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86 Cards in this Set

  • Front
  • Back
Physiological functions of autacoids
Inflammation
Blood Pressure
Smooth muscle contraction
GI function
Body temperature
Platelet aggregation
Major Autacoids to Know for the exam!
Histamine
Platelet activating factor (PAF)
Serotonin
Cyclooxygenase metabolites
Prostaglandins, thomboxanes
Lipoxygenase metabolites
Leukotrienes
Bradykinin
Classical Hormones Defn.
Classical hormones act on distant organs, traveling primarily through the blood stream
Autacoids Defn.
Autacoids act on neighboring cells, traveling primarily through local tissues.
Also found in the blood stream
Decreased stability, local action
Inflammatory Response: Host Defense
Host defense:
Makes tissues accessible for immune system cells
Activates leukocytes and phagocytes
Inflammatory Response: Phases of Inflammation
Phases of inflammation
Acute transient response (incr. capillary permeability)
Delayed subacute phase (cellular infiltration)
-->results in Resolution (tissue healing) or
Chronic Proliferative Phase
(Tissue degeneration and fibrosis)
Histamine Storage
KNOW!
It is primarily found stored in: mast cells (tissue: such as skin, intestinal mucosa, and lung mucosa) and basophils (blood)

stored in granules with heparin and proteases
Histamine Release
KNOW!
Histamine is released immediately upon synthesis from: epidermal cells, gastric mucosal cells, CNS neurons, and cells of rapidly growing or regenerating tissue
high turn-over of histamine
levels controlled by presence of L-histidine decarboxylase
Histamine Receptor Subtypes
Histamine effects are mediated via three histamine receptor subtypes:
H1, H2, H3
Histamine
Physiological Actions
All
CV System:
vasodilation, increased capillary permeability

Neurons:
Stimulates sensory nerve endings as well as substance P release from C fibers(H1), Neurotransmitter in CNS(H3)

Lewis Triple Response:
Flush, Flare, Wheal

Extravascular SM:
Constrict

Gastric Acid Secretion:
Increased
Histamine
Physiological Actions
Cardiovascular system
Vasodilation
-H1 endothelium NO, PGI2 release (rapid onset, short-lasting)
-H2 vascular smooth muscle by ­cAMP (slow onset, more sustained)
-Increased capillary permeability (H1)
contraction of endothelial cells of postcapillary venules
Histamine
Physiological Actions
Neurons
Stimulates sensory nerve endings as well as substance P release from C fibers (H1)
epidermis itching
dermis pain
important in urticarial response to insect and nettle stings

Neurotransmitter in CNS (H3)
Found in hypothalamus and regions of cerebellum and forebrain
involved in regulation arousal and wakefulness (H1 receptors also play an important role in wakefulness
Histamine
Physiological Actions
Triple Response of Lewis
Triple Response of Lewis
The triple response is similar to the effect of a bee sting and can be elicited directly by histamine injection.
In nature, histamine is released from mast cells upon either chemical or mechanical stimulation
FLUSH: a localized red spot, a few mm in diameter, that appears within a few seconds to 1 minute. The reddening is due to HA-induced vasodilation.
FLARE: the reddening extends more slowly to several cm. The flare is due to axonal reflexes that result in an indirect vasodilation.
WHEAL: the skin is raised in the area occupied by the original red spot. The wheal is caused by HA mediated edema via increased capillary permiability.
Histamine Physiological Actions
Extravascular Smooth Muscle
constricts extravascular smooth muscle (H1)
airways ® bronchoconstriction (used diagnostically in bronchial provocation tests)
gastrointestinal ® diarrhea
note how this is different from vascular smooth muscle responses to HA
Histamine Physiological Actions
Gastric Acid Secretion
Gastric Acid secretion
Histamine causes an increase in gastric acid secretion (H2 mediated)
histamine released from gastric mucosal cells
major regulator of gastric acid secretion
Histamine H1 Antagonists
1st Generation
Cross BBB, CNS effects, Sedation, last 4-6 hours
Diphenhydramine
Dimenhydrinate
Doxylamine
Chlorpheniramine
Promethazine
Histamine H1 Antagonists
2nd Generation
Terfenadine
Astemizole
Dont cross BBB, less sedation, last 12-24 hours
Loratidine
Desloratidine(metabolite)
Fexofenadine
Cetirizine
H1 Antagonists Recptors
H1 antagonists act as competitive inhibitors of histamine H1 receptor action
variable antagonistic actions at
a-adrenergic,
serotonin,
dopamine and
muscarinic receptors
(some of these non specific effects are clinically important!)
H1 Antagonists
Therapeutic Uses
1. Anti-Allergy
2. Sedation (1st gen. only)
H1 Antagonists
Therapeutic Uses
Anti-Allergy
Antihistamine activity depends on the contribution of histamine relative to other autacoids

