SECTION IV DRUGS WITH 1

IMPORTANT ACTIONS ON
SMOOTH MUSCLE
 2

HISTAMINE, SEROTONIN,
& THE ERGOT ALKALOIDS CHAPTER 16
• autacoid group of drugs- Histamine, serotonin, endogenous peptides ,
prostaglandins and leukotrienes

• histamine and serotonin-due to undesirable effects- neither has any

clinical application in the treatment of disease
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HISTAMINE

• important mediator of immediate allergic (urticaria) and inflammatory

reactions, and a modest role in anaphylaxis

• important role in gastric acid secretion

• functions as a neurotransmitter and neuromodulator

• Newer evidence- a role in immune functions and chemotaxis of WBC

 4

HISTAMINE

Chemistry & Pharmacokinetics

• occurs in plants and in animal tissues

• component of some venoms and stinging secretions

• Once formed, histamine is either stored or rapidly inactivated

• The major metabolic pathways involve conversion to N -methylhistamine,

methylimidazoleacetic acid, and imidazoleacetic acid
 5

HISTAMINE
Chemistry & Pharmacokinetics

• Conditions increases excretion of histamine (increased numbers of mast cells

or basophils)-systemic mastocytosis,urticaria pigmentosa, gastric carcinoid,
and myelogenous leukemia

• Most tissue histamine is sequestered and bound in granules (vesicles) in mast

cells or basophils

• The bound form of histamine is biologically inactive

 6

HISTAMINE
Chemistry & Pharmacokinetics

• Mast cells are especially rich at sites of potential tissue injury—nose,

mouth, and feet; internal body surfaces; and blood vessels, particularly at pressure
points and bifurcations

• Non-mast cell histamine is found in several tissues, including the brain(a

neurotransmitter)
 7

HISTAMINE
Chemistry & Pharmacokinetics

• brain functions- neuroendocrine control, cardiovascular regulation, thermal

and body weight regulation, and sleep and arousal

• enterochromaffin-like (ECL) cells of the fundus of the stomach- 2nd important

nonneuronal site of histamine storage and release

• ECL cells release histamine, one of the primary gastric acid secretagogues,
to activate the acid-producing parietal cells of the mucosa
 8

HISTAMINE
Storage & Release of Histamine

Mechanisms of release of histamine from mast cells:

1. Immunologic Release-most important, mast cell and basophil

• if sensitized by IgE antibodies attached to their surface membranes, degranulate
explosively when exposed to the appropriate antigen

• Degranulation- simultaneous release of histamine

• mediator in immediate (type I) allergic reactions

• Substances released during IgG- or IgM-mediated immune reactions that activate

the complement cascade can also release histamine from Mast cells and Basophils
 9

HISTAMINE
Chemistry & Pharmacokinetics

2. Chemical and Mechanical Release

• Certain amines, including drugs such as morphine and

tubocurarine,can displace histamine from its bound form within
cells

• Chemical and mechanical mast cell injury causes degranulation

 10

HISTAMINE

Pharmacodynamics

A. Mechanism of Action-

• Histamine exerts its biologic actions by combining with specific cellular

receptors- surface membrane.

• Histamine Receptors:H1-H4
 11

HISTAMINE
 12

HISTAMINE
• B. Tissue and Organ System Effects of Histamine

• 1. Nervous system-

• Histamine-powerful stimulant of sensory nerve endings-mediating pain and itching

• H 1 -mediated effect is an important component of the urticarial response and

reactions to insect and nettle stings.

