DRUGS ACTING ON

URINARY SYSTEM

Farmakologi Veteriner

Fakultas Kedokteran Hewan UB

OBJECTIVE

Upon completion of this chapter, the reader should be able to:

Describe the basic anatomy and physiology of the urinary system.

Outline the biological process of urine formation.

Explain how diuretics affect urine production.

Describe the modes of action of various diuretics.

Describe the ways various hypertensive drugs affect urine production.

Describe the use of the following drugs employed in veterinary medicine: cholinergics, anticholinergics, adrenergics, adrenergic antagonists, hormones, skeletal muscle relaxants, urinary acidifiers and alkalinizers, and xanthine oxidase inhibitors.

Anatomy and Physiology of

The Urinary System

PHYSIOLOGY OF RENAL SYSTEM

The primary function of the renal system is to :

regulate blood volume and plasma osmolarity

waste removal via urine

Urine is a waste byproduct formed from excess water and metabolic waste molecules during the process of renal system filtration.

Urine formation occurs during three processes:

Filtration

Reabsorption

Secretion

Individual structures that do the actual work of the

kidneys, referred to as the functional units of the kidney,

are called nephrons.

The nephron consists of the glomerulus, Bowman’s

capsule, the proximal convoluted tubule, the loop of

Henle, a distal convoluted tubule, and a collecting duct.

Urine is formed in the nephron via the processes of

glomerular filtration, tubular reabsorption, and

tubular secretion.

Glomerular Filtration

A glomerulus is a cluster of capillaries that is responsible

for glomerular filtration.

Basically, the glomerulus filters substances from blood

into the glomerular filtrate (water and dissolved

substances).

Glomerular filtration is affected by :

blood pressure (and hence blood volume and flow rate),

plasma osmotic pressure (related to particles in the blood),

capsule pressure (which can alter resistance to blood flow).

Tubular Reabsorbtion

The tubules are responsible for reabsorption or secretion

of substances.

The substances needed by the body are reabsorbed from

the filtrate (fluid within the tubules) through the tubular

cell wall, and then they reenter the plasma.

These substances include water, glucose, amino acids, and

ions (sodium [Na+ ], potassium [K+ ], calcium [Ca+2 ],

chloride [Cl– ], and bicarbonate [HCO3 – ]).

If these substances are in excess or are not useful, they

remain in the filtrate to be excreted in the urine.

Tubular Secretion

Tubular secretion is the process in which substances are

carried into the tubular lumen.

These substances are secreted by active transport and

include K+, H+, NH3+, creatinine, and drugs.

Tubular secretion is helpful in maintaining blood pH and

in excreting drugs.

Collecting ducts collect urine from the nephron and carry

it to the renal pelvis.

The main responsibilities of the urinary system are to

remove from the body waste products produced

during metabolism and to maintain homeostasis, a

steady state in the internal environment of the body.

The urinary system removes waste products from the

body by the constant process of blood filtration.

The major waste product of protein metabolism is urea,

which is filtered by the kidney and used in some

diagnostic tests to determine the health status of the

kidney.

URINARY SYSTEM DISORDER

Disorders of the urinary system

Urinary tract infections

Inflammation and irritation of the urinary tract causing

smooth muscle spasms, renal failure

Uroliths (urinary stones)

Urinary incontinence

Disorders of the urinary system

Bacterial infections of the urinary system (particularly the urinary bladder) may lead to inflammation, pollakiuria (increased frequency of urination), and dysuria (painful urination), which may result in inappropriate urination for household pets.

Crystals in the urine can cause urinary tract inflammation and irritation and may lead to the development of uroliths.

Renal failure may lead to an increase of nitrogenous waste products and electrolytes in the blood that may cause severe illness in an animal.

Urinary incontinence may be due to a variety of issues (including trauma and systemic disease) and may lead to skin lesions, infection, and the inability of the owner to care for the animal.

Disorders of The Urinary System

Clinical signs :

inappropriate urination, inability to urinate, frequent urination,

increased urination, or pain

Some of the clinical signs that an animal develops relating

to the urinary system may be due to treatment of

other diseases such as heart disease and hypertension.

