I.

Answer the following questions:

1. Pharmacokinetics and pharmacodynamics of Furosemide, Hydrochlorothiazide,

Clopamide, Ethacrynic Acid, osmotic diuretics (Mannitol). Indications for use, side effects. The
concept of forced diuresis
Ans:
Pharmacokinetics, sometimes described as what the body does to a
drug, refers to the movement of drug into, through, and out of the body—the
time course of its absorption, bioavailability, distribution, metabolism, and
excretion.

Four phases of pharmacokinetics

The main processes involved in pharmacokinetics are absorption, distribution, and the two routes of
drug elimination, metabolism and excretion. Together they are sometimes known by the acronym
'ADME'
They are absorption, distribution, metabolism, and excretion. Each of these processes is
influenced by the route of administration and the functioning of body organs
The pharmacokinetic characteristics can be quantitatively expressed by its parameters, such
as the elimination rate constant (denoted as K), half-life (t 1/2), apparent volume of distribution (V d)
and total clearance rate (CL)

Pharmacokinetics of a drug depends on patient-related factors as well as on the drug’s chemical

properties. Some patient-related factors (eg, renal function, genetic makeup, sex, age) can be
used to predict the pharmacokinetic parameters in populations. For example, the half-life of some
drugs, especially those that require both metabolism and excretion, may be remarkably long in
older people (see figure Comparison of pharmacokinetic outcomes for diazepam in a younger man
[A] and an older man [B]). In fact, physiologic changes with aging affect many aspects of
pharmacokinetics (see Pharmacokinetics in Older Adults  and Pharmacokinetics in Children ).
Other factors are related to individual physiology. The effects of some individual factors (eg, renal
failure, obesity, hepatic failure, dehydration) can be reasonably predicted, but other factors are
idiosyncratic and thus have unpredictable effects. Because of individual differences, drug
administration must be based on each patient’s needs—traditionally, by empirically adjusting
dosage until the therapeutic objective is met. This approach is frequently inadequate because it
can delay optimal response or result in adverse effects.

Knowledge of pharmacokinetic principles helps prescribers adjust dosage more accurately and
rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed
therapeutic drug monitoring.

Furosemide is a potent loop diuretic that works to increase the excretion

of Na+ and water by the kidneys by inhibiting their reabsorption from the
proximal and distal tubules, as well as the loop of Henle. It works directly acts
on the cells of the nephron and indirectly modifies the content of the renal
filtrate.
 The pharmacokinetics and pharmacodynamics of furosemide were compared after an oral
administration or a direct administration of Lasix into the duodenum in humans (40 mg).
Furosemide was absorbed quickly after a direct administration of Lasix into the duodenum; the
peak plasma concentration of furosemide was reached within 1 h in both routes of
administration, and the peak concentration was higher in all four subjects after a direct
administration into the duodenum than after an oral administration. Furosemide was absorbed
considerably after a direct administration of Lasix into the duodenum; the values of the area
under the plasma concentration-time curves of furosemide from time zero to 4 h (AUC0-4 h,
93.6 versus 122 micrograms min mL-1, p < 0.123) and the cumulative amounts of the dose
excreted in 8 h (10,600 versus 15,000 micrograms, p < 0.0185) and 24 h (11,300 versus 15,400
micrograms, p < 0.0192) urine as unchanged furosemide were significantly higher after a direct
administration into the duodenum than after an oral administration. However, the amounts
excreted in urine as glucuronide conjugates, a metabolite of furosemide, tended to increase
after an oral administration (4030 versus 1670 micrograms as expressed in terms of furosemide,
p < 0.0858) when compared to a direct administration into the duodenum, possibly due to the
increased gastric first-pass metabolism of furosemide. The 8 h urine output and 8 h urinary
excretion of sodium did not increase significantly after a direct administration of Lasix into the
duodenum, despite the significantly greater amount of the drug delivered to the active site after
a direct administration into the duodenum. This could be explained by the fact that the urinary
excretion rates of furosemide after a direct administration into the stomach were closer to the
values of maximally efficient urinary excretion rate of furosemide during the 8 h experimental
period than after a direct administration into the duodenUses

 Precautions
 Interactions
 Overdose
 Images
 Reviews (860)

Uses

This medication is used to treat high blood pressure. Lowering high blood

pressure helps prevent strokes, heart attacks,
and kidney problems. Hydrochlorothiazide belongs to a class of drugs known
as diuretics/"water pills." It works by causing you to make more urine. This
helps your body get rid of extra salt and water.This medication also reduces
extra fluid in the body (edema) caused by conditions such as heart
failure, liver disease, or kidney disease. This can lessen symptoms such as
shortness of breath or swelling in your ankles or feet.
How to use Hydrochlorothiazide

Take this medication by mouth as directed by your doctor, usually once daily

in the morning with or without food. If you take this drug too close to bedtime,
you may need to wake up to urinate. It is best to take this medication at least
4 hours before your bedtime.

The dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you
remember, take it at the same time each day. Keep taking this medication
even if you feel well. Most people with high blood pressure do not feel sick.

If you also take certain drugs to lower your cholesterol (bile acid-binding

resins such as cholestyramine or colestipol), take hydrochlorothiazide at least
4 hours before or at least 4 to 6 hours after these medications.