allergic rhinitis, conjunctivitis, edema and urticaria: symptoms in patients that respond

anaphylaxis (an acute allergic response): antihistamines have little effect (only small inhibition of hypotension, no effect on bronchoconstriction)...
however, epinephrine, a physiological antagonist of histamine is a potent blocker of anaphylaxis.

Pharmacological antagonist: blocks one receptor or receptor family

Physiological antagonist: blocks a physiological system
H1 Antagonists
Therapeutic Uses
Sedation
Not just a side effect…
Mediated by CNS H1 and H3 receptors
Requires penetration of the blood brain barrier
Second generation antihistamines (terfenadine, loratadine, astemizole) excluded from CNS hence do not have sedative properties.
Sedative effect useful for treatment of urticarial conditions
Also used as sleep aids
These agents work with variable effect from patient to patient
Histamine Antagonists
Non-H1 mechanisms
KNOW!!!
Know recptor system anticholinergic vs. dopaminergic etc.
--Nonallergic rhinorrhea (anticholinergic) inhibits muscarinic Ach receptors
--Motion sickness prevention (anticholinergic)
--CNS effect (2nd generation antihistamines do not have this property
--Antiparkinson (anticholinergic)
--Antiemetic (antidopaminergic, D2 antagonist)
CNS effect (again)
--Local anesthetic (voltage sensitive sodium channels)
Diphenhydramine and promethazine, for example, are more sensitive than procaine
Useful for patients who are allergic to classical local anesthetics
Dirty drug defn.
Dirty drugs-bind to more than one receptor system, 1st generation antihistamines mostly
H1 Antagonists
Side Effects
LIST
1. Sedation
2. Dry mouth, urinary retention, blurred vision
3. CNS excitation
4. Tolerance
5. GI disturbances
H1 Antagonists
Side Effects
In Detail
Sedation
first generation antihistamines, (esp. ethanolamines) affects 50% of users
second generation antihistamines, e.g. terfenadine, astemizole (affects 7% of users)

Dry mouth, urinary retention, blurred vision
Due to antimuscarinic activity
Not seen in second generation antihistamines as these do not have antimuscarinic

CNS excitation (toxic overdose)
hallucinations, ataxia, convulsions (autonomic symptoms similar to atropine poisoning)

tolerance
increased drug metabolism through induction of liver enzymes (upregulate enzymes)

gastrointestinal (common)
nausea, vomiting, constipation, loss of appetite (can be reduced by giving with a meal)
Torsades de Pointes Defn.
H1 Antagonist Side Effect
Cardiac toxicity
occurs when astemizole or terfenadine is combined with either ketaconazole or erythromycin

manifests as a lengthened QT interval
Leads to an increased action potential duration
early after-depolarizations
ventricular tachycardia
Torsades des Pointes
H1 antagonists side effect
Molecular Effects
Hepatic metabolism of astemizole converts it to a therapeutically active form.
CYP3A4 is the converting enzyme

