The Arachidonic Acid Cascade

The Arachidonic Acid Cascade

Sandra P. Welch, Ph.D. Professor Pharmacology & Toxicology S m i t h 7 3 4 , 8 2 8-8 4 2 4 , s w e l c h @ h s c . v c u . e d u

A r a c h i d o n i c A c i d M e t a b o l i s m - S y n t h e s i s a n d A c t i o n o f P r o s t a g l a n d i n s ( P G s ) , T h r o m b o x a n e ( T x ), Leukotrienes (LTs), Epoxyeicosatrienoic Acids (EETs) and Anandamide glutamic acid

“B O U N D ” PHOSPHOLIPID ARACHIDONIC ACID

leukotriene C

glycine

LTD

4

Learning Objectives: After studying this material, the student LTE

4

LT receptor blockers

4

leukotriene B 4 ( d i h y d r o x y ) ↑ chemotaxis

neurotransmitters

PH

ACh, NE, etc. bradykinin

+

thrombin trauma

Epoxyeisatrienoic

↑ vascular permeability ↑ neutrophil secretion

b r o n c h . s.m. contraction

Acids (EETs) ↑ C a2+ i n f l u x

O

SP

others

glutathione

H

O

IP

AS

vasodilation i n h i b N a-K A T P a s e mitogenic

5 LO inhibitor HPETE

L

antiinflammatory steroids “B l i s s ”

should:

↑ WBC stickiness

(Zafirlukast, Montelukast)

(z i l e u t o n )

5 -, 12-, or 15lipoxygenase (LO)

E

O2

K n o w t h e f a t t y a c i d p r e c u r s o r f r o m w h i c h t h e 2 -s e r i e s o f

p r o s t a g l a n d i n s ( P G2 ) i s m a d e .

8,9-E E T

“F R E E ”

enzyme uncertain

1.

5,6-E E T

P 4 5 0 monooxygenase “epoxygenase”

COOH

O2

1 1 , 1 2-E E T

2.

Know the 4 major enzyme pathways for production of

Anandamide 1 4 , 1 5-E E T

(arachidonyl

1 ( C O X -1) - constitutive

ethanolamine

ethanolamide)

O2

cycloA s p i r i n - irreversible O t h e r N S A I D s - reversible

oxygenase PGG2

Binds to marijuana ( ∆

9-

hydroperoxidase

THC)

P G Synthase 2 ( C O X -2), inducible, ↑ during inflammation

c y c l o o x e n a s e plus hydroperoxidase

receptor biologic effects

oxygen radicals

PGH2

biochemical/ physiological/

arachidonic acid metabolites.

i s o m e r a s e , reductase

s e l e c t i v e C O X -2 inhibitors, e.g. celecoxib (Celebrex ®) blocks only COX -2, therefore less GI and platelet effects

v a s c u l a t u r e - I 2 synthase

3.

Understand the actions of the enzymes phospholipase

and cyclooxygenase and how steroids, aspirin and aspirin substitutes affect these enzymes.

platelet - T x synthase ( P 4 5 0 )

behavioral effects

5.

P G E 2 , P G F 2 α, P G D 2 vasodilation

↓ gastric acid

↑ v a s c . permeability sensitize to pain

↑ gastric mucous C a2+ m o b i l i z a t i o n

↑ body temperature uterine contraction

↑ N a + H 2O excretion

P G I 2 (t

1

/2 = 5 m i n )

Thromboxane A

inhibits platelet aggregation vasodilation

2

(t

1

4.

/2 = 3 0 s e c )

induces platelet aggregation smooth muscle contraction

6 -k e t o-P G F 1 α

TxB2

+

stimulates

Understand the difference between cyclooxygenase 1

( C O X -1 ) a n d c y c l o o x y g e n a s e 2 ( C O X -2 ) . 6.

Know the importance of and the point at which oxygen

radicals are formed in the arachidonic acid metabolic pathway. 7.

Know the major cyclooxygenase products (no

structures required) and give the major known biological activity or activities of the more important cyclooxygenase products. 8.

Be able to describe the major effects of prostaglandins

in the CNS

Know the difference between how aspirin and aspirin

substitutes affect cyclooxygenase enzyme activity. blocks

9.

U n d e r s t a n d h o w P G E 2 , P G F2 a , P G I 2 a n d T x A 2 c a n

a f f e c t v a s c u l a r a n d n o n -v a s c u l a r s m o o t h m u s c l e t o n e . 10.