Clopamide is categorised as a thiazide-like diuretic and works in similar way as

the thiazide diuretics do. It acts in the kidneys, at the distal convoluted tubule (DCT) of
the nephron where it inhibits the sodium-chloride symporter. Clopamide selectively
binds at the chloride binding site of the sodium-chloride symporter in the PCT cells on
the luminal (interior) side and thus interferes with the reabsorption of sodium chloride,
causing an equiosmolar excretion of water along with sodium chloride

Etacrynic acid or ethacrynic acid, trade name Edecrin, is a loop diuretic used to treat high blood

pressure and the swelling caused by diseases like congestive heart failure, liver failure, and kidney

failure. 

osmotic diuretic is a type of diuretic that inhibits reabsorption of water and sodium. They are
pharmacologically inert substances that are given intravenously. They increase the osmolarity of
blood and renal filtrate. Two examples are mannitol and isosorbide. 
Osmotic diuretics

 glycerin (Glycerol)
 Isosorbide.
 Mannitol IV.
 Urea.
 Osmotic Diuretics (Examples: Mannitol, Glycerin, Isosorbide, Urea) Osmotic diuretics are
relatively inert substances; they do not directly interact with renal transport systems

They increase the osmolarity of blood and renal filtrate. Two examples are mannitol and
isosorbide. In the nephron, osmotic diuretics act at the portions of the nephron that are water-
permeable. Osmotic diuretics work by expanding extracellular fluid and plasma volume, therefore
increasing blood flow

2. Uricosuric (antigout agents). Classification, principles of action. Drugs used in acute gouty
attack.

Uricosuric medications (drugs) are substances that increase the excretion of uric acid in

the urine, thus reducing the concentration of uric acid in blood plasma. In general, this
effect is achieved by action on the proximal tubule of the kidney. Drugs that reduce blood
uric acid are not all uricosurics; blood uric acid can be reduced by other mechanisms
(see other help dissolve these crystals, while limiting the formation of new ones.
However, the increased uric acid levels in urine can contribute to kidney stones. Thus, use
of these drugs is contraindicated in persons already with a high urine concentration of
uric acid (hyperuricosuria). In borderline cases, enough water to produce 2 liters of urine
per day may be sufficient to permit use of an uricosuric drug.
By their mechanism of action, some uricosurics (such as probenecid) increase the blood
plasma concentration of certain other drugs and their metabolic products. While this is
occasionally exploitable to good effect (see oseltamivir), assessment of drug interactions
is very important when using uricosuric drugs in the presence of other medications.

general, uricosuric drugs act on the proximal tubules in the kidneys, where they interfere
with the absorption of uric acid from the kidney back into the blood. Several uricosurics
are known to act in vitro by blocking the function of a protein encoded by the
gene SLC22A12, also known as urate transporter 1 or URAT1. URAT1 is the central
mediator in the transport of uric acid from the kidney into the blood. In some persons
with loss-of-function mutations of URAT1, the uricosurics benzbromarone and losartan
had no effect, suggesting these drugs act on URAT1 in vivo.[1] Thus, uricosuric drugs may
be candidates for management in a personalized medicine model

Uricosuric medications (drugs) are substances that increase the excretion of

uric acid in the urine, thus reducing the concentration of uric acid in blood
plasma. In general, this effect is achieved by action on the proximal tubule of
the kidney.

Allopurinol is in a class of medications called xanthine oxidase inhibitors. It works by reducing the
production of uric acid in the body. High levels of uric acid may cause gout attacks or kidney stones.
Allopurinol is used to prevent gout attacks, not to treat them once they occur.
Uricosuric Agents
Uricosuric agents lower uric acid levels by inhibiting renal tubular reabsorption
of uric acid, thereby increasing net renal excretion of uric acid. These agents
increase the risk of renal stones, with about a 9-10% risk for probenecid. They
should not be started during an attack of acute gouty arthritis. The goal of
therapy is to lower serum uric acid to approximately 5-6 mg/dL without
causing renal stones.

 Primary uricosurics. The primary uricosuric drugs include probenecid, benzbromarone and
sulfinpyrazone.
 Secondary uricosurics. Drugs with other primary uses, that have known uricosuric properties,
include losartan, atorvastatin, and fenofibrate. ...
 Pharmacology. ...
 Antiuricosurics. ...
 See also. ...
 References. ...
 External links.

Uricosurics are drugs that promote the excretion of uric acid and are used in patients who have gout
(high uric acid levels leading to uric acid crystal formation in joints).
Uricosuric drugs were the first agents used to control hyperuricemia in patients with
gout.1 Any drug that increases renal excretion of uric acid, independently of the
mechanism through which it exerts its effect, may be considered a uricosuric
drug. Salicylates were the first drugs to be used to correct hyperuricemia of gout, as
they showed a paradoxical effect on renal handling of uric acid: they reduce renal
excretion at low doses and increase renal excretion at high doses. 2
The concept that underlines the term “uricosuric” may be misleading, if one considers
that these drugs will exert an effect on the renal handling of urate that will induce what
could be considered a hyperuricosuric state. However, it may certainly occur in subjects
who show normal renal excretion of uric acid in the hyperuricemic state.
The most actual concept would be to consider uricosuric drugs as drugs to be used to
correct hyperuricemia derived from “inefficient renal excretion” (IRE) of uric acid, 3 lately
known as “underexcretion,” that conceptually means that renal excretion of uric acid is
not found to the amount expected based on serum urate concentration (SUR) levels
and glomerular filtration, that is to say to the filtered load.4 Thus, our clinical approach to
the use of uricosurics will be to recognize them as means to normalize renal excretion
of uric acid in patients with IRE of uric acid. 5
In this chapter, we will further discuss the concept, targets, and clinical assessment of
IRE; drugs that increase renal excretion of uric acid, either approved, not approved, or
in development; and clinical management of uricosuric therapy, including combination
of xanthine oxidase inhibitors (XOIs) and uricosurics.

