial
tone




?


Uterine
tone




?
?
?
Platelet
Aggreg.
or  _ _


?
?
?
?
?



Leukocyte ?
chemotaxis
?
 Arrow = Gq >> Ca2+ pathway;  Arrow = cAMP pathway
Remember bolds
Cyclooxygenases
(COX; prostaglandin endoperoxide synthases)
 Of the two COX isozymes that convert arachidonic acid to prostaglandin:
• COX-1 is constitutively expressed (always present), widely distributed, and
has ‘housekeeping functions’
• COX-2 is inducible (expression depends on the stimulus) and is an
immediate early response gene product whose expression is stimulated by
growth factors, tumor promoters, and cytokines
 Nonsteroidal anti-inflammatory drugs (NSAIDs) that produce their
effects by acting as COX inhibitors include:
• Meclofenamate & ibuprofen - equipotent on COX-1 and COX–2,
• Celecoxib and rofecoxib inhibit COX-2 preferentially
• Aspirin irrevewrsibly inhibits both enzymes but to different degrees
 Eicosanoids produce many highly variable effects by binding to
prostaglandin and thromboxane receptors in:
•
•
•
•
Smooth muscles
Platelets
Blood cells
Kidney
Smooth muscle effects - 1
 Exerted on vascular, GI, airway, and reproductive systems
 Vascular effects may be mitogenic, constrictor, or dilator
• Thromboxane (TXA2) is mitogenic and vasoconstrictor by
increasing intracellular calcium
• PGE2 and PGI2 cause vasodilation by increasing
intracellular cAMP
 Gastrointestinal tract:
• Longitudinal muscles are contracted and
• Circular muscles are relaxed
• PGE2 and PGF2a cause colicky cramps
 Bronchial muscles may be:
• Relaxed by PGD2, PGE1, PGE2 or PGI2
• Contracted by TXA2 and PGF2a
Smooth muscle effects - 2
 Reproductive organs:
• Male – exact function of PGs in semen is conjectural

The name ‘prostaglandin’ is a misnomer because it arose from
the mistaken belief that PGs in semen originate from the
prostate, but the major source is actually the seminal vesicle

Semen PG content high in fertile, but low in infertile men

PG production in human semen is enhanced by testosterone
and reduced by aspirin

PGE1 (alprostadil) relaxes smooth muscles in the corpus
cavernosum to enhance penile erection
Smooth muscle effects - 2
 Reproductive organs:
• Female - PGE2 and PGF2a have potent oxytocic actions and will
end pregnancy by promoting uterine contractions

Used for first- and second-trimester abortion (misoprostol, an oral
PG)

Also for priming or ripening the cervix before abortion; softens
cervix by increasing proteoglycan content and changing
biophysical properties of collagen

Common adverse effects include vomiting, diarrhea, fever, and
bronchoconstriction

May also cause hypo- or hypertension, syncope, flushing,
dizziness

PGE2 (dinoprostone) is given vaginally for abortion
Blood and Renal Effects
 On blood:
• Platelet aggregation is enhanced by TXA2 and inhibited by PGE1
and PGI2
• Monocytes and eosinophils have high PG synthesis capacity
 On kidneys:
• Both medulla and cortex, can synthesize PGs
• Major products of the renal cortex are PGE2 and PGI2
• PGE1, PGE2, and PGI2 increase GFR by vasodilation
• Loop diuretics stimulate COX activity to increase PG
synthesis; hence, concurrent administration of COX
inhibitors like aspirin may diminish loop diuretic effects
Clinical Uses of Prostaglandins - 1
 Abortion: PGE2 and PGF2a have very potent oxytocic
actions and can be used to stimulate uterine contractions
and terminate pregnancy at any stage
• Used for first- or second-trimester abortion and for priming or
ripening the cervix before abortion
• 80% effective for causing abortion when infused intravenously
• Common adverse effects include vomiting, diarrhea, fever, and
bronchoconstriction