Know how prostaglandins affect gastric function.

11.

Understand how cyclooxygenase inhibitors and PGI 2

(p r o s t a c y c l i n ) a f f e c t p l a t e l e t f u n c t i o n a n d t h u s a f f e c t hemostasis . 12.

Be able to provide three lines of reasoning which

support the importance of prostaglandins in inflammation.

I. 13.

1930's

Know the name of the enzyme or enzyme

History Discovered by K u r z o k & Lieb

systems responsible for the synthesis of leukotrienes

Characterized and named by Goldblatt & von Euler,

and H E T E s and know the major biological effects of

thought substances came from prostate gland, hence the

the products of these enzyme systems.

n a m e p r o s t a g l a n d i n ( a b b r e v i a t e d P G) 1960

Bergstrom - elucidated chemical structure

1971

Vane - discovered that MOA of aspirin is

of PGs 14.

Be able to describe the role of lipoxygenase

products in immediate hypersensitivity reactions and

inhibition of PG formation

asthma. Also know the major lipoxygenase enzyme

mid 1970s - 80s

inhibitor and the major antagonist of the leukotriene

S a m u e l s s o n - elucidated

structure of t h r o m b o x a n e and lipoxygenase metabolites

receptor.

1982

Bergstrom, Vane & S a m u e l s s o n share

Nobel Prize for work in elucidation of the "Arachidonic 15.

Acid Cascade"

Be aware of the possible role and function of

1980’s Epoxygenase pathway elucidated and

anandamide (arachidonyl ethanolamide) on

functions studied

cannabinoid (marijuana) receptors.

1992

Anandamide (arachidonyl ethanolamide)

discovered

II.

Function

III.

Substrates

Formed from polyunsaturated fatty acids Modulation of cell function Arachidonic acid metabolites are found in virtually all cells and tissues. Each cell type appears to have a characteristic

(PUFA). Phospholipases release the PUFA precursors

balance of metabolites.

from phospholipids.

C o m p o u n d s a r e s y n t h e s i z e d locally , o n d e m a n d , a n d

These PUFA can then be metabolized by

are not stored for future release.

cyclooxygenase, lipoxygenase enzymes or

T h e y act locally i n t h e a r e a i n w h i c h t h e y a r e f o u n d

P 4 5 0 “ e p o x y g e n a s e ”.

and in general do not have distant sites of action, as do many other types of chemical modulators or hormones.

III. 20:3

Substrates IV.

(di -h o m o -g -l i n o l e n i c a c i d ) , n o t v e r y p r e d o m i n a n t i n

n a t u r e , f o r m s P G1 20:4

Synthesis of Arachidonic Acid Metabolites

(a r a c h i d o n i c a c i d , e i c o s a t e t r a e n o i c a c i d ) f o r m s P G2 , 2 double bonds, predominant in nature. Metabolites of eicosatetraenoic acid are referred to as ‘eicosanoids”.

A. 20:5

(e i c o s a p e n t a e n o i c a c i d ) f o r m s P G3 , 3 double bonds. Eicosapentaenoic acid (EPA)

abundant in fish oil and increased in those who consume increased amounts of fish. Eicosapentaenoic acid can compete with arachidonic acid for enzyme metabolism. Increased EPA reduces formation of the P G2 s e r i e s .

Four General Pathways of Arachidonic Acid Product Formation



leukotriene C

1.

glycine

LTD

4

LTE

4

4


leukotriene B 4 ( d i h y d r o x y ) ↑ chemotaxis

PH


+

thrombin



Epoxyeisatrienoic

c y c l o o x y g e n a s e 2 ( C O XX- 2 ) .

Acids (EETs)

C O XX- 1 i s

↑ C a2+ i n f l u x

O

trauma

SP

glutathione

H

others

O

L

IP

AS




2

↑ WBC stickiness


neurotransmitters

c y c l o o x y g e n a s e – 2 i s o f o r m s, c y c l o o x y g e n a s e 1 ( C O XX- 1 ) a n d

(z i l e u t o n )

normally present in brain and kidney and is

5,6-E E T


E

n o r m a l l y p r e s e n t i n m o s t t i s s u e s . C O XX- 2 i s

O2

8,9-E E T

“F R E E ”

enzyme uncertain


COOH

O2

induced in most tissues during inflammation

1 1 , 1 2-E E T


(arachidonyl


ethanolamine

ethanolamide)

Binds to m a r i j u a n a ( ∆ 9- T H C )

O2

1

4

A s p i r i n - irreversible O t h e r N S A I D s - reversible

oxygenase

P G Synthase -

PGG2

2 ( C O X -2), inducible, ↑ during inflammation

hydroperoxidase

and injury.