3. Agents affecting the myometrium. Classification. General characteristics of

myometrium stimulants. Using of prostaglandins (Dinoprost, Dinoproston, Misoprostol) and
hormones in obstetrics and gynecology.
Myometrium
The myometrium is organized into strata: an external hoodlike layer
covering the fundus, a dense network of fibers beneath it, and an
innermost layer surrounding the internal os and tubal ostia. Magnetic
resonance imaging (MRI) of the uterus of women of reproductive age
reveals two distinct myometrial zones: the junctional zone underlying
the endometrium (which has low signal intensity) and the
outer myometrium (which has relatively high signal intensity).  The
288

junctional zone corresponds to the hypoechogenic layer of the

myometrium, the subendometrial halo observed in ultrasound images.
The lower T2-weighted signal intensity of the junctional zone is due to
the lower water content (mostly a consequence of contractile activity
of this zone that decreases its blood volume), less extracellular matrix,
and more tightly packed smooth muscle cells. This zonal anatomy is
apparently dependent upon sex hormones because it is not evident
prior to menarche or in post-menopausal women who are not
receiving hormone replacement therapy. MRI images reveal that the
junctional zone is altered in early pregnancy, evidently as a
consequence of embryo-derived factors.
The functions of the junctional zone of the myometrium appear to be
linked to events in the menstrual cycle and the establishment of early
pregnancy; those of the outer myometrium are related to pregnancy
and parturition. The junctional zone has several unique features that
distinguish it biochemically and functionally from the outer
myometrium. Although steroid hormone receptors are expressed
throughout the myometrium, the junctional zone exhibits cyclic
changes in expression of estrogen and progesterone receptors that
parallel those of the endometrium. This differs from the “outer”
myometrium, which does not show marked cyclic changes in receptor
expression.
During the menstrual cycle, subendometrial peristalsis has been
observed by ultrasonography and ultra-fast MRI.  The frequency,
289-292

intensity, and direction of the subendometrial contractions vary during

the menstrual cycle. They average two to three cycles per minute and
flow from cervix to fundus at midcycle; diminish in the luteal phase;
and increase again during menstruation, but in a fundal-to-cervical
direction. Changes in steroid hormone levels, expression of hormone
receptors, and prostanoids govern the peristaltic activity. Some
authors have suggested that the contractile activity of the junctional
zone alters uterine shape from an elongated configuration in
the follicular phase to a piriform configuration in the luteal phase,
changes that make the uterine cavity more spherical after ovulation. 293
In some pathological states, including endometriosis or adenomyosis,
dystonic uterine contractions have been observed.  Whether or not
294-296

these aberrant contraction patterns contribute to infertility and other

symptoms of endometriosis remains to be determined. It is tempting to
speculate that disruptions in the normal fundal-to-cervical contractions
during menstruation might worsen the sensation of uterine cramping
associated with endometriosis, and perhaps even contribute to the
retrograde menstruation thought to underlie the pathogenesis of this
disorder.
The myometrial compartment changes dramatically during pregnancy,
primarily as a result of muscle hypertrophy, the elaboration of
extracellular matrix, and an increase in lymphatics and blood vessels.
The wet weight of the human uterus increases tenfold during
pregnancy, and its carrying capacity increases from 300 mL to 4.5 L,
largely owing to hypertrophy and hyperplasia of the myometrium. The
myometrial hyperplasia is steroid hormone-dependent and probably
mediated by growth factors, particularly the IGFs.  The primate
102

myometrium expresses all components of the IGF signaling system,

including IGF-1, IGF-2, and the type 1 growth factor receptor, as well
as IGF-binding proteins (IGFBPs 2, 3, 4, and
5). Progesterone enhances expression of IGF-1 mRNA stimulated by
estrogen. The stimulation of IGF-1 expression is accompanied by an
increased number of Ki67– positive myometrial cells, indicating
myometrial cell proliferation.

Uterine Smooth Muscle

Susan Wray, Sarah Arrowsmith, in Muscle, 2012
Overview
The myometrium is a spontaneously active smooth muscle
(myogenic): it is able to produce regular contractions without hormonal
or nervous input (1). Like many visceral smooth muscles,
contractions of the myometrium are phasic in nature; they show
maintenance of a resting tone with cycles of discrete, intermittent
contractions of varying frequency, amplitude, and duration. It is these
parameters of uterine contractile activity that are varied to equip it for
its main physiological functions and which must be well controlled if
problems such as preterm or dysfunctional labors are to be avoided.
An example of in vitro contractility of human myometrium is shown
in Figure 90.1. A similar pattern of activity would be recorded in
vivo via an intra-uterine pressure catheter.
Sign in to download full-size image

Figure 90.1 . Simultaneous measurement of force (black trace) and calcium

(red trace) measured using the fluorometric indicator indo-1 in spontaneously

contracting strips of human myometrium. In (A), strips were superfused with PSS

(pH7.4, 37°C) followed by high potassium (40 mM KCl) depolarization (KCl, black

bar). In (B), the effect of removing external calcium (0Ca, black bar) on inhibition of

spontaneous contractions can be clearly seen.