Clinical signs that present with urinary system disease

may need to be treated to prevent other complications :

dehydration, electrolyte alterations, or toxic

accumulations of nitrogenous waste products in blood.

URINARY SYSTEM DRUGS

Many different types of drugs are used in the management

of renal disease and urinary system disorders.

Some urinary drugs directly influence urine production and

electrolyte balance.

Others maintain blood pressure and reduce urinary

system disease.

URINE PRODUCING (Diuretics)

Diuretics increase the volume of urine excreted by the

kidneys and thus promote the release of water from the

tissues.

This process called diuresis, lowers the fluid volume in

tissues.

The two main purposes of diuretic use are to decrease

edema and to lower blood pressure.

Diuretics effectively reduce the edema associated with

these conditions, as well as edemas of nonspecific nature,

pulmonary edema, pulmonary congestion, and any

pathological accumulation of noninflammatory liquid.

Urine formation is

“Where sodium goes, water will follow.”

The kidneys secrete and reabsorb sodium and chloride

ions as they make urine.

Diuretics block the reabsorption of these ions, so

the sodium has nowhere to go but out of the kidneys and

into the urinary bladder.

Water then follows the sodium out of the kidneys and

into the urinary bladder, and diuresis occurs.

The Classes of Diuretics

Thiazides

Loop agent

Potassium-sparing diuretics,

Carbonic anhydrase inhibitors

Osmotics agent

Aldosterone antagonist

ADH antagonist

All diuretics act directly on renal tubular epithelia at

specific sites in the nephron

Nephron Segment Diuretic

Proximal convoluted tubule CA inhibitors (e.g., acetazolamide)

Osmotic agents (e.g., mannitol)

Xanthines (e.g., aminophylline)

Ascending loop of Henle Loop agents (e.g., furosemide)

Osmotic agents

Early distal convoluted tubule Thiazides (e.g., hydrochlorothiazide)

Late distal tubule and collecting

duct

K+-sparring diuretics (e.g., triamterene or

spironolactone)

Thiazides Thiazides are diuretics that act directly on the distal convoluted tubules to

block sodium reabsorption and promote chloride ion excretion.

Thiazides most often manage edema associated with congestive heart failure.

Oral administration of thiazides produces diuresis in all animal species, with few documented side effects.

This effect remains even with prolonged use, but long-term thiazide use does cause:

excessive potassium secretion

leading to hypokalemia (potassium deficiency)

cardiac dysfunction.

To prevent hypokalemia, veterinarians suggest that potassium-rich diets or potassium supplements accompany thiazide diuretics.

DRUGS :

Hydrochlorothiazide (HydroDIURIL®), the standard thiazide drug, is given intravenously, intramuscularly, and orally to small animals, horses, and cattle.

Other veterinary thiazides include chlorothiazide (Diuril®), hydroflumethiazide (Saluron®), and bendroflumethiazide (Naturetin®).

Loop diuretics

The loop of Henle, a U-shaped renal tubule, is the sodium-reabsorbing site that lends its name to this type of diuretic.

Loop diuretics influence the reabsorption action at the loop of Henle.

Furosemide (Lasix®, Disal®, Diuride®) and ethacrynic acid (Edecrin®), two loop diuretics, are potent and effective drugs that block absorption of the following ions: chloride, potassium, calcium, hydrogen, magnesium, and bicarbonate.

The result of blocking reabsorption of all of these electrolytes is tremendous diuresis.

Loop diuretics

The main side effects of loop diuretics are

electrolyte imbalances, especially hypokalemia, which can

lead to cardiac arrhythmias.

Parenteral administration produces diuresis immediately

on a fully functional kidney.

In small animal practice, furosemide is used to treat

congestive heart failure, pulmonary edema,

and hypertension.

In large animal practice, furosemide is used in dairy cattle

with udder edema and in racing horses to control

respiratory hemorrhaging, which appears as a nosebleed.