Astemizole itself, binds to cardiac delayed rectifier potassium channels.
Blocks channel function
Decreased potassium efflux keeps the membrane depolarized for a longer period of time
Macrolide antibiotics such as erythromycin and antifungal agents such as ketoconazole can inhibit CYP3A4.
Overdose of astemizole or terfenadine can cause a similar effect.
Loratadine, fexofenadine, and cetirizine are metabolized by CYP3A4 but are not associated with this effect (don’t bind to rectifier channel)
H2 Antagonists
Therapeutic Effects
Cimetidine, ranitidine, famotidine, and nizatidine
1. Acid reflux
2. Ulcers:
Peptic duodenal, Gastric
3. Zollinger-Ellison syndrome (gastrin secreting tumor)
4. Regulate Stomach acid secretion (by blocking H2 recptors which normally promote GA secretion)
Drugs which block acid secretion through non-H2 mechanisms
pirenzepine
M1 muscarinic antagonist which blocks ACh at the paracrine cell

misoprostol
prostaglandin analog

omeprazole
Covalent inhibitor of the H+K+ ATPase. Omeprazole is a pro-drug which is trapped by H+ ions and converted to its active form
H2 antagonists
Side Effects
Low incidence of side effects. H2 antagonists are poor at crossing the blood brain barrier into the CNS. In other organs, H2 receptors work in conjunction with other receptor systems.
headache, nausea, dizziness
gynecomastia (men), galactorrhea (women), loss of libido (cimetidine)
this occurs through cimetidine function as an androgen receptor antagonist after long term treatment
CNS effects in elderly
delirium, confusion, slurred speech

Cimetidine causes an inhibition of cytochrome P450 oxidative metabolism of other drugs
slows metabolism by mixed function oxidases.
e.g. warfarin, phenytoin, sulfonylureas, and calcium channel blockers
Platelet Activating Factor (PAF)
Biosynthesis
synthesized "de novo" in response to a stimulus such as antigen-antibody reactions, thrombin, collagen, and other autacoids

PAF is synthesized in platelets, neutrophils, monocytes, mast cells, eosinophils, and vascular endothelium
PAF
Physiological Actions
--Complex cardiovascular effects:
vasodilator (potent) --> decreased peripheral vascular resistance -->decreased blood pressure
increased vascular permeability (edema)
synthesized and utilized within the vascular endothelial cell (not secreted)
contraction of vascular endothelium found in post-capillary venules
also increases expression of surface molecules which bind to neutrophils
Vasoconstrictor of coronary vessels.

--potent stimulator of platelet aggregation
Promotes the release of TXA2 and 5HT

--chemotaxis and activation of eosinophils, neutrophils and monocytes

--contracts gastrointestinal, uterine PGE-mediated, and airway smooth muscle LT and TX-mediated peripheral airways

--ulcerogenic (potent); I.V. administration in animal models ® hemorrhagic erosions of gastric mucosa

--involved in ovulation, implantation and labor
rupture of follicle dependent on PAF
PAF from embryo stimulates blastocyst activation and implantation
PAF contracts myometrium (direct + PGE2-mediated) ® labor
PAF
Therapeutic Uses
--Successful implantation and pregnancy in in-vitro fertilization correlates with PAF production by the embryo. (may be used to identify best embryos for implantation).

--In addition, PAF is being used to supplement human embryo growth media and has resulted in a 50% increased success rate
PAF Antagonists
Therapeutic Uses
--*currently under development for treatment of ischemic heart disease.
remember that PAF induces vasoconstriction of coronary vessels.

--PAF receptor antagonists are derived from:
PAF analogs
terpenes isolated from the Chinese tree Ginko biloba
Serotonin
(5-hydroxy-tryptamine, 5-HT)
formed from L-tryptophan

Inactivated by monoamine oxidase (MAO inhibitors ­ serotonin levels).
Serotonin receptor subtypes
Serotonin effects are mediated via a variety of receptor subtypes.
Some are G protein linked and some are linked to ion channels.
For most known serotonin receptors, their physiological functions are unknown
KNOW!:
5HT1D
5HT2A, 5HT2C
5HT3
5HT4
Serotonin
Physiological Actions
LIST
1. CNS neurotransmission
2. Vasoconstriction--
3. Vasodilation: a special case--SKM arterioles, coronary vessels
4. Stimulates ANS
5. Constriction of non-vascular smooth muscle
6. Capillary permeability
7. Platelet Aggregation
8. Migraine Headaches--induces vasospasm
Serotonin
Physiological Actions
CNS Neurotransmission
Most of the many serotonin receptor subtypes identified are found in the CNS