• H 1 and H 3 receptors-roles in appetite and satiety-antipsychotic drugs that block

these receptors cause significant weight gain

• H 3 agonists reduce the release of acetylcholine, amine, and peptide transmitters in

various areas of the brain and in peripheral nerves
 13

HISTAMINE
• B. Tissue and Organ System Effects of Histamine

• 2. Cardiovascular system

• injection or infusion of histamine causes a ↓ in sys & dias BP & ↑ HR

• direct vasodilator action on arterioles and precapillary sphincters-BP

Changes

• Flushing, a sense of warmth, and headache-vasodilation

• Vasodilation elicited by small doses of histamine is caused by H 1 -receptor

activation and is mediated mainly by release of nitric oxide from the
endothelium
 HISTAMINE
14

• B. Tissue and Organ System Effects of Histamine

• 2. Cardiovascular system

• Histamine-induced edema- action of the amine on H 1 receptors in the vessels of

the microcirculation, esp postcapillary vessels.

• Responsible for urticaria (hives), which signals the release of histamine in the skin

• Contraction of actin and myosin within these cells-separation of endothelial cells

• Direct cardiac effects-increased contractility and increased pacemaker rate-

mediated by H 2 receptors
 15

HISTAMINE
• B. Tissue and Organ System Effects of Histamine

• 3. Bronchiolar smooth muscle

• Bronchoconstriction-H 1 receptors

• patients with asthma are very sensitive to histamine

• bronchoconstriction induced in these patients-hyperactive neural response,

also respond excessively to many other stimuli
 16

HISTAMINE
B. Tissue and Organ System Effects of Histamine

4. Gastrointestinal tract smooth muscle

• Histamine causes contraction of intestinal smooth muscle

• Large doses of histamine may cause diarrhea

• mediated by H 1 receptors

5. Other smooth muscle organs

• insignificant effects on the smooth muscle of the eye and genitourinary tract

• pregnant women suffering anaphylactic reactions may abort as a result of

histamine-induced contractions
 17

HISTAMINE
B. Tissue and Organ System Effects of Histamine

6. Secretory tissue

• a powerful stimulant of gastric acid secretion and, to a lesser extent, of

gastric pepsin and intrinsic factor production

• stimulates secretion in the small and large intestine

• Very high concentrations can cause adrenal medullary discharge

 18

HISTAMINE
B. Tissue and Organ System Effects of Histamine
7. Metabolic effects
• intensive research- whether H 3 agonists are useful in the treatment of
obesity
8. The “triple response”
• Intradermal injection of histamine-characteristic red spot, edema, and flare
response
• effect involves three separate cell types: smooth muscle in the
microcirculation, capillary or venular endothelium, and sensory nerve
endings
• flare is said to be caused by an axon reflex
 19

HISTAMINE

B. Tissue and Organ System Effects of Histamine

9. Other effects possibly mediated by histamine receptors

• analgesia is said to be comparable to that produced by opioids, but

tolerance, respiratory depression and constipation have not been reported
 20

HISTAMINE
HISTAMINE ANTAGONISTS
• Physiologic antagonists-epinephrine, have smooth muscle actions opposite
to those of histamine, act at different receptors
• injection of epinephrine can be lifesaving in systemic anaphylaxis and in
other conditions with massive release of histamine
• Release inhibitors reduce the degranulation of mast cells that results from
immunologic triggering by antigen-IgE interaction-Cromolyn and nedocromil
• Beta 2 -adrenoceptor agonists- capable of reducing histamine release
• Histamine receptor antagonists represent a 3rd approach to the reduction of
histamine-mediated responses.
• selective H 2 -receptor antagonists-therapy for peptic disease
 21

HISTAMINE
HISTAMINE RECEPTOR ANTAGONISTS

H 1 -RECEPTOR ANTAGONISTS

• competitively block histamine or act as inverse agonists at H 1

receptors -treatment of allergic conditions

• “cold pills” and “sleep aids”

 22

HISTAMINE
HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS

Chemistry & Pharmacokinetics

• divided into first-generation and second-generation agents

• relatively strong sedative effects- 1st-gen drugs

• 1st-gen agents-more likely to block autonomic receptors

• 2nd-gen H 1 blockers are less sedating-less distribution into the CNS

• All the H 1 antagonists are stable amines

• rapidly absorbed after oral administration, with peak blood concentrations occurring in
1–2 hours
 HISTAMINE
23