Potassium-Sparing Diuretics

Drugs in this group are used as mild diuretics or in combination with other drugs. Potassium-sparing diuretics are weaker diuretics than thiazides or loop

diuretics.

Potassium-sparing diuretics act on the distal convoluted tubules to promote sodium and water excretion and potassium retention.

Mechanism of action : interfering the sodium-potassium pump that is controlled by aldosterone (a mineralocorticoid produced by the adrenal cortex that affects sodium and potassium levels). Potassium is reabsorbed, and sodium is excreted.

DRUGS in this category include spironolactone (Aldactone®), triamterene (Dyazide®), and amiloride (Midamor®).

The main side effect of these drugs is hyperkalemia.

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors, such as acetazolamide (Diamox®) and dichlorphenamide (Daranide®),

Mechanism of action : block the action of the enzyme carbonic anhydrase.

This enzyme is used by the body to maintain acid-base balance (mainly between hydrogen and bicarbonate ions).

Inhibition of this enzyme causes increased sodium, potassium, and bicarbonate excretion.

The main side effect with prolonged use of carbonic anhydrase inhibitors is metabolic acidosis.

Indication : mainly used to decrease intraocular pressure with open-angle glaucoma

Osmotic Diuretics

Mechanism of action : Osmotic diuretics increase the osmolality (concentration) of the filtrate in the renal tubules.

This results in excretion of sodium, chloride, potassium, and water.

Indication : use to prevent kidney failure, to decrease intracranial pressure, and to decrease intraocular pressure (i.e., glaucoma).

Mannitol (Osmitrol® and generic) and glycerin (Osmoglyn®) are examples of osmotic diuretics.

Side effects are uncommon with osmotic diuretics, but can include fluid and electrolyte imbalance and vomiting.

BLOOD PRESSURE LOWERING

Drugs used to decrease hypertension, called

antihypertensives

The primary factor in hypertension is increased

resistance to blood flow, resulting from the narrowing of

peripheral blood vessels.

If left untreated, animals with elevated blood pressure are

at risk for developing cardiac and renal dysfunction.

Some drugs that affect blood pressure

include the following :

Diuretics

Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)

Calcium Channel Blockers

Direct-Acting Arteriole Vasodilators

Beta-Adrenergic Antagonists

Alpha-Adrenergic Antagonists

Diuretics

Diuretics have an antihypertensive effect by promoting

sodium and water loss, which causes a decrease in fluid

volume and blood pressure.

Angiotensin-Converting Enzyme Inhibitors

(ACE Inhibitors)

The kidneys regulate blood pressure via the renin-angiotensin system. Renin, an enzyme released by the kidneys, stimulates the conversion of

angiotensin I to angiotensin II (a potent vasoconstrictor).

Angiotensin II causes the release of aldosterone (a mineralocorticoid from the adrenal cortex that promotes retention of sodium and water).

Retention of sodium and water increases fluid volume, which elevates blood pressure.

Mechanism of Action : ACE inhibitors block the conversion of angiotensin I to angiotensin II, which decreases aldosterone. Clinically, ACE inhibitors are used to treat hypertension.

DRUGS : enalapril (Enacard®, Vasitec®), captopril (Capoten®), lisinopril (Zestril®), and benazepril (Lotensin®).

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Calcium Channel Blockers

Mechanism of Action : Calcium channel blockers block

the influx of calcium ions into the myocardial cells

Resulting in an inhibition of cardiac and vascular smooth

muscle contractility.

This decreased resistance to blood flow reduces blood

pressure, thus affecting glomerular filtration.

Side effects include hypotension and edema.

Examples include diltiazem (Cardizem®), verapamil

(Isoptin®), and nifedipine (Procardia®).

Direct-Acting Arteriole Vasodilators

Mechanism of Action : Direct-acting arteriole

vasodilators relax smooth muscles of the blood vessels,

mainly arteries, causing vasodilation.

The main side effect of this drug group is edema due to

sodium and water retention.

Examples include hydralazine (Apresoline®) and minoxidil

(Loniten®).