Functions affected by serotonin include sleep, cognition, mood, motor activity, thermoregulation, pain perception, blood pressure control, as well as neuroendocrine effects, and sexual behavior

The majority of serotonergic neurons are found in the Raphe nuclei of the brain stem and project throughout the brain
Serotonin
Physiological Actions
Vasoconstriction
3 distinct Mechanisms:
1. 5-HT acts directly on splanchnic, renal, pulmonary and cerebral vasculature

2. 5-HT also sensitizes vessels to other constrictors, e.g., NE, angiotensin II
G protein coupling to receptors can be modulated by other receptor systems

3. 5-HT facilitates NE release (5HT2A)
Serotonin
Physiological Actions
Vasodilation: a special case
Occurs in skeletal muscle arterioles (SM) and coronary vessels (SM)

5-HT induces the release of NO and prostaglandins from endothelial cells

NO and prostaglandins induce vasodilation (remember HA induced vasodilation)
Serotonin
Physiological Actions
Stimulation of Autonomic System
sensory nerves--> pain, itching (5HT3)
[also inhibition of sensory nerves via 5HT1D]

chemoreceptors, baroreceptors (5HT3) --> ¯ blood pressure, ¯ HR
Serotonin
Physiological Actions
Constriction of non-vascular smooth muscle
regulation of GI motility (5HT2A)
Serotonin is synthesized and stored in enterochromaffin cells of the GI tract and released by mechanical, chemical, or neuronal stimulation
Serotonin acts to ­ GI tone and ­ motility of stomach and large intestine
Enteric nervous system: Serotonergic neurons also regulate GI motility.

Airways--> bronchoconstriction

Uterus -->uterine contractions (contributes to labor)
Serotonin
Physiological Actions
Capillary permeability
Increased capillary permeability (5HT2A)

Edema
Serotonin
Physiological Actions
Platelet Aggregation
Platelets do not synthesize serotonin
Instead, they take up circulating serotonin on passage through intestinal blood vessels.
Uptake is active (requires ATP)

Platelet release of serotonin is regulated(Ca2+ mediated)
The serotonin is stored in vesicles similar to neurotransmitters.
Serotonin is released in response to tissue damage as platelets begin to adhere to the damaged area.

Platelet aggregation requires several signals
Serotonin (supplied by the platelet itself)-autacoid function
Collagen (supplied by the damaged basement membrane)

Platelet aggregation is limited to damaged tissues
When vessel damage occurs and platelets come in contact with the basement membrane, serotonin has a much increased effect on aggregation and thus clotting.
This is primarily due to interactions of the platelets with collagen.

If the vessel is damaged to the point that vascular smooth muscle is exposed, serotonin induces contraction of the smooth muscle, further stopping bleeding
Serotonin
Physiological Actions
Migraine Headaches
cerebral vasospasm -> localized ischemia -> aura + prodromal neurological signs (classic migraine)
vasodilation in the trigeminovascular system (­ flow) ->pain
release of sensory neuropeptides from pain fibers -> local edema and amplification of pain
CNS sensitization: changes in the trigeminal area leading to increased sensitivity to pain
*Spasm of vasculature in the brain, localized lack of nutrients(ischemia) which produces the aura and prodrome
Reflex: vasodilation in the trigeminal region which is what causes the pain
Trigeminal area changes, which leads to increased sensitivity to the pain
Serotonin is what induces the vasospasm
Evidence for Serotonin Involvement in Migraines
Increased 5HIAA in urine of 50% migraineurs during a migraine attack (principal 5HT metabolite)
The majority of serotonergic neurons are found in the dorsal Raphe nuclei and serotonin release is thought to eminate frrom these neurons during the migraine.
5HT in platelets at onset of an attack (falls by 20-40%)
Efficacy of serotonergic drugs (see below).
Triggering of migraine by agents which release 5HT (e.g. reserpine)
Serotonergic Drugs
Methysergide
5HT2A and 5HT2C receptor antagonist
blocks vasoconstrictor effects of 5HT

