prostaglandins, thromboxanes

arachidonic acid (AA)

20 carbon poly-unsaturated fatty acid

precursor to the PG, TX, and leukotrienes

stored in cell’s lipid membrane as a phospholipid

can be metabolized once released by cyclooxygenase/lipoxygenase

phospholipase A2

lipase that regulates the release of AA

activation of this occurs in response to tissue damage, toxin exposure, and hormonal stimulation

glucocorticoids (hydrocortisone)

suppress phospholipase A2 activity

considered anti-inflammatory

how do we determine whether or not AA will be metabolized by cyclooxygenase and/or lipoxygenase?

dependent on cell/tissue type and the type of stimuli

prostaglandin synthesis general process

prostaglandin H2 (PGH2) is converted by specific enzymes to each type of PG

the amount of each specific synthetase released varies from tissue to tissue

the specific type of prostaglandin produced is dependent on where PGH2 is produced

platelets have high concentrations of:

TXA synthetase

TXA2 is released and causes aggregation/vasoconstriction in response to vascular injury

vascular endothelial cells have high concentrations of:

PGI synthetase

PGI2 is produced by uninjured cells to control platelet aggregation/constriction

cyclooxygenase (COX) I

always present in all tissues that produce PG and TX

is involved in: gastric protection, platelet aggregation, inhibition of platelet aggregation (which is COX II mediated), vasoconstriction/dilation

COX II

inducible and present in inflammation

increased amounts are produced in inflammatory and immune cells in response to growth factors, tumor promotors, cytokines, and endotoxins

corticosteroids can inhibit its expression

it is also normally present in certain tissues

PG nomenclature characteristics

see image for nomenclature details

5,6 double bond is always Z/cis

13,14 double bond is always E/trans

enzymatic metabolism and degradation of PG

see image for details

involves beta oxidation of one of the tails

reduction of the 13, 14 DB

changing of the 15 alcohol to a ketone

and addition of a COOH on the end of the second tail

chemical metabolism and degradation of PG

see image for details

involves using water to reduce the epoxide to 2 alcohol groups in thromboxane A2 to B2

using natural PGs as drugs

natural PGs are very potent but:

• susceptible to rapid degradation

• short half life

• effect is dependent on tissue

• not orally active (due to degradation)

• can cause NVD and cramping

generally applied/injected into the desired tissue

using modified PGs as drugs

chemical modification increases half life and ease of delivery

COOH → ester = increased lipophilicity

adding a phenyl/acetylene group increases lipophilicity and prevents oxidation

aprostadil

natural PG that is used to treat ED (urethral suppository) and ductus arterious-dependent congenital heart defects

• ED: causes relaxation of arterial smooth muscle, increasing blood flow

• heart defect: relaxation of ductus so that blood can continue to flow from the pulmonary vein to the aorta

ADME: short duration, ~80% first-pass metabolism

dinoprostone

natural PG that is used to cause cervical ripening and labor induction at or near term (vaginal suppository, endocervical gel), for 2nd trimester pregnancy termination, or for evacuation of uterine contents in fetal death

may take up to 17hrs to work

mechanism: causes uterine contractions

• this is one reason why NSAIDs should not be used in pregnancy

ADME: 95% first pass through lungs, half life 2.5-5min, some systemic absorption, can cause n/v and increased body temp

epoprostenol

natural PG used for primary pulmonary hypertension or scleroderma

mechanism: causes vasodilation of pulmonary and systemic vessel beds and inhibits platelet aggregation - directly opposes TXA2

ADME: 6min half life (continuous infusion required), inactivated through hydrolysis at physiological pH, effect dissipates 2-3min after end of infusion

carboprost

15 methyl PGF2-alpha

modified PG used to treat postpartum bleeding that does not respond to conventional methods (IV oxytocin, uterine massage, IM ergot) or for 2nd trimester abortions

given IM due to 15-methyl 15-OH not converting to ketone

DOA is 4hrs

ADRs: n/v/d, bronchoconstriction, increased body temp

misoprostol

15 methyl PGE1 methyl ester

modified PG used to prevent NSAID-induced gastric ulcers in high risk populations (elderly, debilitating disease, history of gastric ulcers)

ADME: extensively absorbed, rapid hydrolysis to free acid (active form), oxidation of both chains and ring ketone reduction inactivates it, food/antacids decrease absorption, 80% excreted in urine. increased ½ life in renal impairment

mechanism: anti-secretory (decrease gastric acid) and mucosal protective. NSAIDs inhibit PG synthesis in gastric cells which can cause mucosal damage

WARNING: due to PGE2 and PGF2 similarity, it can induce abortions

ADRs: abdominal pain, n/v/d, Increased body temp

treprostinil

PGI2 analog

advantage: chemically stable and can be given SQ continuous infusion outpatient

used to treat pulmonary arterial hypertension (PAH)

mechanism: causes vasodilation and inhibits platelet aggregation

ADME: 100% absorbed SQ, 91% protein bound, extensive CP450 metabolism but does not inhibit major enzymes, major route of elimination is in the urine as metabolites

ADR: infusion site pain/rxn, hypotension

iloprost

PGI2 analog, but note no oxygen-containing ring = stable

16-methyl inhibits oxidation of OH

acetylene group increases lipid nature and inhibits oxidation

used for PAH

causes vasodilation and inhibits platelet aggregation

ADME: inhaled, 60% protein bound, metabolized by beta oxidation of CA chain, eliminated as free and conjugated metabolites in urine

ADR: hypotension

travoprost

F series modified PG ophthalmic analog with an isopropyl ester and aromatic ring

used to decrease IOP in pts with open-angle glaucoma and ocular hypertension who are intolerant to other agents

MOA: selective PF receptor and increases outflow

ADME: absorbed across the cornea, hydrolyzed by esterase, metabolized by beta oxidation

ADR: well tolerated, eyelid rim, eyelashes and pigmented eye tissue may darken

bimatoprost

F series modified PG analog with an amide and an aromatic ring

used to decrease IOP in pts with open-angle glaucoma and ocular hypertension who are intolerant to other agents AND for eyelash browth

MOA: same as travoprost, but not a prodrug

ADME: absorbed across the cornea, redistribution leads to metabolism of inactive metabolites, parent and metabolites excreted via urine/feces

ADR: same as travoprost

latanoprost

F series modified PG analog with a 13-14 DB isopropyl ester and an aromatic ring

use, MOA, and ADR same as travoprost

ADME: absorbed across cornea, ester hydrolyzed to free acid, eliminated in urine

no ketone metabolite observed

½ life: aqueous humor 4h, plasma 1h

unoprostone

F series modified PG analog, no 13-14 DB or 15 ketone

uses, MOA, ADR same as others in the class

ADME: absorbed across cornea, hydrolyzed to free acid

low levels of free acid/ester in systemic circulation

excreted primarily unchanged

talfluprost

F series modified PG analog with a fluorine replacing the 15 OH

uses, MOA, ADR same as others in hte class

ADME: absorbed across cornea, hydrolyzed to free acid, low level of free acid/ester in circulation, metabolized in liver by beta oxidation and eliminated in urine