May also cause hypotension, hypertension, syncope, flushing, dizziness
• Synthetic PGE2, dinoprostone, given as vaginal suppository is also
an effective abortifacient
• Also used to soften the cervix by stimulating collagenase  break
down collagen network and  proteoglycan content
Clinical Uses of Prostaglandins - 2
 Facilitation of labor: PGE2,
PGF2a, and their analogs are also
effective for initiating and
stimulating labor
• PGF2a is one tenth as potent, but
has more GIT toxicity than PGE2
• PGE2 and PGF2a are both as
effective as oxytocin for inducing
labor, but with more GI adverse
effects of nausea, vomiting, and
diarrhea
 Dysmenorrhea: can be relieved by
using NSAIDs that inhibit PG
formation because dysmenorrhea
may result from increased
endometrial synthesis of PGE2 and
PGF2a
• Aspirin is also effective against
dysmenorrhea as a nonselective
COX inhibitor
Oxytocin - 1

Is the current drug of choice for inducing labor

Synthesized in the hypothalamus together with vasopressin and
secreted from the posterior pituitary

Acts via specific membrane receptors which alter transmembrane
ionic currents to activate voltage-sensitive calcium channels in
uterine smooth muscles to produce sustained contractions

Uterine sensitivity to oxytocin increases during pregnancy because
the number of oxytocin receptors increases markedly in late gestation

Cause milk ejection by contracting myoepithelium in mammary
alveoli; normal lactation cannot occur without oxytocin-induced
contraction

Has much weaker antidiuretic and pressor activity than vasopressin

Oxytocin may have a protective role against stress-related diseases.
Oxytocin - 2
 Clinical uses are to:
• Induce labor: in uterine inertia, incomplete abortion, or
conditions requiring early vaginal delivery (e.g.,
maternal diabetes)
• Control postpartum hemorrhage
• Induce milk ejection
• Diagnose placental circulatory reserve
 Serious adverse reactions are rare, but maternal deaths
due to hypertension, uterine rupture, water intoxication,
and fetal death have been reported
In a 55-year-old hypertensive man with normal renal function,
renin secretion is most likely to increase upon treatment
with which of the following medications?
A) Atenolol
B) Clonidine
C) Methyldopa
D) Propranolol
E) Sodium nitroprusside
ANS = E
All currently uses antihypertensive
medications except beta blockers and centrally-acting
sympatholytic drugs increase plasma renin activity
Drugs related to autacoids
Histamine
Serotonin agonists
Sumatriptan (5-HT1D)
Cisapride (5-HT4)
Tegaserod (5-HT4)
Buspirone (5-HT1A)
Ergot alkaloids
and related
compounds
Serotonin
Serotonin
antagonists
Methysergide
Ondansetron (5-HT3)
Granisetron (5-HT3)
Peptides
Bromocriptine
Dihydroergotamine
Ergonovine
Ergotamine
Lysergic acid
diethylamide (LSD)
Pergolide
Eicosanoids
Alprostadil (PGE-1; ED)
Carboprost tromethamine (PGF-2α; Abort)
Dinoprostone (PGE-2; obstet)
Epoprostenol (prostacyclin, PGI2)
Latanoprost (PGF-2α; eye)
Misoprostol (PGE-1; GI)
Inhibition of eicosanoid synthesis
Corticosteroids
NSAIDs
Leukotriene receptor antagonist
Zafirlukast
-lukast
-triptans
-setrons
Angiotensin II
Angiotensin
antagonists
Converting
enzyme inhibitors
Losartan
Valsartan
Captopril
Enalapril
Kinins
Other peptides
Bradykinin
Vasopressin
DDAVP
V1 = PI = vasculature
V2 = cAMP = kidney
-sartan
-pril
Which of the following antihypertensive
medications is likely to elevate plasma renin
activity when administered to a 46-year-old
obese woman with hypertension and
diabetes?
A. Atenolol
B. Clonidine
C. Enalapril
D. Methyldopa
E. Reserpine
Answer: C
-prils block negative
renal feed back produced
by Ang II
A 39-year-old woman takes intranasally
administered dihydroergotamine for the
treatment of migraine headaches. The
therapeutic effect of this medication is due
primarily to which mechanism in this patient?
A.
B.
C.
D.
E.
Agonist activity at alpha-1 adrenergic receptors
Agonist activity at 5-HT-3 serotonin receptors
Agonist activity at 5-HT-1D serotonin receptors
Antagonist activity at DA-2 dopamine receptors
Antagonist activity at 5-HT-3 serotonin receptors
Answer: C
III. Bronchodilators and Other Agents Used in
Asthma
 Understand the pathogenesis of bronchial asthma.
 Know the mediators released from mast cells.
 Understand the role of the autonomic nervous system in