Therapeutic uses
prophylactic treatment of migraine - probably by antagonistic action at 5HT2C (not 5HT2A because ketanserin has no effect in migraine)
not effective acutely-only works before the migraine
onset and offset of protective effect takes 1 - 2 days
rebound headaches on drug withdrawal
inhibits diarrhea associated with carcinoid syndrome (serotonin-secreting tumor)
Side effects
heart burn, diarrhea, nausea, vomiting (GI effects)
euphoria, hallucinations, psychotic episodes (CNS effects)
retroperitoneal, pericardial, pleural fibrosis limits long-term treatment
Pursue treatment for 4 months, then take 1 month holiday (during which the patient uses another prophylactic agent)
Serotonergic Drugs
Triptans
5HT1D, 5HT1B agonists (no effect on 5HT2 or 5HT3 receptors)
constricts intracranial vessels
attenuates neurogenic inflammation in dura mater (presynaptic inhibition of substance P)
Block of peripheral pain receptors associated with migraine and cluster headaches

Therapeutic uses
acute treatment of migraine
constriction of dilated blood vessels (through 5HT1B receptors) ® decreased pain caused by dilated vessels.
Block of nociceptive pain receptors (through activation of 5HT1D receptors)

Side effects
altered sensations tingling, warmth
dizziness, muscle weakness, neck pain
chest pain/discomfort (5%) contraindicated in patients with ischemic heart disease or variant angina

Sumitriptan
Naratriptan
Rizatriptan
Zolmitriptan
Electriptan
Frovatriptan
Almotriptan malate
Serotonergic Drugs
Ketanserin
ritanserin
competitive 5HT2A antagonist
blocks most 5HT-induced vasoconstriction and platelet aggregation
little effect on blood clotting
ketanserin also blocks a1-adrenergic receptors and D2 receptors.

Therapeutic uses
treatment of vascular diseases thought to involve 5HT released from platelets
intermittent claudication (sticky blood, pre-clotting)
Raynaud's phenomenon (poor circulation in digits)
hypertension
Adrenergic receptor blockade, inhibition of platelet aggregation and inhibition of 5HT-induced facilitation of NE may contribute to beneficial effects in these conditions
Serotonergic Drugs
Ondansetron
Granisetron
5HT3 antagonists

Therapeutic uses
prevention of nausea and vomiting from cancer chemotherapy

Side effects
diarrhea, headache
Serotonergic Drugs
Alosetron
Cilansetron
5HT3 antagonists
Alosetron was withdrawn from US market however it has been re-approved with some restrictions (a very rare event!) because it can cause:
Ischemic colitis
Severely obstructed or ruptured bowels
Cilansetron currently in phase III trials

Therapeutic use
Irritable bowel syndrome (decreases abdominal discomfort)

Side effects
constipation
Serotonergic Drugs
Tegaserod
Prucalopride
5HT4 agonist

Therapeutic uses
Irritable bowel syndrome

Side effects
diarrhea
Ergotism Defn.
Symptoms
Ingestion of ergot alkaloids derived from the fungus: Claviceps purpurea, growth of mold on rye