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS

Chemistry & Pharmacokinetics

• first-generation drugs enter the CNS readily

• Some are extensively metabolized by microsomal systems in the liver

• effective duration of action of 4–6 hours following a single dose

• meclizine and several 2nd-generation agents are longer-acting,-duration of

action: 12–24 hours
 HISTAMINE
24

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS
Chemistry & Pharmacokinetics
• newer agents-less lipid soluble than the 1st-generation drugs
• active metabolites of hydroxyzine, terfenadine, and loratadine- (cetirizine,
fexofenadine, and desloratadine).
Pharmacodynamics
• Both neutral H 1 antagonists and inverse H 1 agonists reduce or block the
actions of histamine by reversible competitive binding to the H 1 receptor
• histamine-induced contraction of bronchiolar or gastrointestinal smooth
muscle can be completely blocked by these agents, but the effects on
gastric acid secretion and the heart are unmodified.
 HISTAMINE
25

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS

Pharmacodynamics

Other actions of 1st-gen H 1 -receptor antagonists in addition to blockade of

the actions of histamine

• 1. Sedation-useful as “sleep aids”

• effect resembles that of some antimuscarinic drugs and is considered very
different from the disinhibited sedation produced by sedative hypnotic drugs
 HISTAMINE
26

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS
Pharmacodynamics
2. Antinausea and antiemetic actions
• Several 1st-gen H 1 antagonists can prevent motion sickness
3. Antiparkinsonism effects
• Some of the H 1 antagonists, especially diphenhydramine , have significant
acute suppressant effects on the extrapyramidal symptoms
4. Anticholinoceptor actions
• Many 1st-gen esp. those of the ethanolamine and ethylenediamine
subgroups, have significant atropine-like effects on peripheral muscarinic
receptor-nonallergic rhinorrhea but can cause urinary retention and blurred
vision
 HISTAMINE
27

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS

Pharmacodynamics

5. Adrenoceptor-blocking actions— Alpha-receptor blocking effects can be

demonstrated for many H 1 antagonists

• phenothiazine subgroup, eg, promethazine - cause orthostatic hypotension

in susceptible individuals.

6. Serotonin-blocking action— Strong blocking effects at serotonin receptors

have been demonstrated for some first-generation
HISTAMINE
28
 HISTAMINE
29

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS
Pharmacodynamics

7. Local anesthesia— Several 1st-gen H 1 antagonists are potent local

anesthetics.

• Diphenhydramine and promethazine are actually more potent than

procaine as local anesthetics.

• used to produce local anesthesia in patients allergic to conventional local

anesthetic drugs.
 HISTAMINE
30

HISTAMINE RECEPTOR ANTAGONISTS

BASIC PHARMACOLOGY OF H 1 -RECEPTOR ANTAGONISTS

Pharmacodynamics

• 8. Other actions— Certain H 1 antagonists, eg, cetirizine, inhibit mast cell

release of histamine and some other mediators of inflammation.

• The mechanism is not fully understood but could play a role in the beneficial
effects of these drugs in the treatment of allergies such as rhinitis.
 SEROTONIN
31

• 5-HYDROXYTRYPTAMINE

• important neurotransmitter

• a local hormone in the gut

• a component of the platelet clotting process

• role in migraine headache and several other clinical conditions,

including carcinoid syndrome
 SEROTONIN
32

BASIC PHARMACOLOGY OF SEROTONIN

• Chemistry & Pharmacokinetics

• widely distributed in nature, being found in plant and animal tissues, venoms,
and stings- like histamine

• pineal gland-serotonin serves as a precursor of melatonin, a melanocyte-

stimulating hormone

• 90% of the serotonin in the body is found in enterochromaffin cells in the

gastrointestinal tract
 SEROTONIN
33

BASIC PHARMACOLOGY OF SEROTONIN

• Chemistry & Pharmacokinetics

• found in platelets- concentrate the amine by means of an active serotonin

transporter mechanism (SERT) similar to that in the membrane of serotonergic nerve
endings.