control of bronchial motor tone.
Understand how pulmonary function tests, such as FEV1,
can be used to evaluate patients with asthma.
Understand the mechanism of action, uses and
limitations of cromolyn sodium.
Understand the mechanism of action of methylxanthines
at a biochemical level.
Know the pharmacodynamics, toxicity and the
pharmacokinetics of methylxanthines.
Understand the cellular and biochemical mechanism of
actions of sympathomimetics used in bronchial asthma.
Know the advantages and disadvantages of using
epinephrine, isoproterenol and ephedrine.
 Understand the uses, advantages, limitations and toxicities of









beta-2 adrenergic agonists.
Understand the advantages and limitations of aerosol delivery of
anti-asthmatic drugs.
Know the mechanism of action and clinical use of muscarinic
antagonists in asthma.
Know that zileuton is a 5-lipoxygenase inhibitor
(DISCONTINUED)
Know that zafirlukast and montelukast are leukotriene
antagonists
Know the clinical uses of corticosteroids, including systemic and
inhalational.
Know the limitations and toxicity of corticosteroids.
Understand the bases for selecting therapeutic agents in
bronchial asthma, depending on the severity and duration of the
symptoms.
Understand the approach to treatment of acute and severe
asthma.
Understand the bases for more aggressive anti-inflammatory
therapy in asthma, including potential use of methotrexate.
B. Important Drugs Used in Asthma


















1. Sympathomimetics
ALBUTEROL
LEVALBUTEROL
BITOLTEROL
EPHEDRINE
EPINEPHRINE
FOMETEROL
ISOPROTERENOL
METAPROTERENOL
PIRBUTEROL
SALMETEROL
TERBUTALINE
2. Antimuscarinic agent
IPRATROPIUM BROMIDE
TIOTROPIUM
3. Mast cell stabilizer
CROMOLYN SODIUM
NEDOCROMIL


