3

cyclo-

c y c l o o x e n a s e plus hyfroperoxidase


oxygen radicals


PGH2





behavioral effects

P G E 2 , P G F 2 α, P G D 2

P G I 2 (t

vasodilation

↓ gastric acid





1

/2 = 5 m i n )

Thromboxane A


2

(t

1

/2 = 3 0 s e c )

induces platelet aggregation smooth muscle contraction blocks


TxB2

+

stimulates



leukotriene C

glycine

LTD

4

LTE

4


4

leukotriene B 4 ( d i h y d r o x y ) ↑ chemotaxis ↑ WBC stickiness


neurotransmitters

PH


+

thrombin trauma

Cyclooxygenase

Arachidonic Acid

O

SP

glutathione

H

O


L

IP

AS

antiinflammatory steroids


(z i l e u t o n )

E

O2

8,9-E E T

“F R E E ”

enzyme uncertain

•O O

5,6-E E T


“P

ro S y stag nt l h a and s e in ” Cyclooxygenase


others

“B l i s s ”

Epoxyeisatrienoic




COOH

O2

1 1 , 1 2-E E T


(arachidonyl

O


ethanolamine

ethanolamide)

O2


oxygenase PGG2

Binds to

hydroperoxidase

m a r i j u a n a ( ∆ 9- T H C )

O


c y c l o o x e n a s e plus hydroperoxidase

biologic effects

oxygen radicals

PGH2





Hydroperoxidase

O OH

Pg G2

receptor

O


behavioral effects

P G E 2 , P G F 2 α, P G D 2

P G I 2 (t

vasodilation

↓ gastric acid





1

/2 = 5 m i n )


Thromboxane A

2

(t

1

/2 = 3 0 s e c )

O



TxB2

+

Pg H2

stimulates

OH



2.

lipoxygenase

leukotriene C

glycine

LTD

4

LTE

4


4



neurotransmitters

PH


+

thrombin trauma


O

SP

others

glutathione

H

O

IP

AS



L


Epoxyeisatrienoic



(z i l e u t o n )

5,6-E E T


E

O2

8,9-E E T

“F R E E ”

enzyme uncertain


COOH

O2

1 1 , 1 2-E E T


(arachidonyl


ethanolamine

ethanolamide)

O2


oxygenase PGG2

Binds to

hydroperoxidase

m a r i j u a n a ( ∆ 9- T H C )


c y c l o o x e n a s e plus lipoxygenase


oxygen radicals

PGH2






behavioral effects


↓ gastric acid





P G I 2 (t

1

/2 = 5 m i n )


Thromboxane A

2

(t

1

/2 = 3 0 s e c )



TxB2

+

stimulates



leukotriene C

4



PH


P - 4 5 0 m o n o o x y g e n a s e “e p o x y g e n a s e ”

LTE

4


neurotransmitters

3.

glycine

LTD

4

+

thrombin


O

trauma

SP

glutathione

H

others

O

IP

AS



L


Epoxyeisatrienoic



(z i l e u t o n )

5,6-E E T


E

O2

8,9-E E T

“F R E E ”

enzyme uncertain


COOH

O2

1 1 , 1 2-E E T


(arachidonyl


ethanolamine

ethanolamide)

O2


oxygenase

P G Synthase -

PGG2

Binds to

2 ( C O X -2), inducible, ↑ during inflammation

hydroperoxidase

m a r i j u a n a ( ∆ 9- T H C )



oxygen radicals


PGH2





behavioral effects

P G E 2 , P G F 2 α, P G D 2

P G I 2 (t

vasodilation

↓ gastric acid





1

/2 = 5 m i n )

Thromboxane A


2

(t

1

/2 = 3 0 s e c )



TxB2

+

stimulates



leukotriene C

anandamide

LTE

4


4



neurotransmitters

4.

glycine

LTD

4

PH


+

thrombin trauma


O

SP

others

glutathione

H

O

IP

AS



L


Epoxyeisatrienoic



(z i l e u t o n )

5,6-E E T


E

O2

8,9-E E T

“F R E E ”

enzyme uncertain


COOH

O2

1 1 , 1 2-E E T


(arachidonyl


ethanolamine

ethanolamide)

O2


oxygenase PGG2

Binds to

hydroperoxidase

m a r i j u a n a ( ∆ 9- T H C )




oxygen radicals

PGH2






behavioral effects

B.