Symptoms include: acute vasoconstriction leading to gangrene of the limbs, spontaneous abortions, intense nausea and emesis, halucinations/visions
Clinically used ergot alkaloids
ergotamine, ergonovine, methysergide, bromocriptine, dihydroergotamine.
act as agonists/antagonists/partial agonists on 5HT2, a-adrenergic receptors, dopamine receptors
**Just know names of drugs, and that they have various effects on various receptor systems
Ergot alkaloids
Physiological Effects
vasoconstriction
Ergotamine constricts veins and arteries through a-adrenergic receptor and 5HT2 partial agonist activity
Dihydroergotamine is more potent at venous vasoconstriction than arterial constriction.
pregnancy associated effects
Ergonovine and ergotamine ­ force and frequency of uterine contractions (especially at term). Use often results in abortions
Never used to induce or facilitate labor, used instead to control bleeding postpartum or post abortion.
Bromocryptine causes ¯ prolactin secretion (dopamine D2 receptor agonist activity in anterior pituitary).
Numerous ergot alkaloids variably contract gastrointestinal smooth muscle.
Both through direct effects on GI smooth muscle and through alterations of CNS regulation
Ergot alkaloids
Therapeutic effects
Ergotamine or dihydroergotamine are given during the prodrome to treat migraine acutely. This effect is stimulated by caffeine (administered directly with drug).
caffeine does a number of things including:
increase rate of absorption
potentiate vasoconstrictive effect

Ergonovine is used to control late uterine bleeding during post-partum hemorrhage.

Bromocriptine
pituitary tumors or excessive lactation through DA agonist activity.
Dyskinesias associated with Parkinson’s disease
Acromegaly (over production of growth hormone)
Ergot Alkaloids
Side Effects
GI effects: diarrhea, nausea, vomiting (activation of medullary vomiting centers)

gangrene: ergonovine, ergotamine
by prolonged vasoconstriction - Saint Anthony’s Fire, an ancient disease
Eicosinoid Structure
compounds derived from polyunsaturated fatty acids with 20 carbons
include metabolites of cyclooxygenase, lipoxygenase (or epoxygenase).
**If change the structure of the fatty acids, we will change the biological activity of the eicosinoid made
Structure is important and enzymes can process a variety of eicosinoids…three major enzymes
Eopxygenase makes very reactive metabolits
Focus on cyclooxygenase(PG and TXA) and lipoxygenase makes leucotrienes
Eicosinoid Biosynthesis
Eicosanoids are not stored. They are always synthesized de novo.
Eicosanoid synthesis is limited by the availability of free precursor fatty acids
A variety of specific and non-specific stimuli activate the phospholipases including physical stimuli, hormonal stimuli, ­ cytosolic Ca2+
Arachadonic acid—major fatty acid used, which is processed into TXA, PG

The specific prostanoid formed is dependent upon the enzymes present in the cell
TXA synthase:
platelets, macrophages
PGI synthase:
endothelial and smooth muscle cells
Prostanoids
Prostaglandins and Thromboxanes

Biosynthesis
formed by the action of cyclooxygenase (= prostaglandin synthase) on arachidonic acid.
cyclooxygenase I (COX I) predominant form in body
cyclooxygenase II (COX II) inducible form

Cyclooxygenase– arachidonic acid to PGH2. other enzymes turn intermediate into other things:TXA2, PGE2, PGF alpha, PGI2
Predominant form-GI tract
Inducible form—context of inflammation
Prostanoid Receptor Subtypes
different prostaglandin receptor subtypes expressed on different cells determines activity on those cells
Complex relationship b/w ligands and their receptors
PGE can bind to multiple receptors
One recptor that can bind to multiple prostaglandins
Prostanoid Inactivation
Prostanoids are local hormones because they are rapidly inactivated
nonenzymatic degradation: PGI2, TXA2 t1/2 = 30 sec - 3 min.
pulmonary clearance: PGE2, PGF2a
active uptake + metabolism in endothelium, 90% cleared in one passage through lung
Prostanoids
Physiological Actions
(see slide 79 in Autacoids lecture for table)
Competition b/w actions
Prostaglandins important in the renal system in the elderly
TXA2 comes from macrophages
Physiological Actions
PGE2
(see slide 79 in Autacoids lecture for table)
PGE2 Actions:
GI mucus secretion--induce
gastric acid secretion--inhibit
fever(CNS)--induce
afferent nerve activity (pain)-induce
Physiological Actions
PGI2
(see slide 79 in Autacoids lecture for table)
PGI2 Actions: Opposite of TXA2
systemic BVs--dilate
renal BVs--dilate
platelet aggregation--inhibit
immune system--inhibit
Physiological Actions
TXA2
(see slide 79 in Autacoids lecture for table)
TXA2 Actions: Opposite of PGI2
systemic BVs--constrict
renal BVs--constrict
platelet aggregation--induce
immune system--induce
Physiological Actions
PGF2alpha
(see slide 79 in Autacoids lecture for table)
PGF2alpha Actions:
bronchial airway SM: constrict
uterine SM: constrict
Prostaglandin Therapeutic Uses
LIST
1. Severe Peripheral Vascular Disease
2. Pulmonary Hypertension
3. Glaucoma
4. Gastric Ulceration
5. Dialysis
6. Abortion
7. Labor
8. Neonatal heart surgery
Prostaglandin Therapeutic Uses
Severe Peripheral Vascular Disease
Raynaud’s phenomena