4. Aerosol corticosteroids
BECLOMETHASONE
DEXAMETHASONE
FLUNISOLIDE
FLUTICASONE
MOMETASONE
TRIAMCINOLONE
5. Methylxanthines
AMINOPHYLLINE
THEOPHYLLINE
6. Oral corticosteroids
METHYLPREDNISOLONE
PREDNISONE
7. Monoclonal antibody
OMALIZUMAB
8. Leukotriene antagonist
ZAFIRLUKAST
MONTELUKAST
CHARACTERISTICS OF ASTHMA - 1
 Recurrent episodes of: coughing, shortness of breath, chest
tightness, and wheezing
 Intensity varies from:
[1] Mild – occasional symptoms occurring on exposure to
allergens or pollutants, after exercise or upper viral
respiratory infection
[2] Severe – frequent attacks of wheezing dyspnea especially
at night, resulting in limitation of activity
 Affects at least 10 million Americans and is the leading cause
of lost school days in children or work days among adults
 Physiologic features are:
• Increased bronchial and tracheal responses to various
stimuli
• Widespread narrowing of the airway passages
CHARACTERISTICS OF ASTHMA - 2
Pathologic features are:
• Contraction of airway smooth muscles
• Mucosal thickening from edema and cellular infiltration
• Inspissation in airway lumen of thick, viscid mucus plugs
Bronchoconstriction from smooth muscle
contraction is most easily reversed by
bronchodilator drugs while reversal of edema and
cellular infiltration requires sustained treatment with
anti-inflammatory drugs
Thus, antiasthmatic drugs can be classified as:
• Bronchodilators or ‘short-term relievers’
• Anti-inflammatory agents or ‘long-term controllers’
Classes of Antiasthmatic Drugs
I.
Bronchodilators relax airway smooth muscles, but
will not relieve mucosal edema, cellular infiltration, or
mucus formation
DRUG CLASS
PROTOTYPE DRUGS
b2-adrenergic
Agonists
Albuterol, levalbuterol,
bitolterol, pirbuterol,
metaproterenol, terbutaline
long-acting
Salmeterol, formoterol
Sympathomimetics Epinephrine, ephedrine,
isoproterenol
Methylxanthines
Aminophylline, theophylline
dyphylline, pentoxifylline
Muscarinic
Ipratropium, tiotropium,
Antagonists
atropine
Bronchospasm in asthma
results from:
[1] mediator release
[2] bronchial hyperreactivity
Three main drug classes
are:
[1]bronchodilators
(relievers)
[2] anti-inflammatory
agents (controllers)
[3] prophylactic agents
Classes of Antiasthmatic Drugs
II. ANTI-INFLAMMATORY  to reduce bronchial responsiveness
DRUG CLASS
PROTOTYPE DRUGS
Glucocorticoids
Beclomethasone, budesonide,
dexamethasone, flunisolide,
fluticasone, mometasone
Leukotriene
Antagonists
Montelukast, zafirlukast
Anti-IgE Antibody Omalizumab
Classes of Antiasthmatic Drugs
III. PROPHYLACTIC  to prevent mast cell
degranulation
 Cromolyn sodium
 Nedocromil sodium
Drug-Induced Bronchodilation
 Bronchodilation is promoted by cAMP which can be increased by:
• b2-adrenergic agonists that increase its synthesis by adenylyl cyclase
• Phosphodiesterase (PDE) inhibitors that slow its degradation
 Bronchoconstriction can be inhibited by: muscarinic or adenosine antagonists
I. Bronchodilators: A. Methylxanthines
 Theophylline, theobromine, and caffeine are found in
beverages (i.e., tea, cocoa, and coffee respectively)
 Aminophylline, dyphylline, pentoxifylline, and
theophylline are given as oral sustained-release or
parenteral preparations
 Declining use because of greater effectiveness of other
drugs but theophylline is still used because of low cost
 Act by inhibiting phosphodiesterase to increase intracellular
cAMP  cardiac stimulation and smooth muscle relaxation
 May also act partly as an adenosine antagonist
Methylxanthine Pharmacodynamics
 Bronchodilation is the main therapeutic action
 CNS stimulation results in alertness and deferred fatigue but with
adverse effects of:
•
•
•
•
Nervousness
Insomnia
Tremors
Convulsions
 Positive inotropic and chronotropic effects with increased CO may
produce arrhythmias and increase BP
 Stimulate secretion of gastric acid and digestive enzymes
 Are weak diuretics due to increased GFR and diminished tubular Na
reabsorption
 Also improve contractility of skeletal muscle and the diaphragm;
improved diaphragmatic function will diminish dyspnea
Methylxanthine Clinical Uses
The most effective methylxanthine bronchodilator is
theophylline
 It relieves airflow obstruction in acute asthma and reduces symptom
severity in chronic asthma
 Is inexpensive and can be taken orally
 Sustained-release oral tablets produce therapeutic blood levels for 12
hrs or more
 Should be used only when blood levels can be measured because
therapeutic and toxic effects are related to plasma levels
 Toxic doses may produce insomnia, anorexia, nausea, vomiting,
headache, anxiety, arrhythmias, or seizures
 Metabolized by the liver


So toxicity may increase in liver disease
Many drug-drug interactions
I. Bronchodilators: B. b2-adrenergic Agonists

Act by stimulating adenylyl cyclase to  intracellular cAMP  smooth
muscle relaxation and bronchodilation

The drugs of choice for acute asthmatic attacks because they produce
bronchodilation with minimal adverse cardiac effects; Drugs include:
•
•
•
•
•
•
Albuterol
Levalbuterol
Terbutaline
Metaproterenol
Pirbuterol
Bitolterol
Salmeterol, arformoterol, and formoterol:
longer acting drugs (12 hours)

Have a longer duration of action than epinephrine when given orally or by
inhalation

Bronchodilation is maximal by 30 min and lasts for 3-4 hrs

Generally safe and effective when given in doses that avoid adverse
systemic effects

Common adverse effects are skeletal muscle tremor, nervousness, and
occasional weakness

