Page 344 - Basic _ Clinical Pharmacology ( PDFDrive )

330 SECTION IV Drugs with Important Actions on Smooth Muscle

of TXA . Theoretically, TXA synthase inhibitors or receptor with COX inhibitors may be due, in part, to increased release of
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antagonists should improve renal function in these patients, but norepinephrine as well as to inhibition of the endothelial synthesis
no such drug is clinically available. Hypertension is associated of the vasodilators PGE and PGI . PGE and PGI sensitize the
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with increased TXA and decreased PGE and PGI synthesis in peripheral nerve endings to painful stimuli. PGE acts via EP
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some animal models, eg, the Goldblatt kidney model. It is not and EP receptors to potentiate excitatory cation channel activity
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known whether these changes are primary contributing factors and inhibit hyperpolarizing K channel activity, thereby increas-
or secondary responses. PGF may elevate blood pressure by ing membrane excitability. Prostaglandins also modulate pain
2α
regulating renin release in the kidney. Although more research is centrally. Both COX-1 and COX-2 are expressed in the spinal
necessary, FP antagonists have potential as novel antihypertensive cord and release prostaglandins in response to peripheral pain
drugs. stimuli. PGE , and perhaps also PGD , PGI , and PGF , con-
2α
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tribute to so-called central sensitization, an increase in excitability
D. Reproductive Organs of spinal dorsal horn neurons, that augments pain intensity, wid-
1. Female reproductive organs—Animal studies demonstrate ens the area of pain perception, and results in pain from normally
a role for PGE and PGF in early reproductive processes such as innocuous stimuli. PGE acts on the EP receptor to facilitate pre-
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ovulation, luteolysis, and fertilization. Uterine muscle is contracted synaptic release of excitatory neurotransmitters and block inhibi-
by PGF , TXA , and low concentrations of PGE ; PGI and high tory glycinergic neurotransmission as well as postsynaptically to
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2α
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concentrations of PGE cause relaxation. PGF , together with enhance excitatory neurotransmitter receptor activity.
2α
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oxytocin, is essential for the onset of parturition. PGI also assists
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in promoting uterine smooth muscle cell maturation. The effects F. Inflammation and Immunity
of prostaglandins on uterine function are discussed below (see PGE and PGI are the predominant prostanoids associated with
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Clinical Pharmacology of Eicosanoids). inflammation. Both markedly enhance edema formation and
leukocyte infiltration by promoting blood flow in the inflamed
2. Male reproductive organs—Despite the discovery of pros- region. PGE and PGI , through activation of EP and IP, respec-
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taglandins in seminal fluid, the role of prostaglandins in semen is tively, increase vascular permeability and leukocyte infiltration.
still conjectural. The major source of these prostaglandins is the Through its action as a platelet agonist, TXA can also increase
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seminal vesicle; the prostate, despite the name “prostaglandin,” platelet-leukocyte interactions. Although probably not made by
and the testes synthesize only small amounts. The factors that lymphocytes, prostaglandins may potently regulate lymphocyte
regulate the concentration of prostaglandins in human seminal function. PGE and TXA may play a role in T-lymphocyte devel-
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plasma are not known in detail, but testosterone does promote opment by regulating apoptosis of immature thymocytes. PGI
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prostaglandin production. Thromboxane and leukotrienes have contributes to immune suppression by interfering with dendritic
not been found in seminal fluid. Men with a low seminal fluid cell maturation and antigen uptake for presentation to immune
concentration of prostaglandins are relatively infertile. cells. PGE suppresses the immunologic response by inhibiting
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Smooth muscle-relaxing prostaglandins such as PGE enhance differentiation of B lymphocytes into antibody-secreting plasma
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penile erection by relaxing the smooth muscle of the corpora cells, thus depressing the humoral antibody response. It also inhib-
cavernosa (see Clinical Pharmacology of Eicosanoids).
its cytotoxic T-cell function, mitogen-stimulated proliferation of
T lymphocytes, and maturation and function of Th1 lympho-
E. Central and Peripheral Nervous Systems cytes. PGE can modify myeloid cell differentiation, promoting
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1. Fever—PGE increases body temperature, predominantly via type 2 immune-suppressive macrophage and myeloid suppressor
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EP , although EP also plays a role, especially when administered cell phenotypes. These effects likely contribute to immune escape
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directly into the cerebral ventricles. Exogenous PGF and PGI in tumors where infiltrating myeloid-derived cells predominantly
2α
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induce fever, whereas PGD and TXA do not. Endogenous pyro- display type 2 phenotypes. PGD , a major product of mast cells, is
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gens release interleukin-1, which in turn promotes the synthesis a potent chemoattractant for eosinophils in which it also induces
. This synthesis is blocked by aspirin, other
and release of PGE 2 degranulation and leukotriene biosynthesis. PGD 2 also induces
antipyretic NSAIDs, and acetaminophen. chemotaxis and migration of Th2 lymphocytes, mainly via activa-
tion of DP , although a role for DP has also been established. It
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2. Sleep—When infused into the cerebral ventricles, PGD remains unclear how these two receptors coordinate the actions of
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induces natural sleep (as determined by electroencephalographic PGD in inflammation and immunity. A degradation product of
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analysis) via activation of DP receptors and secondary release of PGD , 15d-PGJ , at concentrations actually formed in vivo, may
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adenosine. PGE infusion into the posterior hypothalamus causes also activate eosinophils via the DP (CRTh2) receptor.
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wakefulness. 2
3. Neurotransmission—PGE compounds inhibit the release G. Bone Metabolism
of norepinephrine from postganglionic sympathetic nerve end- Prostaglandins are abundant in skeletal tissue and are produced by
ings. Moreover, NSAIDs increase norepinephrine release in vivo, osteoblasts and adjacent hematopoietic cells. The major effect of
suggesting that the prostaglandins play a physiologic role in prostaglandins (especially PGE , acting on EP ) in vivo is to increase
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this process. Thus, vasoconstriction observed during treatment bone turnover, ie, stimulation of bone resorption and formation.