As in all smooth muscles, for contraction to take place there needs to

be significant interaction between actin and myosin myofilaments and
this is also true of the myometrium. Uterine contractions are triggered
by transient increases in intracellular calcium concentration ([Ca ] ), 2+
i

which in turn are initiated and controlled by myometrial action

potentials (2). Figure 90.1(A) shows the Ca  transients reported by the
2+

fluorescent, Ca -sensitive indicator Indo-1, which underlie the

2+

simultaneously recorded force changes. The sequence of events

between action potential generation and contraction initiation is known
as excitation–contraction (EC) coupling (ECC). The free [Ca ]  is key 2+
i

for controlling the uterine contractions as it is the rise in intracellular

Ca  and its subsequent binding to calmodulin which activates myosin
2+

light chain kinase (MLCK). This enzyme is responsible for myosin

phosphorylation, enabling acto-myosin cross-bridge
cycling, hydrolysis of ATP and promotion of force. A variety of
mechanisms residing in the plasma and sarcoplasmic reticular
membranes control the level of intracellular Ca  in the myometrium
2+

(discussed later). Myocyte membrane voltage plays the most

important role in controlling the entry of Ca  into the cell, through
2+

gating L-type Ca  channels. The effects on contractions and

2+

Ca  transients of removing external Ca  can clearly be seen in Figure

2+ 2+

90.1(B) – both are abolished. In turn, the changes in membrane

voltage and resting membrane potential are controlled by a number of
ion channels and transport mechanisms residing in the plasma
membrane that are responsible for cell excitability.

Uterine Contractility
TERTTU KATILA, in Current Therapy in Equine Reproduction, 2007
PHYSIOLOGICAL BASIS OF MYOMETRIAL CONTRACTILITY
The myometrium consists of two layers of smooth muscle with a
vascular zone in between. The muscle fibers of the outer longitudinal
layer are arranged parallel and those of the inner circular layers
concentrically around the long axis of the uterus. The spindle-shaped,
membrane-bound muscle cells are arranged into bundles of 10 to 50
cells. Neighboring cells come in close apposition in certain specialized
regions of their plasma membranes forming cell-to-cell contacts, which
are termed gap junctions. They are modifications of the apposing
plasma membranes of the adjacent cells and couple them electrically
and metabolically. The gap is a narrow space of about 2 to 3 nm, and
it is composed of a few thousand channels. 1

The contractile activity in the uterus is a direct consequence of the

electrical activity in the smooth muscle cells. This activity is
characterized by cyclic depolarization and repolarization of the plasma
membrane and termed action potentials. Depolarization is mainly due
to an increased permeability to Ca  and, to a lesser extent, to Na .
2+ +

Both ions have higher concentrations in the extracellular space and

hence easily move into the intracellular space, making the membrane
potential more positive. The membrane repolarizes by increasing the
permeability to K  (high concentration in intracellular fluid), which
+

results in outward movement of K .+ 1

Some muscle cells are specialized for pacesetting uterine

contractions. Pacemaker regions are 2 to 4 mm in size and contain
one or more specialized pacemaker cells. Any myometrial cell is
capable of assuming the role of a pacemaker. Therefore pacemaker
regions can shift from one site to another. The individual muscle cell is
the unit for excitation of the myometrium, but a bundle of muscle cells
is the unit of propagation of the electrical stimulus. Gap junctions are
the sites of intercellular propagation of action potentials. The gap
junction channels exhibit rapid transformations between open and
closed states. 1

The number of gap junctions and their permeability determines the

efficiency of electrical and metabolic coupling of cells in the
myometrium and the speed of conduction of action potentials.
The magnitude of uterine contractions is dependent on the total
number of simultaneously and synchronously active smooth muscle
cells. A single action potential can generate a twitch contraction. A
synchronized contraction of many uterine smooth muscle cells
(estimated to be billions) decreases the diameter of uterine lumen. At
an action potential discharge rate around 1 cycle per second, a tetanic
type of contraction is produced. 1

Pregnancy and Parturition

Charles A. Ducsay, Joon W. Rhee, in Advances in Organ Biology,
1996
B. Steroid Regulation of Myometrial Adrenoceptors
In the myometrium, the effects of catecholamines are dependent upon
the proportion and distribution of the various adrenoceptor subtypes.
In turn, the concentration and sensitivity of these receptors appear to
be under regulation by steroid hormones, primarily estrogen
and progesterone (Roberts et al., 1989). While the majority of data in
this area was derived from rodent and rabbit models, the same
general principles of regulation appear to apply to the human.
The endogenous adrenergic agonists, norepinephrine and
epinephrine, interact with the three principal myometrial receptor
subtypes. The cumulative response, therefore, is determined by the
relative changes in the products of PIP  hydrolysis (α -receptors) and
2 1

changes in cAMP (α -and β -receptors). These effects increase or

2 2

decrease the available calcium concentration, respectively, ultimately

acting on myosin light chain kinase.
Myometrium contracts in response to norepinephrine, and estrogen
treatment increases myometrial contractile sensitivity to
norepinephrine. Estrogen treatment results in a dramatic increase in α
adrenoceptor concentration while β receptor number is relatively
unchanged (Roberts et al., 1989). Although the effects of
norepinephrine appear to be mediated through the α -receptor
1

subtype, estrogen increases the α -adrenergic sensitivity of the rabbit

1

myometrium without changes in α -receptor number. It has been

1

suggested that the increased sensitivity is due to a post-receptor

effect of estrogen. Specifically, stimulation of α -adrenergic receptors
1

activates phosphatidylinositol 4,5 bisphosphate-
specific phospholipase C (PIP -PLC). This reaction catalyzes the
2

hydrolysis of PIP  to form IP . IP  is responsible for the release of

2 3 3

calcium from intracellular stores and the cascade of events leading to

contraction of the myometrium. Thus, IP  acts as a second
3

messenger, activating calcium responses and the production of IP  is3

enhanced by estrogen treatment.