Longer acting salmeterol, formoterol are used for prophylaxis
Specific Considerations of some β2Adrenergic Receptor Agonists
Salmeterol, arformoterol, and formoterol:
longer acting drugs (12 hours)
• Should not be used to treat acute asthma attacks
• USA boxed warning
 Long-acting beta2-agonists may increase the risk of asthmarelated deaths; especially in African Americans
 Long-acting β2-receptor agonists should be combined with
inhaled steroids to prevent receptor down-regulation
Levalbuterol
• R-isomer and active form of racemic albuterol
• Inhalant which is claimed to have fewer central nervous
system (CNS) and cardiac adverse effects
I. Bronchodilators: B. Sympathomimetics
 Two sympathomimetics also used as
bronchodilators are ephedrine and
epinephrine
 But by stimulating b1-adrenergic receptors
both drugs cause more cardiac adverse
effects (i.e., tachycardia, arrhythmia, and
worsening of angina)
 Epinephrine, by inhalation or injected SC, is
effective and rapid acting for acute asthmatic
attacks
 Ephedrine was also often used but now much
less frequently
I. Bronchodilators: C. Muscarinic Antagonists
 Act by blocking acetylcholine (ACh) at muscarinic receptors
 Because ACh released at vagal nerve endings contracts bronchial SM
and increases mucus secretion, muscarinic antagonists inhibit responses
to vagal stimulation to relax bronchial SM and decrease mucus secretion
but without affecting those to nonmuscarinic stimuli
 Do not always work because parasympathetic involvement in
bronchospastic responses varies widely
 Atropine given IV or by inhalation produces bronchodilation lasting for 5
hrs, but may cause mouth drying, urinary retention, tachycardia, loss of
visual accommodation, and agitation
 Ipratropium bromide (Atrovent) given by aerosol or nasal spray allows
delivery of large doses because it is poorly absorbed and therefore has
minimal CNS effects
 Tiotropium has a longer duration of action (24 hrs); used for COPD
II. ANTI-INFLAMMATORY Drugs A. Corticosteroids (Glucocorticoids)
 Preparations include:
• Beclomethasone
• Budesonide
• Ciclesonide >> An inhaled prodrug that is activated by esterases in bronchial
epithelial cells
•
•
•
•
Flunisolide
Fluticasone
Mometasone
Triamcinolone
 Do not relax smooth muscles directly, but act by inhibiting the production
of inflammatory cytokines to:
• Reduce bronchial reactivity
• Increase airway caliber
• Reduce frequency of asthmatic attacks
 Given orally, by injection, or by aerosol
II. ANTI-INFLAMMATORY Drugs A. Corticosteroids (Glucocorticoids)
 Oral or parenteral administration may produce severe adverse effects
(weight gain with puffy face and truncal obesity, acne, hypokalemia,
hypertension, diabetes, peptic ulcer, osteoporosis, glaucoma, muscle
wasting, acute psychosis, etc)
• When used long-term
• Cusingnoid effects
 Systemic administration reserved only for patients requiring urgent
treatment
 Beclomethasone, budesonide, dexamethasone, flunisolide,
fluticasone, and mometasone are effective as aerosols which have
negligible systemic effects compared with oral doses
 Inhaled preparations may cause oropharyngeal candidiasis or
hoarseness from vocal cord irritation . Oral thrush can be prevented by
use of spacers and mouth washing after inhalation.
 Effective in reducing symptoms and improving pulmonary function in mild
asthma
II. ANTI-INFLAMMATORY Drugs B. Leukotriene (LT) Pathway Inhibitors
 Leukotrienes, LTC4 and LTD4 are formed by 5-lipoxygenase acting on
arachidonic acid in airway inflammatory cells (i.e., mast cells,
eosinophils, macrophages, and basophils)
 Are potent bronchoconstrictors secreted in asthma and anaphylaxis
 Produce many asthmatic effects including mucosal edema, mucus
hypersecretion, increased bronchial reactivity, and bronchoconstriction
