Pharmacodynamics of Drugs Acting on Genital-Urinal System
Session 16: Pharmacodynamics of Drugs Acting on Genital-Urinal System
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Drugs acting on Genital-Urinal System
Describe drug interactions associated with Drugs acting on Genital-Urinal System
Describe side effects of Drugs acting on Genital-Urinal System
Describe contraindications of Drugs acting on Genital-Urinal System
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Drugs acting on
Mechanism of Action of Drugs acting on
2
2
45 minutes
45 minutes
Buzzing
Genital-Urinal System
Genital-Urinal System
Buzzing
Genital-Urinal System
Genital-Urinal System
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With Drugs
Drug Interactions Associated With Drugs
3
3
20 minutes
20 minutes
brainstorming
acting on Genital-Urinal System
acting on Genital-Urinal System
brainstorming
acting on Genital-Urinal System
acting on Genital-Urinal System
4
4
20 minutes
20 minutes
Presentation
Side Effects of Drugs acting on Genital-Urinal
Side Effects of Drugs acting on Genital-Urinal
4
4
20 minutes
20 minutes
Presentation
System
System
System
System
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Drugs acting on Genital-
Contraindications of Drugs acting on Genital-
5
5
20 minutes
20 minutes
Brainstorming
Urinal System
Urinal System
Brainstorming
Urinal System
Urinal System
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 130 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Drugs Acting on Genital-Urinal System (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do drugs acting on genital-urinal system produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below Diuretics
Thiazides Diuretics: (Hydrochlorothiazide, chlorothiazide, chlorthalidone)
o Thiazide diuretics are used first-line treatment for hypertension, edema and nephrogenic diabetes insipidus (DI) (rare).
o Thiazide diuretics inhibit the Na+/Cl− co-transporter channel in the distal tubule of the nephron leading to reduction in Na+ reabsorbed in kidney leading to rise in Na+ lost in urine hence more water lost in urine.
o Therefore Na+, Cl− (and water) remain in the lumen of the tubule hence natriuresis and diuresis.
o In addition, the actions of the thiazides impact other ions as follows: A passive Na+/H+ exchange occurs at a distal site in the tubule. Na+ gradients drive this exchange. When the Na+/Cl− cotransporter is blocked, the Na+ concentration in the lumen of the tubule is high, this facilitates Na+ reabsorption in exchange for excretion of H+ ions at this distal site. Therefore thiazides create alkalosis by H+ ion loss through a secondary, passive exchange.
o Similarly, Na+ is exchanged for K+ at a distal site in the tubule. By enhancing delivery of Na+ to distal sites of the nephron, Na+ is exchanged for K+, leading to enhanced K+ excretion, in a similar manner to the K+ depletion that occurs with loop diuretics.
o Thiazides also promote Ca+2 reabsorption through a poorly understood mechanism.
PST 05104 Pharmacology & Therapeutics 131 NTA Level 5 Semester 1 Facilitator Guide
Owing to the fact they act so distally in the nephron, after much of the Na+ reabsorption has already occurred, thiazides are relatively weak diuretics when compared with loop diuretics.
Thiazides are also vasodilators, an effect independent of their diuretic actions. Their antihypertensive effect is probably related mainly to this mechanism and not the
diuretic mechanism.
Effect on plasma ion concentrations: Decreased Na+, Cl−, K+, Mg+2, Increased Ca+2, Increased HCO3−. (This creates a metabolic alkalosis.) This is a result of H+ ion loss. Remember that the equation will shift left with a loss of H+:
i.e H+ + HCO3 – →H2O+CO2
Loop Diuretics: ( furosemide, ethacrynic acid, torsemide, bumetanide )
Loop diuretics are used in management of edema in Heart failure, Nephrotic
syndrome and Liver failure. They are also used in acute hypercalcemia.
Loop diuretics inhibit the Na+/K+/2Cl− co-transporter channel in the thick ascending limb (Henle‘s loop) of the renal tubule. This results in less Na+ being reabsorbed back into the body. Cl− and K+ also move in the same direction through this ion channel, as does Na+. Therefore Na+, Cl−, and K+ are lost in the urine hence Natriuresis and diuresis.
Blockade of the Na+/K+/2Cl− cotransporter has effects on other ions as well as
follows:
Blockade of the Na+/K+/2Cl− cotransporter interferes with the ability of K+ and Cl-channels to create the positive to negative gradient.