In contrast to α-adrenoceptors, adrenergic inhibition of contraction is
mediated by β-receptors. The response to β-receptor activation is an
increase in cAMP and this effect is mediated through a conformational
change in the receptor favoring an interaction with a
guanyl nucleotide sensitive coupling protein (G ; Bottari et al., 1983).
s

Like a-receptor stimulation of IP , β-mediated stimulation of cAMP and

3

subsequent myometrial relaxation is mediated by alterations in steroid

environment. Myometrial cAMP generation is potently stimulated by β-
agonists in progesterone treated rabbits but the stimulation disappears
following estrogen treatment (Roberts et al., 1989).

Pregnancy and Parturition

Jonathan J. Hirst, Geoffrey D. Thorburn, in Advances in Organ
Biology, 1996
IX. Oxytocin Sensitivity Changes During Pregnancy
The sensitivity of the myometrium to oxytocin is maximal near term in
all species studied so far (Fuchs et al., 1991). In women the sensitivity
of the myometrium to oxytocin is significantly elevated by mid-
pregnancy compared to the early pregnant and non-pregnant
myometrium. We have found oxytocin sensitivity also increased
progressively over the five nights preceding delivery in rhesus
monkeys. As described above, we also found that nocturnal plasma
oxytocin concentration rose with advancing gestation (Hirst et al.,
1993b). There was no further increase in the magnitude of the
nocturnal rise over the two nights before labor onset, although uterine
activity did increase. These observations indicate that oxytocin
sensitivity increases during this period and suggest that increasing
oxytocin sensitivity as well as rising plasma levels contribute to the
initiation of labor at night in rhesus monkeys (Hirst et al., 1993b).
Myometrial oxytocin receptors are of high oxytocin binding affinity with
an equilibrium dissociation constant (Kd) of 1–3 nM and similar values
have been observed in other tissues (Fuchs et al., 1982). As with
sensitivity, myometrial oxytocin receptor concentrations are much
higher in late pregnancy than in the non-pregnant myometrium. In
women, at term, receptor concentrations are 100-fold greater than in
nonpregnancy (Fuchs et al., 1982). These receptor concentration
changes are consistent with the observed heightened levels of
oxytocin sensitivity and support the view that the concentrations of
circulating oxytocin need only rise by a small extent to elicit uterine
contractions at term. These receptor changes are, therefore, also
responsible for the low doses of exogenous oxytocin required to
initiate contractions at term. We have found that oxytocin receptor
concentrations rise, in parallel with oxytocin sensitivity, at the time of
labor in rhesus monkeys (Hirst et al., 1991). These observations
indicate that labor at night in rhesus monkeys may result from the
combined effect of elevated nocturnal plasma oxytocin concentrations
and increased oxytocin receptor levels.
The factors that regulate oxytocin receptor levels in primates remain
unclear. Studies in rats, however, suggest the steroid hormone
environment has a critical role. Oxytocin receptor concentrations in the
rat show a pattern of changes during gestation that is similar to that
observed in women, with receptor levels rising during late gestation
followed by a sharp increase at term (Fuchs et al., 1983). Parturition in
rats is preceded by a rise in estrogen levels and a fall
in progesterone concentrations and these changes are correlated with
rising receptor levels. Fuchs et al. (1983) have shown by treating rats
with steroids that estrogen treatment up-regulates oxytocin receptors,
whereas progesterone blocks this effect by estrogens. Estrogen
treatment in women during late pregnancy does increase oxytocin
sensitivity suggesting that estrogens stimulate oxytocin receptor
concentrations and are, at least in part, responsible for the increase in
receptor levels in late pregnancy (Pinto et al., 1964). Novy et al.
(1977) have reported that the fall in maternal estradiol concentrations
following fetal death results in the suppression of nocturnal uterine
activity episodes in rhesus monkeys. These investigators also showed
that the episodes were reestablished by estradiol infusions and
suggested that the fall in estradiol concentration was responsible for
the inhibition of nocturnal uterine activity. These results suggest that a
critical level of estrogens is required to maintain oxytocin receptor
concentrations so that the nocturnal rise in oxytocin concentrations
can initiate uterine activity. These findings further indicate that the
permissive role of estrogens in the initiation of labor in rhesus
monkeys likely involves the maintenance of oxytocin receptor
concentrations.
The role of progesterone in the regulation of receptor levels is unclear.
Since progesterone levels do not fall prior to labor in women, oxytocin
receptors in primates may be insensitive to down-regulation by
progesterone. This possibility would best be addressed by antagonist
studies in a non-human primate model, but to our knowledge these
studies have not yet been performed.

Female Reproduction
Peyvand Amini, Sam Mesiano, in Encyclopedia of Reproduction
(Second Edition), 2018
The Myometrium
For most of pregnancy the myometrium is relaxed, quiescent and
compliant, and grows mainly by stretch-induced cellular hypertrophy of
myometrial cells to accommodate the growing conceptus. The initial
phase of parturition involves a phenotypic transformation whereby
myometrial cells gain the capacity to contract forcibly, rhythmically and
coordinately, and become more responsive to uterotonic hormones
(factors that directly induce uterine contraction) such as oxytocin (OT)
and prostaglandin-F  (PGF ). This transformation involves increased
2α 2α

expression of a specific cohort of genes encoding factors collectively

referred to as contraction-associated proteins (CAPs). Some
important CAPs include connexin-43 (CX43) that forms gap-
junctions between myometrial cells, allowing rapid electrical, and
chemical signaling between adjacent cells to permit synchronous
contractions, receptors for stimulatory uterotonins (e.g., OT and
PGF  receptors) leading to increased responsiveness to hormones
2α

that stimulate uterine contraction, and ion channels that decrease the

resting membrane potential to increase excitability by lowering the
threshold for contraction.