 Two drugs now available as oral tablets are:
• Montelukast and zafirlukast = LTD4-receptor antagonists
• Both are given orally as an adjunct therapy and especially useful in children
unable to comply with inhalation therapy
 Zileuton which inhibits 5-lipoxygenase to reduce leukotriene formation
• Associated with liver toxicity
II. ANTI-INFLAMMATORY Drugs –
C. Anti-IgE Monoclonal Antibody
Preparation: omalizumab
Monoclonal antibody that inihibits binding of IgE
to mast cells but does not inactivate already
bound IgE
Lowers plasma IgE levels and reduces
bronchospastic antigen responses
Lessens asthma severity and reduces
corticosteroid requirement
III. PROPHYLACTIC DRUGS
 Preparations:
• Cromolyn sodium
• Nedocromil sodium
 Effective only when given prophylactically
 Have an acute protective effect when given before exercise or
allergen exposure
 Inhibit bronchial hyperreactivity in antigen- and exercise-induced
asthma
 Do not affect bronchial smooth muscles or asthmatic
bronchospasm
 Cromolyn is also used for Systemic Mastocytosis, a rare
condition characterized by infiltration of liver, spleen, lymph
nodes, and G.I. Tract with mast cells.
III. PROPHYLACTIC DRUGS
 Act by altering delayed chloride channels in cell
membranes to:
• Inhibit mast cell activation
• Reduce release of histamine and other mediators
 Given as aerosols because of poor GI absorption
Less potent or effective compared with inhaled
corticosteroids
Adverse effects are minor and localized to sites of
deposition; such as throat irritation, cough, mouth
dryness, chest tightness, and wheezing
Serious adverse effects are rare
National Asthma Education Program Panel
(NAEPP) Guidelines 1997
Mild Intermittent: Symptoms < 2X a week; Nighttime
symptoms < twice/month; Asymptomatic between
exacerbations.
Mild Persistent: Symptoms >2X a week but < once
daily
Nighttime symptoms > twice/month; affect activity.
Moderate Persistent: Daily symptoms; Nighttime
symptoms > once/week; Exacerbations > 2X a week; Daily
use of b2 agonist; Exacerbations affect activity.
Severe Persistent: Continual symptoms, Frequent
exacerbations, Nighttime symptoms are frequent;
Limited
physical activity.
Stepwise Approach to Asthma Therapy
Mild Intermittent: No Daily Medication
Short-acting b2-agonists as needed
Mild Persistent: Daily Anti-inflammatory Medication
-low-dose inhaled corticosteroids
-Nedocromil or Cromolyn
-sustained-release Theophylline
-short-acting b2-agonist as needed
Moderate Persistent: Low-Medium dose inhaled
corticosteroids Plus
-Long-acting inhaled/oral b2-agonist*
Severe Persistent: High dose inhaled corticosteroids Plus
LABA, or oral b2-agonist
Sustained-release theophylline And
Oral Steroids
A 20-year-old man with a history of bronchial asthma,
complains of dyspnea and coughing. Physical
examination shows inspiratory and expiratory wheezes
with decreased breath sounds, respiratory distress with a
rate of 30/min, BP 120/96 mm Hg, HR 130 beats/min,
pulsus paradoxus = -18 mm Hg, and temperature = 37.8o
C. Which of the following would you choose for the
immediate treatment of this patient?
A) Albuterol
B) Ipratropium
C) Mometasone
D) Nedocromil
E) Pentoxifylline
ANS = A
Inhaled beta-2
agonist
In a 32-year-old woman with a long history of
bronchial asthma, use of mometasone aerosol for
treatment is likely to produce which of the
following?
A) Diabetes mellitus
B) Essential hypertension
C) Truncal obesity
D) Susceptibility to infection
E) Voice hoarseness
ANS = E
Inhaled steroids cause voice hoarsness
and oropharyngeal candidiasis
Drugs acting on the respiratory system
Inhibitors of
mediator release
Cromolyn
Nedocromil
Methylxanthines
Sympathomimetic
agents
Theophylline
Caffeine
Nonselective
Epinephrine
Isoproterenol
Ephedrine
β2-selective