Beta-Adrenergic Antagonists

Beta-adrenergic antagonists, also known as beta blockers, can affect the heart and bronchi.

Beta-1 blockers work on the heart

Beta-2 blockers work on the bronchial receptors.

Mechanism of Action : Nonselective beta blockers will inhibit the activity of beta-1 and beta-2 receptors, resulting in bradycardia and bronchoconstriction.

Side effects include decreased blood pressure, decreased cardiac output, and bronchospasm.

An example of a nonselective beta blocker is propranolol (Inderal®).

Alpha-Adrenergic Antagonists

Alpha-adrenergic antagonists block the alpha-1 adrenergic

receptors, resulting in vasodilation.

UROLITH TREATMENT

Uroliths (also known as urinary calculi) are abnormal

mineral masses in the urinary system.

Uroliths are composed of a large amount of crystalline

material (organic and inorganic crystalloids) and a small

amount of organic matrix (typically mucoid material).

Treatment

The development of urolith formation is not fully

understood, but dietary factors are known to be

important in some cases.

Uroliths in the urinary bladder cause hematuria (blood in

the urine) and dysuria.

Uroliths that lodge in the urethra may cause obstruction,

which is a major concern in male cats and male sheep

because of the narrow diameter of the urethra.

Antibiotic therapy (if warranted)

Medical dissolution of the uroliths

Surgical removal of the uroliths.

Medical dissolution of uroliths

Medical dissolution of uroliths depends on the type of

urolith found and the area of the urinary tract in

which it occurs.

The pH of the urine in which the urolith is found also

plays a role in the type of urolith formed.

Medical dissolution of uroliths

Animals with uroliths that form in alkaline (basic)

urine (struvite uroliths) >>

fed a urine-acidifying diet that dissolves uroliths (Hill’s

Prescription Diet s/d®)

prescribed urinary acidifiers such as methionine (Methio-tabs®,

Methigel®) and ammonium chloride (Uroeze®).

Once the uroliths are dissolved or removed, animals are

then maintained on diets that produce acid urine

(Hill’s Prescription Diet c/d®, Iams Low pH/s™).

Medical dissolution of uroliths

Animals with uroliths that form in acid urine (calcium

oxalate, cystine, and ammonium urate uroliths)

fed urine-alkalinizing diets (Hills Prescription diet k/d®, Iams

Moderate pH/O™ diet, or Purina’s NF-Formula® diet)

prescribed urinary alkalinizers such as potassium citrate (Urocit-

K®) and sodium bicarbonate (generic).

Animals that have renal disease should not be fed

acidifying diets or prescribed urinary-acidifying drugs.

Medical dissolution of uroliths

Some uroliths, such as ammonium urate uroliths, also

indicate the need for a low-protein, low-purine, low-

oxalate diet to prevent recurrence (Hill’s Prescription diet

u/d®, Purina’s NF Kidney Function® diet).

Animals with ammonium urate uroliths are also often

prescribed xanthine oxidase inhibitors.

This group of drugs decreases the production of uric acid.

Decreasing uric acid production helps prevent the formation of

ammonium urate uroliths.

Allopurinol (Zyloprim®, Lopurin®) is an example of a

xanthine oxidase inhibitor.

Side effects of allopurinol use are rare.

URINARY INCONTINENCE

Urinary incontinence is the loss of voluntary control

of micturition (a twostage process involving the passive

storage of urine and the active voiding of urine).

Urinary incontinence can be divided into two main

categories:

1. Disorders due to neurologic disorders

2. Nonneurologic disorders.

Neurologically Caused Incontinence

Cholinergic agonists (parasympathomimetic agents) are used to treat animals with ―spinal cord bladders‖—that is, damage to the nerves that control relaxation of the urinary bladder outflow sphincters. This nerve damage results in the retention of urine.

Mechanism of Action : The cholinergic agonist binds to the receptors on smooth muscles, allowing sodium and calcium to enter the cells. Cholinergic agonists promote voiding of urine from the urinary bladder.

These drugs simulate the action of acetylcholine by direct stimulation of cholinergic receptors.