Synthesis and Action of

Prostaglandins, Thromboxane, Leukotrienes, Epoxyeicosatrienoic Acids and Anandamide


↓ gastric acid





V.

P G I 2 (t

1

/2 = 5 m i n )


Thromboxane A

2

(t

1

/2 = 3 0 s e c )



TxB2

+

Inhibitors of Arachidonic acid (AA) Metabolism

stimulates

A.

Cyclooxygenase Pathway

S u m m a r y o f t h e A c t i o n o f N o n-s e l e c t i v e v s . C O X -2 S e l e c t i v e I n h i b i t o r s

N o n -s t e r o i d a l a n t i -i n f l a m m a t o r y d r u g s ( N S A I D s ) i n h i b i t c y c l o o x y g e n a s e

C O X -1 & C O X -2 i n h i b i t o r s Aspirin (irreversible) & other (reversible) nonselective N o n -s t e r o i d a l a n t i -i n f l a m m a t o r y d r u g s (N S A I D s)

metabolism. Aspirin - irreversibly acetylates cyclooxygenase 1 and 2

C y c l o o x y g e n a s e 1 ( C O X -1) constitutive - m e a n i n g

Most other NSAIDs - reversibly, competitively inhibit cyclooxygenase 1 and 2

(– )

(– )

enzyme always there. Found in virtually all cells,

kidney), is induced to form in inflammatory cells during

including platelets and GI mucosa inhibitors, e.g. C e l e c o x i b (Celebrex ®)

( C e l e b r e x ® ) – r e v e r s i b l y , c o m p e t i t i v e l y , i n h i b i t C O X -2 , w h i c h i s n o r m a l l y i n f l a m m a t i o n . R e l a t i v e l y l i t t l e e f f e c t o n C O X -1 , w h i c h i s p r e s e n t i n m o s t

inflammation C O X -2 s e l e c t i v e

Selective cyclooxygenase 2 (COX - 2) inhibitors – Celecoxib present in brain and kidney and is induced in other tissues duri ng

C y c l o o x y g e n a s e 2 ( C O X -2) inducible, i.e. not present all the time (except brain &

(– )

R o f e c o x i b (V i o x x ®) Thromboxane A 2 (platelets → → aggregation)

Constitutive PGs (includes GI → → protective)

tissues and important to protect GI mucosa and induce platelet aggregation.

Induced PGs (includes pro -i n f l a m m a t o r y P G s )

Structures of Cyclooxygenase (COX) Isoenzymes COX-1

No Inhibition of COX-1 by Celecoxib at Therapeutic Concentrations COX-1

COX-2

Active site Active site

Active site

Hydrophobic channel

Arachidonic acid

“Side pocket” Hydrophobic channel N N

Celecoxib

Inhibition of COX-2 by Celecoxib COX-2 B.

Lipoxygenase Pathway

Agents which have been tested and found effective at reducing the occurrence of asthmatic symptoms and the need Active site

f o r b e t a -a g o n i s t s t o p r o d u c e b r o n c h i o l a r d i l a t i o n i n c l u d e

Celecoxib

z i l e u t o n (Z y f l o ® ) , a 5 -l i p o x y g e n a s e e n z y m e i n h i b i t o r, a n d N Arachidonic acid

z a f i r l u k a s t (A c c o l a t e ® ) a n d m o n t e l u k a s t (S i n g u l a i r ® ) ,

N

competitive leukotriene receptor blockers. “Side pocket”

A.

Nervous System

PgE 2 Facilitates

PGs are thought to be modulators of neuronal activity. They can increase or decrease

Stimulus

release of neurotransmitters and cause changes in

VI.

Biological Actions of Metabolites of Arachidonic Acid

Nociceptor

behavior.

PgE2

PGs can also sensitize pain receptors.

Hypothalamus

Anandamide binds to marijuana receptors and

IL-1ββ

causes analgesia and decreased locomotion. PGs given intraventricularly into the brain can induce

Inflammation

fever.