agonists
(most used)
Albuterol
Levalbuterol
Metaproterenol
Salmeterol
Terbutaline
Antimuscarinic
drugs
Ipratropium
Tiotropium
Leukotriene
inhibitors
Zafirlukast
Montelukast
Corticosteroids
Prednisolone
Methylprednisolone
Aerosols
Beclomethasone
Dexamethasone
Flunisolide
Fluticasone
Triamcinolone
Bronchodilators vs. antiinflammatory
Tremor
A 14-year-old girl who is taking oral sustained
release aminophylline plus inhaled fluticasone
and uses an albuterol inhaler for the treatment of
acute bronchospasms is brought to the
Emergency Department in state of status
asthmaticus. Which of the following medications
is the most appropriate first drug given after the
administration of oxygen to treat status
asthmaticus in this patient?
A.
B.
C.
D.
E.
Albuterol (inhalation)
Fluticasone (iv)
Hydrocortisone (im)
Terbutaline (sc)
Theophylline (iv)
Answer: D
terbutanie (sc)
preferred treatment
for status asthmaticus
A 10-year-old boy has been taking
medications for 7 years to manage his severe
asthma. Which of the following medications
is most likely to cause significant adverse
effects when used daily in the treatment of
asthma in this patient?
A.
B.
C.
D.
E.
Albuterol
Flunisolide
Cromolyn
Montelukast
Prednisolone
Answer: E
Oral steroids sometimes have
to be used to treat severe asthma;
Keep course as short as possible
to avoid cushingnoid adverse effects
Extra Credit Quiz
Section
MANAGEMENT OF ACUTE SEVERE ASTHMA
 A 23-year-old woman with known bronchial asthma
presents with acute dyspnea. She is already taking
maintenance therapy with an inhaled corticosteroid twice
daily and, when needed, an inhaled short-acting beta2
sympathomimetic agent. The clinical and laboratory
findings are as follows: ❃ Shortness of breath while
speaking and at rest ❃ Respiratory rate 32/min ❃
Orthopnea ❃ Expiratory wheezes ❃ Prolonged
expiratory phase ❃ FEV1 = 2.2 L (61% of normal) ❃
FEV1/IVC = 53% ❃ Arterial blood gases: pO2 = 65
mmHg, pCO2 = 25 mmHg, pH= 7.49 A acute severe
asthma attack is diagnosed
Treatment Objectives
 To relieve symptoms
 To prevent complications and recurrence
Non Pharmacological T/t
• Avoid triggers of an acute asthmatic attack
• Avoid smoking
Pharmacological T/t
• Oxygen, intranasal or by mask ,In high concentration
Plus
• Salbutamol, nebulized, Adults 2.5 -5 mg 6 hourly
Children 2.5 mg 6 hourly
Plus
• Aminophylline, IV, (slow bolus injection where patient is
still distressed after 3-4 initial doses of nebulized
salbutamol)
Adults 250 mg over 20 minutes and repeat after 30
minutes if necessary , Children 3-5 mg/kg over 20 minutes
as a slow bolus injection or by infusion
Pharmacological T/t
Plus
• Hydrocortisone, IV, (to be given simultaneously with
bronchodilators)
Adults 200 mg stat then 100 mg 6 hourly until clinical
improvement,Children,6-2 years; 100 mg 8 hourly ,1-5
years; 50 mg 8 hourly, <1 year; 5 mg 8 hourly
Plus
• Prednisolone, oral, (start as a single dose at the same
time as hydrocortisone, soon after breakfast)
Adults 30-40 mg daily ,Children > 5 years; 30-40 mg as a
single daily dose for 3-5 days,2-5 years; 20 mg as a single
daily dose for 3-5 days,< 2 years; 1-2 mg/kg daily as a
single dose for 3-5 days
Pharmacological T/t
• If patient is improving -leave on maintenance
therapy
• Continue with oxygen
• Plus
• Prednisolone, oral, 30-40 mg daily (20-40 mg a day in
children) until stable. Continue for 5-7 days, or may
choose to tail off dose over 2 weeks
• Plus
• Salbutamol, nebulised, 2-5mg 2-4 hourly
• Or
• Aminophylline, IV,
Adults 250 mg 6 hourly ,Children 3-5 mg/kg 6-8 hourly
over 20 minutes as a slow bolus injection
Pharmacological T/t
•
•
•
•
If patient is not improving
Continue oxygen
Plus
Salbutamol, nebulised, 2-5 mg more frequently every
15-30 minutes
• Plus
• Aminophylline, IV,