• Once transported into the platelet or nerve ending, 5-HT is concentrated in vesicles
by a vesicle-associated transporter (VAT) that is blocked by reserpine

• also found in the raphe nuclei of the brainstem, contains cell bodies of serotonergic
neurons that synthesize, store, and release serotonin as a transmitter
 SEROTONIN
34

BASIC PHARMACOLOGY OF SEROTONIN

• Chemistry & Pharmacokinetics

• Brain serotonergic neurons are involved in:

• mood, sleep, appetite, and temperature regulation, as well as the perception of
pain, the regulation of blood pressure, and vomiting

• involved in clinical conditions such as depression, anxiety, and migraine

• Carcinoid tumors- produces high amount of serotonin

• Banana-high in serotonin
 SEROTONIN
35

BASIC PHARMACOLOGY OF SEROTONIN

Pharmacodynamics

• A. Mechanisms of Action-mediated by large number of cell membrane

receptors ( Table 16-3)
• B. Tissue and Organ System Effects
• 1. Nervous system
• precursor of melatonin in the pineal gland
• Melatonin-N -acetyl-5-methoxytryptamine
• produced and released primarily at night
• sleep-wake behavior
• sleep aid by the food supplement industry
 SEROTONIN
36

BASIC PHARMACOLOGY OF SEROTONIN

Pharmacodynamics
• 1. Nervous system
• potent stimulant of pain and itch sensory nerve endings and is responsible for
some of the symptoms caused by insect and plant stings
• Powerful activator of chemosensitive endings located in the coronary
vascular bed
• Bezold-Jarisch reflex-chemoreceptor reflex-Activation of 5-HT 3 receptors on
these afferent vagal nerve endings-marked bradycardia and hypotension
 SEROTONIN
37

BASIC PHARMACOLOGY OF SEROTONIN

Pharmacodynamics

2. Respiratory system
• small direct stimulant effect on bronchiolar smooth muscle
• may also cause hyperventilation as a result of the chemoreceptor reflex or
stimulation of bronchial sensory nerve endings
3. Cardiovascular system
• Contraction of vascular smooth muscle, mainly through 5-HT 2 receptors
• powerful vasoconstrictor except in skeletal muscle and the heart, where it
dilates blood vessels
• constricts veins, and venoconstriction with increased capillary filling
 SEROTONIN
38

BASIC PHARMACOLOGY OF SEROTONIN

Pharmacodynamics

4. Gastrointestinal tract
• powerful stimulant of gastrointestinal smooth muscle, increasing tone and
facilitating peristalsis
• direct action on 5-HT 2 smooth muscle receptors plus a stimulating action on
ganglion cells located in the enteric nervous system
• motility-enhancing or “prokinetic” effect of selective serotonin agonists such
as cisapride
• Overproduction of serotonin (and other substances) in carcinoid tumor is
associated with severe diarrhea
 SEROTONIN
39

BASIC PHARMACOLOGY OF SEROTONIN

Pharmacodynamics

5. Skeletal muscle and the eye

• 5 -HT2 receptors are present on skeletal muscle membranes, but their

physiologic role is not understood

• Serotonin syndrome-skeletal muscle contractions and precipitated when

MAO inhibitors are given with serotonin agonists, especially antidepressants
of the selective serotonin reuptake inhibitor class
 SEROTONIN
40

SEROTONIN-RECEPTOR ANTAGONISTS

• Phenoxybenzamine -long-lasting blocking action at 5-HT 2 receptors

• Cyproheptadine- potent H 1 -receptor–blocking as well as 5-HT 2 –blocking

actions

• Ketanserin blocks 5-HT 2 receptors on smooth muscle and other tissues

• Ritanserin-alter bleeding time and to reduce thromboxane formation

• Ondansetron -5-HT 3 antagonist, prevention of nausea and vomiting

associated with surgery and cancer chemotherapy
 ERGOT ALKALOIDS
41

• produced by Claviceps purpurea , a fungus that infects grasses and grains—

especially rye(under damp growing or storage conditions)