B.

1.

Smooth Muscle

Bronchial and Tracheal

L T C4 a n d L T D 4 a r e v e r y p o t e n t c o n t r a c t o r s o f a i r w a y

Vascular a.

2.

P G I2 i s t h e p r e d o m i n a n t P G p r o d u c e d b y

vascular tissue, mainly by e n d o t h e l i u m .

smooth muscle. The release of these compounds by leukocytes, resident macrophages or mast cells is important in generation of the

b.

PGI 2 a n d P G E 2

- relax muscle,

vasodilation c.

increased airway resistance in asthma and immediate hypersensitivity reactions.

T h r o m b o x a n e A 2 ( T x A 2 ) a n d L T C4 -

contracts

muscle, vasoconstriction

4.

Uterine

PGs cause contraction of uterine smooth muscle.

3.

GI PGs are approved for induction of abortion and also for i n d u c t i o n o f f u l l -t e r m l a b o r .

Generally PGs increase contraction and motility . This is often a side effect following the administration of PGs in other body areas.

Normal uterine production of PGs is thought to contribute to menstrual cramping. The NSAID ibuprofen is effective in reducing cramping. The MOA of this agent is likely the inhibition of formation of contractile PGs, in addition to ibuprofen's analgesic effect.

C.

Hemostasis 2.

1.

Vasculature

-

PGI 2 i s a v e r y p o t e n t i n h i b i t o r o f p l a t e l e t a g g r e g a t i o n

Blood platelets are prolific

induced by ADP, collagen or epinephrine.

metabolizers of AA.

Since PGI 2 is formed by the vascular wall PGI 2 is

P G e n d o p e r o x i d e s ( P G G2 , P G H2 ) a n d

hypothesized to be an important in vivo inhibitor of

T x A2 a r e p r o d u c e d b y p l a t e l e t s a n d

platelet aggregation.

t h e s e c o m p o u n d s induce platelets to adhere to one another, thus inducing

There is evidence that very low doses of oral aspirin (1/8 -

p l a t e l e t a g g r e g a t i o n. n.

1 / 4 t a b l e t ) m a y a c h i e v e a s e m i -s e l e c t i v e i n h i b i t i o n o f platelet but not arterial cyclooxygenase.

Aspirin and other NSAIDs (except

This would

m a x i m i z e t h e a n t i -t h r o m b o t i c e f f e c t o f a s p i r i n s i n c e P G I 2

selective COX - 2 inhibitors) double

inhibits platelet aggregation.

bleeding time because they inhibit the f o r m a t i o n o f t h e s e p r oo- a g g r e g a t o r y cyclooxygenase enzyme metabolites.

E.

GI Function

P G E 2 a n d P G I2 inhibit gastric acid secretion

D.

Kidney Function

T h e k i d n e y p a p i l l a i s r i c h i n A A . PGI 2 a n d P G E

induced by feeding, histamine or gastrin.

2

given into the

renal artery produce diuresis and increase Na+ and K+ e x c r e t i o n. n.

PGs also increase GI mucous secretion. I n h i b i t i o n o f P G s b y N S A I D s ( e x c e p t s e l e c t i v e C O X -2 i n h i b i t o r s ) w i l l t h e r e f o r e h a v e p r oo- u l c e r o g e n i c e f f e c t s

N S A I D s c a n a l t e r k i d n e y f u n c t i o n. n. T h e m e c h a n i s m s b y which PGs alter renal function are not certain, but likely involve redistribution of intrarenal blood flow and a change in tubular transport.

(increased acid, decreased mucous). F o r t h i s r e a s o n , s t a b l e P G a n a l o g s (M i s o p r o s t o l ® ) a r e n o w u s e d i n a n t i -u l c e r t h e r a p y . A l s o , s e l e c t i v e C O X -2 i n h i b i t o r s , w h i c h d o n o t d e c r e a s e G I s y n t h e s i s o f p r o t e c t i v e P G s b y C O X -1 , a r e a v a i l a b l e .

G. F.

Endocrine System

Exogenous PGs can stimulate the release of several hormones. However the exact role of PGs in endocrine function has not been adequately explored.

PGs are known,

however, to stimulate calcium metabolism and bone r e s o r p t i o n. n.