PGE1 and PGE2

Dilates blood vessels
Prostaglandin Therapeutic Uses
Pulmonary Hypertension
A rare condition in which the blood pressure in the pulmonary artery is much higher than normal.
The pulmonary artery carries blood from the heart to the lungs for oxygenation.
The heart must work harder to oxygenate the blood leading to heart failure.
This condition has been associated with use of certain diet pills including fenfluramine and dexfenfluramine.

Treatment: PGI2 administered by intravenous infusion or continuous subcutaneous infusion
Prostaglandin Therapeutic Uses
Glaucoma
Increased fluid pressure in the eye

PGF2a analogs:Travoprost, Latanoprost
fatty acid amide: Bimatoprost
Prostaglandin Therapeutic Uses
Gastric Ulcer
prevent ulcers that occur during long-term treatment with aspirin-like drugs
PGE1 and PGE2
Increased secretion of protective mucus (low doses)
Decreased gastric acid secretion (higher doses)
Prostaglandin Therapeutic Uses
Dialysis
Inhibition of platelet aggregation

PGI2

Improves harvest and shape of platelets for storage or transfusion

Not good for treatment of angina: (coronary steal)

Coronary steal—takes blood away from the heart by increasing the circulation elsewhere, heart gets less blood rather than more blood
Prostaglandin Therapeutic Uses
Abortion
PGE2
terminate pregnancy through uterine contractions.
use 1st or 2nd trimester.
compare intravenous vs. intravaginal administration:
intravenous: approx. 80% success and lots of side effects
intravaginal: approx. 100% success and virtually no side effects
Prostaglandin Therapeutic Uses
Labor
Prostaglandins can facilitate labor

as gestation progresses uterine sensitivity to PGs increase
They can initiate and stimulate labor but there is no evidence of advantages over oxytocin
PGF2a and PGE2 are more useful for promoting ripening and dilation of cervix
Prostaglandin Therapeutic Uses
Neonatal Heart Surgery
Correction of congenital heart defects

Dilation of ductus arteriosus in neonates prior to surgery
The ductus arteriosis supplies blood to the lungs early in neonatal development and then closes off.

PGE2
increased blood flow to lung tissue
increased systemic and pulmonary oxygenation
Prostaglandin Side Effects
fever

Diarrhea

bronchoconstriction (beware in asthmatics)
Leukotrienes
Lipoxygenase metabolites

Biosynthesis
formed by the action of 5-lipoxygenase (LO) on arachidonic acid
5-LO located in: neutrophils, monocytes, macrophages, mast cells and also in lung, brain, spleen, heart

5-LO is part of a larger lipoxygenase family
12-LO in platelets (12HETE involved in promotion of myointimal thickening after endothelial cell damage, e.g. angioplasty)
15-LO in eosinophils

5-LO must bind to an activating protein (FLAP) to become fully functional.
Blockade of protein:protein interactions required for signal transduction is the new strategy for design of pharmaceuticals
Specific leukotrienes formed are dependent on the enzymes present in the cell.