Adults ,250 mg in 500 ml of 5% Dextrose or 0.9% Sodium
Chloride, 6 hourly ,Children ,3-5 mg/kg 6-8 hourly over 20
minutes as a slow bolus injection
• Plus
• Hydrocortisone, IV,
• Adults 200 mg 6 hourly,Children 6-12 years; 100 mg 8
hourly,1-5 years; 50 mg 8 hourly,<1 years; 25 mg 8
hourly
Pharmacological T/t
• Plus
• Prednisolone, oral,
Adults 30-60 mg daily ,Children Prednisolone, oral, 1-2
mg/kg daily (40 mg maximum dose)
• Once patient is improving
• Change to oral steroids
• Wean off aminophyline and stop in 12-24 hours
• Reduce frequency of nebulised Salbutamol. Substitute
with inhaled or oral Salbutamol after 24 hours.
• Give written and oral instructions on how to tail off oral
steroids or steroids may be stopped after 7 days. In
children, give Prednisolone 1-2 mg/kg for 3-5 days
MANAGEMENT OF CHRONIC ASTHMA IN ADULTS &
CHILDREN OF SCHOOL GOING AGE
 The key to preventing acute exacerbations is adequate
management of chronic asthma.
Treatment Objectives
 To alleviate symptoms
 To improve the quality of life of the patient
 To prevent crisis (acute attacks) or hospitalization
 To prevent adverse effects from medications
 To prevent exacerbations
Non Pharmacological T/t
•
•
•
•
•
Involve patient in his/her management
Avoidance of provoking factors where possible
Selection of the best treatment available
Step up treatment as needed for good control
Refer early for specialist care after STEP 2
Pharmacological T/t
• STEP 1
•
Reliever medication: Intermittent use of bronchodilators .
Inhaled salbutamol, 100 microgram, 2 puffs as often as
needed ,If inhaled beta agonists or oral bronchodilators are
needed more than once daily then move to Step 2 where a
doctor should be involved.
• STEP 2
•
•
•
•
•
•
•
Controller medication: regular 12 hourly use of:
Inhaled Budesonide one puff 12 hourly;
Adults and Children > 10 years,200 microgram, Children < 10
years 100 microgram
Inhaled Fluticasone MDI, 2 puffs 12 hourly;
Adults 125 or 250 microgram , Children 50 microgram
Inhaled Beclometasone (Beclomethasone)
100 microgram; 2 puffs 12 hourly in both adults and children
Pharmacological T/t
• Plus
• Reliever medication: inhaled Salbutamol 100 microgram
2 puffs as needed.
• STEP 3
• Controller medication:
• Regular, 12 hourly (twice daily), use of inhaled
combination ICS and long-acting beta-agonist (LABA).
• Fluticasone/salmeterol - doses 50/100 or 50/250; 1 puff
12 hourly (adults, children over 5 years)
• Budesonide/formoterol doses 80/4.5 (children over 5
years) or 160/4.5,(adults); 1-2 puffs 12 hourly
• Plus
• Reliever medication: Inhaled salbutamol 100 microgram
, 2 puffs as needed.
Pharmacological T/t
• STEP 4: Refer to Asthma specialist clinic
• Controller medication: Increase dose of inhaled steroid
in combination with LABA (from Step 3)
• Add on leukotriene antagonist, oral montelukast 10 mg
daily (5 mg daily in children 6 years plus, or zafirlukast
20 mg twice daily (10 mg 12 hourly in children over 6
years),
• Modified-release Theophylline SR (10 mg/kg /day in
children) restrict prescribing to specialists
Plus
• Reliever medication: inhaled Salbutamol as above.
Pharmacological T/t
STEP 5: Refer to Asthma specialist clinic
• Controller medication: Addition to Step 4 treatment of
regular once daily Prednisolone, oral, starting with 3040 mg daily and tailing down to a low maintenance daily
dose.
• In adults, prednisolone tailed off by 5 mg every third
day, reducing to lowest dose possible without provoking
attacks, usually 5-10 mg daily or alternate daily.
• May add on oral Salbutamol 4 mg 8-12 hourly
• Reliever medication: should be used at all steps as
required.
• STEPPING DOWN
• Review treatment every 3-6 months with a view to
stepping down treatment if client is symptom-free or has
minimal symptoms (<1-2 times a week).