Genetics and Genomics of Preterm Birth

Lubna Nadeem, ... Oksana Shynlova, in Human Reproductive and
Prenatal Genetics, 2019
microRNA and Regulation of Labor Onset
The rapid transition of the myometrium at term from a quiescent to a
highly contractile state suggests that the labor genes may also be
regulated at the posttranscriptional level, possibly through the actions
of microRNAs (miRNAs). MiRNAs, often called “micromanagers of
gene expression,” are highly conserved small noncoding RNAs
comprising of 18–25 nucleotides. They recognize a target mRNA
through a complementary sequence within the 3′-untranslated
region [100]. MiRNAs mediate their action by (1) degradation of their
target mRNAs, (2) repression, or (3) stimulation of target gene
translation [101]. There are more than 1000 miRNAs identified so far
that regulate 50% of all human genes [102]. They are implicated in
numerous physiologic and pathologic cellular processes, including
human reproduction, and therefore have been extensively studied for
their role in PTBs.
Several studies examined the expression profile of miRNAs in serum
and uterine tissues from women undergoing term or preterm labor
(i.e., in the placenta, chorioamniotic membranes, myometrium, and
cervix). In one study, miRNAs (that modulate inflammatory and tissue
remodeling genes) from cervical tissue were implicated in the etiology
of PTB through disruption of the epithelial barrier that might allow the
inflammatory factors to enter the cervix and cause premature
ripening [53]. The miRNA cluster C19MC on chromosome 19 is the
largest human miRNA gene cluster. In the placenta, it is regulated by
genomic imprinting and is paternally inherited. Montenegro and
colleagues analyzed 455 miRNAs from the chorioamniotic membranes
and reported differential expression of 39 miRNAs (mostly down-
regulated) in preterm compared to term laboring women while no
difference was detected at membranes from term laboring versus
nonlaboring women [103]. Another study reported differences in the
expression of 32 miRNAs in amnion from laboring and nonlaboring
women; 31 of those were also down-regulated [104]. In particular, they
demonstrated that miR-143 targets prostaglandin-endoperoxidase
synthase 2 (PTGS2) in amnion mesenchymal cells and hypothesized
that the decrease in this miRNA may be responsible for the induction
of PTGS2 preceding parturition. A recent study demonstrated a
significant increase in the expression of miR-200a in the myometrium
of women in labor as compared to not in labor. miR-200a targets
STAT5b, a transcriptional repressor of the P4-metabolizing enzyme
20a-HSD. This results in enzyme up-regulation and subsequent
decline in P4, potentially contributing to a “functional” P4
withdrawal [105].
Besides their regulatory roles in different gestational tissues and cells,
miRNAs can also be detected in various body fluids. These cell-free
circulating miRNAs are either bound to RNA-binding proteins or
lipoproteins such as HDL or LDL or they are encapsulated into
extracellular vesicles (EVs) to escape degradation by RNAses.
Circulating miRNAs have already been used to identify markers for
disease diagnosis or prognosis. Several studies report changes of
specific miRNA concentrations in the serum or plasma of patients in
PTL, but the results are inconsistent or even contradictory and are
influenced by the sample used (serum vs. plasma), the low RNA
concentration in samples, and the lack of robust measurement
technology. We used next-generation sequencing as a platform for
miRNA analysis in whole plasma, EV, and EV-depleted plasma of
women in spontaneous PTL and found a number of miRNAs in EVs
that may be potential biomarkers for PTL [106]. We proposed that
changes in the levels of these miRNAs may reflect pathological
changes of the placenta associated with PTL.

Pregnancy and Parturition

Jane E. Mijovic, David M. Olson, in Advances in Organ Biology, 1996
B. Myometrial Uterotonins
The increased sensitivity of the myometrium to contractile agents is
determined by increased receptor numbers and enhanced receptor
coupling to second-messenger systems. In sheep the change in the
steroid environment to estrogen dominance promotes the formation of
receptors for oxytocin and PGs. In women estrogen treatment in late
pregnancy increases oxytocin sensitivity by stimulating an increase
in oxytocin receptor concentrations. PGs can be identified as positive
feedback agents in this cascade as they further enhance estrogen-
induced expression of oxytocin receptors (for reviews see Fuchs,
1995; Olson et al., 1995).
In addition, estrogens stimulate endocrine and paracrine production of
the oxytocin peptide. The release and synthesis of oxytocin in the
hypothalamus is increased due to stimulation of oxytocin gene
expression by estrogen. Furthermore, in human amnion, chorion and
decidua, estrogen stimulated a fourfold increase in oxytocin mRNA in
vitro which is an increase similar to that seen in tissues obtained
around the time of spontaneous parturition relative to those obtained
earlier in gestation. Progesterone had little effect on this response
alone and inhibited the estrogen response in some experiments.
Oxytocin stimulates phosphatidylinositiol hydrolysis in myometrial cells
resulting in increased inositol triphosphate generation which is a
second messenger step leading to myometrial
contraction. Diacylglycerol is also a product of this hydrolysis; the
action of cellular lipases on diacylglycerol releases arachidonic
acid which is the substrate of PGs. Also, the release of intracellular
calcium initiated by phosphatidylinositol hydrolysis can cause further
mobilization of arachidonic acid from phospholipid stores as the
phopholipases responsible for this reaction are Ca  dependent.
2+
Furthermore, oxytocin has been shown to induce the production of
another uterotonin, endothelin-I, in decidua. Comparable to all these
stimulatory agents, endothelin-I induces calcium influx into myometrial
cells and is equipotent to oxytocin in stimulating uterine contractions.
There is other in vitro evidence that the production of PGs by human
intrauterine tissues is regulated hormonally. In general, estrogen
stimulates PG production while progesterone can either antagonize or
augment estrogen action. In culture, estrogen has been shown to
stimulate the output of PGE  from decidual cell preparations obtained
2

from patients at elective cesarean section. In the

myometrium, dexamethasone decreased prostacyclin synthesis by
90%. Prostacyclin (PGI ) causes myometrial relaxation, and the
2

increase in fetal glucocorticoid production at term described previously

may have a further role in decreasing PGI  synthesis and causing a
2

switch to the production of stimulatory PGF  and PGE .