• This fungus also synthesizes histamine, acetylcholine,tyramine, and other

biologically active products

• Ergotism-epidemics of ergot poisoning due to accidental ingestion of ergot

alkaloids . (St. Anthony’s Fire). The most dramatic effects of poisoning are:
• dementia with florid hallucinations; prolonged vasospasm, which may result in
gangrene; and stimulation of uterine smooth muscle, which in pregnancy may
result in abortion-
 ERGOT ALKALOIDS
42

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

• Chemistry & Pharmacokinetics
• Two major families: -tetracyclic ergoline nucleus can be identified in the:
1. amine alkaloids
2. peptide alkaloids
• variably absorbed from the gastrointestinal tract
• oral dose of ergotamine is about 10 X larger than the IM dose
• Caffeine-speeds absorption and peak blood levels after oral administration
• amine alkaloids are also absorbed from the rectum and the buccal cavity
and after administration by aerosol inhaler.
• Absorption after IM injection is slow but usually reliable.
• Semisynthetic analogs such as bromocriptine and cabergoline are well
absorbed from the gastrointestinal tract
 ERGOT ALKALOIDS
43

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

Pharmacodynamics

A. Mechanism of Action

• act on several types of receptors

• Effects include agonist, partial agonist, and antagonist actions at α

adrenoceptors and serotonin receptors and agonist or partial agonist
actions at central nervous system dopamine receptors

• high affinity for presynaptic receptors, whereas others are more selective for
postjunctional receptors
 ERGOT ALKALOIDS
44

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

Pharmacodynamics

• B. Organ System Effects

• 1. Central nervous system-powerful hallucinogens

• Lysergic acid diethylamide (LSD; “acid”)-synthetic ergot compound

• Bromocriptine-extrapyramidal system

• bromocriptine,cabergoline, and pergolide-highest selectivity for the pituitary

dopamine receptors
• suppress prolactin secretion from pituitary cells by activating regulatory dopamine
receptors
ERGOT ALKALOIDS
45
 ERGOT ALKALOIDS
46

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

Pharmacodynamics
B. Organ System Effects
2. Vascular smooth muscle-constrict most vessels in nanomolar concentrations
• vasospasm is prolonged
• associated with “epinephrine reversal”
• blockade of the response to other α agonists
3. Uterine smooth muscle-combine α agonist, serotonin agonist, and other
effects
• the sensitivity of the uterus to the stimulant effects of ergot increases dramatically
during pregnancy, perhaps because of increasing dominance of α 1 receptors
as pregnancy progresses
 ERGOT ALKALOIDS
47

BASIC PHARMACOLOGY OF ERGOT ALKALOIDS

Pharmacodynamics

B. Organ System Effects

4. Other smooth muscle organs

• little or no significant effect on bronchiolar or urinary smooth muscle

• Nausea, vomiting, and diarrhea may be induced even by low doses

 48

• Clinical pharmacologyl of ergot alkaloids:

• Migraine headache especially if given during the prodromal period. Very
specific for migraine; not used as analgesic for any other condition.
• Often combined with caffeine to facilitate absorption of the ergot alkaloid.