LTB4 is the principle metabolite of neutrophils.

LTC4, LTD4, LTE4 are principle metabolites of mast cells
LT Physiological Actions
(see table on slide 96 of Autacoids lecture)
LTB promotes chemotaxis and pain
LTC, D, and E promote hypotension, airway SM contraction, and increase vascular permeability
LT Antagonists
Prophylactic
Zafirlukast, Montelukast
LTD4/LTE4 receptor competitive antagonist

Zileuton
Inhibitor of 5-LO, inhibit all the LTs

Therapeutic uses:
Prevention and management of asthma as an alternative to (or in addition to) inhaled corticosteroids and/or b2 agonists.
Clinical trials indicate that these drugs can also be used to treat seasonal allergic rhinitis and exercise induced asthma.
Inhibition of leukotriene function does NOT equal bronchodilation. Thus these drugs cannot be used to treat acute asthma

Side effects:
Common: headache, stomach upset, nausea
Serious: increased values on liver function tests. Periodic tests recommended. Contraindicated in patients with impaired liver function
Eicosinoids and the Immune System
KNOW!: B and T lymphocytes do not produce eicosanoids.
They do produce arachidonic acid which is then utilized by other cells (e.g., macrophages) to form eicosanoids

The immune system can be modulated by eicosanoids
Prostaglandins suppress immune function
Thromboxanes induce immune function
May have implications for treating cell-mediated organ transplant rejection. PGI2, PGE2 reverse rejection, TXA2 promotes rejection
Diet and Eicosanoids
Dietary manipulation of the fatty acids in the cell membrane can affect the biological activity of metabolites derived from them.

KNOW!: Eicosapentaenoic acid (C20:5) diet (found in fish oil) as an example:
This fatty acid precursor results in the production of a different class of eicosanoids:
PGI3 (vasodilator and antiaggregatory activity = PGI2)
TXA3 (vasoconstrictor and platelet aggregatory activity << than TXA2)
LTB5 (virtually no chemotactic activity)
Prostanoid Effects on Systemic BVs...
Why eating fish oil is good.
PGI2--dilate
TXA2--constrict
PGI3(fish oil)--dilate
TXA3(fish oil)--no effect

Net decrease in the constrictive balance. Shifted balance towards lower BP. This is molecular reason why eating fish oil is good
Bradykinin
Biosynthesis
formed by the action of kallikrein enzymes activated by tissue damage
have a short half-life ≈15s
kininogens are a2-globulins, made in liver, circulating in plasma
kallikrein is activated by tissue damage
80-90% bradykinin destroyed in one passage through the lung
Bradykinin
Physiological Actions
(similar compared to histamine)
Effects are mediated by 2 receptors: B1 and B2
Algesia (B2)
stimulates superficial layers of the spinal cord, thin unmyelinated nerves, and sensory ganglia
Inflammation (B1)
Induces histamine from mast cells
edema by increased permeability of post-capillary venules (separation of endothelial junctions)
blood vessels (B2)
arteriolar dilation through release of nitric oxide or PGI2 from endothelium
Venoconstriction: a direct effect or via release of PGF2a
Contraction of non-vascular smooth muscle (both B1 and B2)
Bronchial, GI, bladder
Bradykinin
Therapeutic Effects
Mediates some of the effects of ACE inhibitors.
kininase II = ACE
ACE inhibitors lower blood pressure by increasing renal blood flow and Na+ excretion
since bradykinin is also metabolized by ACE, ACE inhibitors ­ bradykinin levels
Bradykinin induces the release of prostaglandins such as PGI2 from vascular endothelia.
Prostaglandins function as vasodilators and thus act to reduce blood pressure.
In addition, ­ bradykinin in the lung elicits coughing, thus bradykinin is responsible for this side effect of ACE inhibitor action.

Bradykinins: very potent proinflammatory molecules(increased edema, decrease BP in local region)
Impart/mediate ACE inhibitor action by inducing release of PGs, vasodilate and lower BP
Elicits coughing, SE of ACE inhibitor