2α 2

Estradiol and progesterone have no effect on the expression of the

two isoforms of prostaglandin endoperoxide H synthase (PGHS), the
enzyme catalyzing the rate limiting step of the conversion of
arachidonic acid to PGE  in cultured amnion cells. A rate-limiting step
2

in metabolism of PGs is the 15-prostaglandin dehydrogenase enzyme

(PGDH) which is found in most intrauterine tissues, especially chorion.
The activity of this enzyme is stimulated by progesterone. Therefore,
under the progesterone domination of pregnancy, PGDH enzyme
levels will be high, reducing the bioactivity of any PGs formed. Local
withdrawal of progesterone at term may reduce PDGH activity, thus
increasing PG bioactivity. In support of this are the observations of
women treated early in pregnancy with the progesterone receptor
antagonist, RU486. Such treatment is associated with a dramatic
decrease in decidual PGDH activity and increased spontaneous
uterine contractility (Hansen, 1976).

Female Reproductive System and Mammae1

Robert A. Foster, in Pathologic Basis of Veterinary Disease (Sixth
Edition), 2017
Adenomyosis.
Adenomyosis is the presence of endometrium within the myometrium,
and the effect generally is negligible in domestic animals, which do not
menstruate. Adenomyosis is found in the cow, bitch, and queen. It is
thought that endometrium is either forced into the myometrium by
pressure of pregnancy or pyometra or that the epithelium “migrates.”
In primates, adenomyosis is considered part of endometriosis, which
is a general term in which endometrium is found in ectopic locations.
Endometriosis, in which endometrium is found on serosal surfaces,
around the ovary, or in the chest, is not reported in domestic species.
Macroscopic changes in adenomyosis are primarily localized
thickening of the myometrium, especially near the cervix. In dramatic
cases, cysts form in the myometrium. Sometimes in bitches, the
uterus undergoes diffuse symmetric or focal asymmetric enlargement
near the cervix (Fig. 18-24). Microscopically, endometrial glands,
stroma, or both are within the myometrium.

The prostaglandins are a group of lipids made at sites of tissue damage or infection that
are involved in dealing with injury and illness. They control processes such as inflammation,
blood flow, the formation of blood clots and the induction of labour

Unlike most hormones, which are produced by glands and transported in the bloodstream to act on
distant areas of the body, the prostaglandins are produced at the site where they are needed.
Prostaglandins are produced in nearly all cells and are part of the body’s way of dealing with injury
and illness.
Prostaglandins act as signals to control several different processes depending on the part of the
body in which they are made. Prostaglandins are made at sites of tissue damage or infection, where
they cause inflammation, pain and fever as part of the healing process. When a blood vessel is
injured, a prostaglandin called thromboxane stimulates the formation of a blood clot to try to heal the
damage; it also causes the muscle in the blood vessel wall to contract (causing the blood vessel to
narrow) to try to prevent blood loss. Another prostaglandin called prostacyclin has the opposite effect
to thromboxane, reducing blood clotting and removing any clots that are no longer needed; it also
causes the muscle in the blood vessel wall to relax, so that the vessel dilates. The opposing effects
that thromboxane and prostacyclin have on the width of blood vessels can control the amount of
blood flow and regulate response to injury and inflammation.
Prostaglandins are also involved in regulating the contraction and relaxation of the muscles in
the gut and the airways.
Prostaglandins are known to regulate the female reproductive system, and are involved in the
control of ovulation, the menstrual cycle and the induction of labour. Indeed, manufactured forms of
prostaglandins - most commonly prostaglandin E2 - can be used to induce (kick-start) labour.

How are prostaglandins controlled?  

The chemical reaction that makes the prostaglandins involves several steps; the first step is carried
out by an enzyme called cyclooxygenase. There are two main types of this enzyme:
cyclooxygenase-1 and cyclooxygenase-2. When the body is functioning normally, baseline levels of
prostaglandins are produced by the action of cyclooxygenase-1. When the body is injured (or
inflammation occurs in any area of the body), cyclooxygenase-2 is activated and produces extra
prostaglandins, which help the body to respond to the injury.  
Prostaglandins carry out their actions by acting on specific receptors; at least eight different
prostaglandin receptors have been discovered. The presence of these receptors in different organs
throughout the body allows the different actions of each prostaglandin to be carried out, depending
on which receptor they interact with.
Prostaglandins are very short-lived and are broken down quickly by the body. They only carry out
their actions in the immediate vicinity of where they are produced; this helps to regulate and limit
their actions.
What happens if my levels of prostaglandins are too
high?
High levels of prostaglandins are produced in response to injury or infection and cause inflammation,
which is associated with the symptoms of redness, swelling, pain and fever. This is an important part
of the body’s normal healing process.
However, this natural response can sometimes lead to excess and chronic production of
prostaglandins, which may contribute to several diseases by causing unwanted inflammation. This
means that drugs, which specifically block cyclooxygenase-2, can be used to treat conditions such
as arthritis, heavy menstrual bleeding and painful menstrual cramps.  There is also evidence to
suggest that these drugs may have a beneficial effect when treating certain types of cancer,
including colon and breast cancer, however research in this area is still ongoing. New discoveries
are being made about cyclooxygenases which suggest that cyclooxygenase-2 is not just responsible
for disease but has other functions.
Anti-inflammatory drugs, such as aspirin and ibuprofen, work by blocking the action of the
cyclooxygenase enzymes and so reduce prostaglandin levels. This is how these drugs work to
relieve the symptoms of inflammation. Aspirin also blocks the production of thromboxane and so can
be used to prevent unwanted blood clotting in patients with heart disease.