• Hyperprolactinemia

• Postpartum hemorrhage (used after delivery of baby NOT before)

• Senil e Cerebral Insufficiency, etc

49
50
 51

WHAT ERGOT ALKALOID WAS ABUSED DURING THE HIPPIES

TIME OF 70’S THAT CAUSES PROLONGED PSYCHOTIC STATES
AND FLASHBACK AS ITS TOXICITY

Lysergic Acid Diethylamide

52
 VASOACTIVE PEPTIDES CHAPTER 17
53

• Peptides are used by most tissues for cell-to-cell communication

• Transmitters in the autonomic and central nervous systems

• direct effects on vascular and other smooth muscles

• Vasoconstrictors- angiotensin II, vasopressin,endothelins, neuropeptide Y , and

urotensin

• Vasodilators- bradykinin and related kinins, natriuretic peptides, vasoactive

intestinal peptide, substance P, neurotensin, calcitonin genereted peptide ,
and adrenomedullin
 VASOACTIVE PEPTIDES CHAPTER 17
54

Renin

• originates in the kidneys

• synthesized and stored in the juxtaglomerular apparatus of the nephron

Control of Renin Release

• rate at which renin is released by the kidney is the primary determinant

of activity of the renin-angiotensin system (RAS)

• Active renin release is controlled by a renal vascular receptor, the

macula densa, the sympathetic nervous system, and ANG II.
 VASOACTIVE PEPTIDES CHAPTER 17
55

Angiotensinogen
• circulating protein substrate from which renin cleaves ANG I
• synthesized in the liver
• production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II

Angiotensin I
• it must be converted to ANG II by converting enzyme

• Converting Enzyme (ACE, Peptidyl Dipeptidase, Kininase II)

• a dipeptidyl carboxypeptidase with two active sites that catalyzes the cleavage of dipeptides from the
carboxyl terminal of certain peptides
• most important substrates are ANG I, which it converts to ANG II, and bradykinin

• Angiotensinase
• peptidases that remove Angiotensin II in the circulation
 VASOACTIVE PEPTIDES CHAPTER 17
56

ACTIONS OF ANGIOTENSIN II

• exerts important actions at vascular smooth muscle, adrenal cortex, kidney, heart, and
brain via the receptors

• RAS-plays a key role in the regulation of fluid and electrolyte balance and arterial blood
pressure
• Excessive activity –HPN and Fluid and electrolyte imbalances

• Blood Pressure-ANG II 40x more potent than norepinephrine

• Adrenal Cortex & Kidney-

• stimulates glucocorticoid synthesis

• renal vasoconstriction, increase proximal tubular sodium reabsorption, and inhibit the release
of renin.
 VASOACTIVE PEPTIDES CHAPTER 17
57

ACTIONS OF ANGIOTENSIN II

• Central Nervous System-stimulate drinking (dipsogenic effect) and increase the

secretion of vasopressin and adrenocorticotropic hormone (ACTH)

• Cell Growth-mitogenic for vascular and cardiac muscle cells and may
contribute to the development of cardiovascular hypertrophy
VASOACTIVE PEPTIDES CHAPTER 17
58
VASOACTIVE PEPTIDES CHAPTER 17
59
VASOACTIVE PEPTIDES CHAPTER 17
60
 61

EICOSANOIDS:PROSTAGLANDINS,THROMBOXANES,
LEUKOTRIENES, &RELATED COMPOUNDS CHAPTER 18

• ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS

• 5,8,11,14-eicosatetraenoic acid, the most abundant of the eicosanoid
precursors
• SYNTHESIS OF EICOSANOIDS
• Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases)
• Two unique COX isozymes convert AA into prostaglandin endoperoxides
• COX1 and COX2
• COX-1 -gastric epithelial cytoprotection
• COX-2 is the major source of prostanoids in inflammation and cancer.
 62

NITRIC OXIDE CHAPTER 19

• gaseous signaling molecule that readily diffuses across cell membranes and
regulates a wide range of physiologic and pathophysiologic processes
including cardiovascular, inflammatory, and neuronal functions

• significant effect on vascular smooth muscle tone and blood pressure

• diffuses to vascular smooth muscle leading to vasorelaxation

 63

NITRIC OXIDE CHAPTER 19

DRUGS USED IN ASTHMA CHAPTER 20
64
DRUGS USED IN ASTHMA CHAPTER 20
65
 66

•MARAMING SALAMAT PO