This influx of sodium and calcium in turn allows muscle contraction.

Tone of the detrusor muscle of the urinary bladder is increased, which may increase detrusor muscle contractions.

An example of a cholinergic agonist is bethanechol (Urecholine®, Duvoid®, Urabeth®).

Side effects include GI signs such as vomiting and diarrhea.

Neurologically Caused Incontinence

Anticholinergics (parasympatholytic drugs) are used to treat urinary incontinence by promoting urine retention in the urinary bladder.

Mechanism of Action : blocking the binding of acetylcholine to its receptor sites and thereby causing muscle relaxation.

Examples of anticholinergics that promote urine retention are propantheline (Pro-Banthine®), dicyclomine (Bentyl®), and butyl hyoscine (Buscpan®).

Side effects of propantheline include decreased gastric motility (may affect absorption of other drugs) and other gastrointestinal problems.

Neurologically Caused Incontinence Adrenergic antagonists are divided into alpha and beta

categories.

Indication : Betaadrenergic antagonists, used in the treatment of hypertension

Alpha-adrenergic antagonists are used to decrease the tone of internal urethral sphincters; they are useful in the treatment of decreased urinary tone due to overdistention of the urinary bladder.

Mechanism of Action : Alpha-adrenergic antagonists work by blocking circulating epinephrine or norepinephrine from binding to their receptors. These drugs are also used to decrease blood pressure.

Examples of alpha-adrenergic antagonists include phenoxybenzamine (Dibenzyline®), prazosin (Minipress®), and nicergoline (Sermion®).

The main side effect of these drugs is weakness due to decreased blood pressure.

Nonneurologically Caused Incontinence

Estrogen (diethylstilbestrol or DES) is used to treat hormone-responsive incontinence.

Hormone-responsive incontinence is seen primarily in spayed female dogs that are more than eight years old.

It is believed that sex hormones contribute to the maintenance of urethral muscle tone; therefore, lack of sex hormones decreases urethral muscle tone and allows urine to dribble from the urethra.

This urine dribbling usually occurs when the animal is relaxed or asleep.

Side effects of estrogen include bone marrow suppression, endometrial hyperplasia, and pyometra.

Nonneurologically Caused Incontinence

Testosterone (testosterone cypionate,

testosterone propionate) is used to treat hormone-

responsive incontinence in castrated male dogs.

Males suffer hormone-responsive incontinence less

frequently than spayed female dogs.

Side effects of testosterone include the development of

prostatic disorders and behavior changes (including

aggression).

Nonneurologically Caused Incontinence

Alpha- and beta-adrenergic agonists increase the tone of the urethral sphincters.

1. phenylpropanolamine (Proin®, Propagest®), an oral medication used to treat stress incontinence.

It may be used before resorting to hormones like estrogen and testosterone in the treatment of hormone-responsive incontinence.

It is an alpha- and beta-adrenergic agonist that increases urethral tone.

2. ephedrine (generic), an alpha and beta agonist that increases urethral tone.

It is used to treat stress incontinence and is available in tablet or injectable form.

Side effects are the same as for phenylpropanolamine.

3. pseudoephedrine (Equiphed®, Sudafed®), an alpha- and

beta-adrenergic agonist used to increase urethral

sphincter tone and produce closure of the urinary

bladder neck.

It is used to treat urinary incontinence and comes in tablet and

liquid forms.

Side effects include restlessness, irritability, hypertension, and

anorexia.

Nonneurologically Caused Incontinence

Skeletal muscle relaxants, such as dantrolene (Dantrium®), aminopropazine (Jenotone®), diazepam (Valium®), and baclofen (Lioresal®) are sometimes used to treat animals that have urge incontinence or urethral obstructions due to increased external urethral sphincter tone.

These drugs may also be used after unobstructing male cats to limit spasticity of the external urethral sphincter.

Side effects of skeletal muscle relaxants include mild tranquilization and sedation.

Dantrolene has the additional side effect of hepatotoxicity.

Drugs acting on Bladder