Inflammation

There is little doubt that arachidonic acid metabolites are important in inflammation. Evidence supporting this conclusion includes that: 1.

e x o g e n o u s P G s a n d LTs c a n p r o m o t e i n f l a m m a t i o n .

2.

P G s a n d L T s a r e f o u n d i n i n f l a m m a t o r y e x u d a t e s. s.

3.

drugs which inhibit cyclooxygenase, reduce inflammation.

Arachidonic acid metabolites contribute to inflammation by: 1.

increasing capillary permeability

2.

inducing local vasodilation and

H.

Commercial Preparations

thus redness 3.

promoting infiltration of inflammatory cells

4. p r o d u c t i o n o f t i s s u e i n j u r i n g o x y g e n f r e e r a d i c a l s d u r i n g t h e s y n t h e s i s o f P G s a n d LTs 5.

p r o d u c i n g i n f l a m m a t i o n -a s s o c i a t e d

hyperalgesia (increased pain)

1.

Aloprostadil (PGE1)

can be used in infants with congenital heart defects in order

2.

to increase pulmonary blood flow until definitive surgery can

C a r b o p r o s t ( 1 5 - m e t h y l P G F2 a )

be performed. induces second trimester abortion. It is a more powerful It is also marketed as Caverject® to treat penile erectile

uterine contractor than oxytocin. The methyl group is present to prevent oxidation.

dysfunction of neurogenic , vasculogenic or psychogenic origin. It causes erection by causing arterial dilation and occlusion of venous outflow.

D i n o p r o s t ( P G F2 a ) t r o m e t h a m i n e i s u s e d i n t r a -a m n i o t i c a l l y t o i n d u c e a b o r t i o n , u s u a l l y i n p r e g n a n c y o f

3.

longer than 15 weeks.

5.

Misoprostol (PGE1) and numerous P G a n a l o g s ( a r b a p r o s t i l , e n p r o s t i l , e n i s o p r o s t, t, deprostil , rioprostil, trimoprostil )

4. D i n o p r o s t o n e ( P G E2 ) i s u s e d i n s u p p o s i t o r y form to induce abortion in pregnancies of less than 28 weeks. I t i s a l s o u s e d t o i n d u c e f u l l -t e r m l a b o r .

inhibit gastric acid and stimulate gastric mucous secretion; this may be inversely related to the mechanism of the gastrointestinal damage that f o l l o w s e x p o s u r e t o n o n -s e l e c t i v e n o n s t e r o i d a l a n t i inflammatory drugs (NSAIDs).

These protective agents are used for the treatment of gastrointestinal ulceration by virtue of their cytoprotective effects on the gastric mucosa. 6. a.

Misoprostol is rapidly absorbed and metabolized in the liver and excreted in the urine. It has a halfhalf -life of less than 30 minutes.

b.

When administered chronically, misoprostol can prevent gastric ulceration caused by NSAIDs.

c.

Dose -related diarrhea can occur in as many as 40% of patients taking misoprostol misoprostol..

Latanoprost

- used for treatment of glaucoma,

acts by decreasing production of intraocular fluid. Works as well as timolol , but has side effect of turning blue eyes brown! Effectiveness and side effects of long term use is less certain.

d. Misoprostol is contraindicated for ulcers during pregnancy. It causes bleeding in 40% of women and, in a lower percentage, partial part ial or complete expulsion of the products of conception.

7.

The French abortion pill

M i f e p r i s t o n e ( R UU- 4 8 6 ,

“morning after pill”) must be taken within 9 weeks of the last m e n s t r u a l p e r i o d . R U -4 8 6 b l o c k s p r o g e s t e r o n e r e c e p t o r s causing the uterus to reject the implanted egg.

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Drugs to Remember: A l o p r o s t a d i l ® M o n t e l u k a s t – S i n g u l a i r® M i s o p r o s t o l® C e l e c o x i b - C e l e b r e x ®

Two days after taking Mifeprestone the woman is given a prostaglandin which causes the cervix to soften and dilate and the uterus to contract and expel the embryo.

PGs are also

used similarly to induce uterine expulsion of the embryo after giving the cytotoxic agent methotrexate.

Recommended Reading: 1.

B a s i c a n d C l i n i c a l P h a r m a c o l o g y , B.G. K a t z u n g , 8th ed., 2001.

2.

Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition, 2001.

Z i l e u t o n - Z y f l o®

R o f e c o x i b - V i o x x®

Zafirlukast - Accolate®