What happens if my levels of prostaglandins are too low?

Manufactured prostaglandins can be used to increase prostaglandin levels in the body under certain
circumstances. For example, administration of prostaglandins can induce labour at the end of
pregnancy or abortion in the case of an unwanted pregnancy. They can also be used to treat
stomach ulcers, glaucoma and congenital heart disease in newborn babies. Further advances in
understanding how prostaglandins work may lead to newer treatments for a number of conditions.

5. Tocolytics (agents decreasing the contractile ability of the myometrium). Classification,

mechanism of action, clinical uses, adverse effects.

Tocolytics (also called anti-contraction medications or labor suppressants) are

medications used to suppress premature labor (from Greek τόκος tókos, "childbirth", and
λύσις lúsis, "loosening"). Tocolytic therapy is provided when delivery would result in premature
birth, postponing delivery long enough for the administration of glucocorticoids, which
accelerate fetal lung maturity but may take one to two days before its effects are seen
 suppression of contractions is often only partial and tocolytics can only be relied on to
delay birth for several days. Depending on the tocolytic used the mother or fetus may require
monitoring (e.g., blood pressure monitoring when nifedipine is used as it reduces blood
pressure; cardiotocography to assess fetal well-being). In any case, the risk of preterm labor
alone justifies hospitalization

These are drugs that inhibit uterine contractions.

Beta-sympathomimetics
Action

Relaxation of the smooth muscle fibres by stimulating the beta receptors present on the cell membrane.

Examples:

Ritodrine (Yutopar):

Dosage: 50 mg of ritodrine in 500 ml of 5% glucose solution. Start by 10 drops per minute and increase by 5 drops
every 10 minutes until uterine contractions cease.

 The infusion should be continued for 12-48 hours after cessation of contractions.
 The treatment is then maintained by oral therapy as one tablet (10 mg) every 8 hours after meal to reduce
its side effects.
 Maternal pulse and blood pressure as well as foetal heart rate should be monitored during treatment to
control the dose.

Side effects

 Maternal:
o Tachycardia,
o hypotension (relaxation of the smooth muscle fibres in the blood vessels wall),
o flushing,
o sweating
o nausea,
o vomiting,
o headache,
o anxiety,
o tremors,
o hyperglycaemia,  
o hypokalaemia,
o acidosis and
o pulmonary oedema.
 Foetal:
o Tachycardia,
o arrhythmia,
o loss of beat-to-beat variation,
o neonatal hypotension and hypoglycaemia.

Contraindications

 Heart disease.
 Hypertension or hypotension.  
 Hyperthyroidism.
 Antepartum haemorrhage (dilatation of the uterine arteries may increase the bleeding).  
 Diabetes.

Other β-sympathomimetic drugs

 Terbutaline,
 Isoxuprine (Duvadilan - vasoxiprine) 20 mg 3-4 times daily.
 Salbutamol.

Calcium Antagonists

Action: Antagonise the action of calcium within the myometrial cells so reduce its contractility.

e.g. Nifedipine 10 mg oral tablet.

Magnesium Sulphate

Action: The intracellular calcium is displaced by magnesium ion leading to inhibition of the uterine activity.
Dosage: The initial dose is 40 cc of 10% solution given slowly IV. The subsequent doses depend upon the response
and the development of MgSO4 toxicity so reflexes and respiratory rate should be observed.

Prostaglandin Inhibiting Agents

Action: Inhibition of uterine contractions by inhibiting prostaglandin synthesis.

Dosage: e.g. indomethacin 100 mg suppository initially, followed by 25 mg orally every 6 hours for up to 24 hours
after contractions ceased.

Ethyl Alcohol

Action

 Inhibits the release of oxytocin from the posterior pituitary gland.

 Suppresses the myometrial activity directly.
 Inhibits prostaglandin F2 a synthesis.

Dosage

It is given IV and the dose is adjusted to maintain blood alcohol level of 0.9-1.6 mg/litre.

Side effects

 Nausea, vomiting and depression.

 Drunken mother and foetus.
 Maternal and foetal acidosis.

II. Write out a prescription and indicate the mechanism of action of the following
drugs:

1. Furosemide in ampoules:

RX: Sol furosemidr 1-2ml Sol

Dt dn 10 in amp

2. Verospiron in tablets:

RX :Sol verospiron 0.005g

Ds do 1 tab bid

3. Ergotamine maleate in ampoules:

RX:sol ergotamine meleate 1 ml Sol

Dtdn 10 in amp

4. Sulfinpyrazone in tablets:
Rx : Sol sulfinpyrazone 0.1g
Ds po 1tab bid

5. Oxytocin in ampoules:
Rx : Sol oxytocin 1ml sol
Dt dn 10 in amp