Disruption of this electrochemical gradient facilitates excretion of Ca+2 and Mg+2. Normally these divalent cations undergo paracellular reabsorption, repelled by the positively charged tubular lumen and attracted to the negatively charged interstitium. Attenuation of the positive to negative gradient reduces paracellular reabsorption of
A passive Na+/H+ exchanger is present at a distal site in the tubule. Na+ gradients drive this exchange. When the Na+/K+/2Cl− channel is blocked, the Na+ concentration in the lumen of the tubule is high, which facilitates the reabsorption of
Na+ and excretion of H+ at this distal site. Therefore furosemide creates alkalosis by H+ ion loss through a secondary, passive exchange.
Similarly, by enhancing delivery of Na+ to distal sites of the nephron, Na+ is exchanged for K+, leading to enhanced K+ excretion, and this further depletes K+.
Like the thiazides, the loop diuretics are also believed to act as vasodilators, an effect independent of their diuretic actions. This may contribute to the anti-hypertensive effects of the loop diuretics.
Potassium-Sparing Diuretics: ( Triamterene, amiloride, Spironolactone and Eplerenone )
Potassium-sparing diuretics are diuretics that result in increased urine production and
also lower blood pressure while increasing serum levels of potassium.
The goal of potassium-sparing diuretics is to prevent this reabsorption of Na+ and subsequent loss of K+ in the late distal tubule or collecting duct of the nephron.
PST 05104 Pharmacology & Therapeutics 132 NTA Level 5 Semester 1 Facilitator Guide
The exchange of Na+ for K+ in the distal nephron is mediated by the actions of the epithelial Na+ channel (ENaC) on the luminal side of the membrane and the Na+/K+-ATPase pump on the basolateral membrane (side opposite the lumen of the tubule).
Triamterene and Amiloride: inhibit this exchange of Na+ for K+ by inhibiting ENaC alone or both ENaC and the Na+/K+-ATPase pump.
Reduced entry of Na+ into the cell reduces the amount of Na+ that can be exchanged for K+ at the ATPase pump. With the Na+/ K+-ATPase pump unable to exchange
Spironolactone and Eplerenone: These drugs directly antagonize aldosterone.
Normally, aldosterone binds to the mineralocorticoid receptor (MR). The MR-aldosterone complex translocates to the nucleus, where it binds to specific DNA sequences to increase the number of ENaC channels and Na+/K+-ATPase pump. Therefore, by blocking the MR, aldosterone antagonists inhibit the activity of ENaC and the Na+/K+-ATPase pump, reducing Na+ reabsorption and producing mild natriuresis and diuresis.
Carbonic anhydrase inhibitors : (Acetazolamide, Dorzolamide, methazolamide )
Carbonic Anhydrase (CA) is classified as a diuretic, but its important clinical effects are related to its effect on acid-base balance and on intraocular fluid formation. CA is present at various sites throughout the nephron, but is mainly found on the luminal
membrane of proximal tubule cells.
Carbonic anhydrase (CA) catalyses the following reaction:
H2CO2 <–> HCO3(-) +H+ <–> CO2+ H2O
CAIs inhibit this enzyme, which results in this reaction occurring at a much slower rate compared with the catalysed rate, effectively stopping the reaction. The difference in reaction speed is over 1000-fold.
The Na+ is transported across the basolateral membrane (the side opposite the tubular lumen) into the blood along with the HCO3−. The net effect of these movements is Na+ and HCO3− reabsorption.
Thus the effect of CAIs is to reduce the reabsorption of both Na+ and HCO3−. The net effect is loss of Na+ and HCO3− in the urine.
The effect of CAIs on the acid-base status is that loss of HCO3− lowers the pH.
Osmotic Diuretics: ( Mannitol )
Osmotic agents freely enter the glomerulus and Bowman‘s space and enter the nephron in the ultrafiltrate.
Osmotic diuretics are not reabsorbed from the lumen of the nephron and create an
osmotic force, pulling more fluid into the lumen. This is then carried out as urine.
As a second primary mechanism for a diuretic, the increased renal blood flow effectively washes away solutes from the renal medulla, reducing tonicity in this region of the kidney.
The hypertonicity of the medulla is a major driving force for reabsorption of fluid from the renal tubule. Reducing this tonicity mitigates the forces that concentrate the urine in the ascending limb of Henle.
PST 05104 Pharmacology & Therapeutics 133 NTA Level 5 Semester 1 Facilitator Guide
Lowering the concentration of Na+ in the ascending limb of Henle reduces the driving force for Na+ reabsorption in this region, leading to diuresis.
Antidiuretic Hormone (Vasopressin) Analogues
Vasopressin, Desmopressin and Terlipressin
o Vasopressin is produced in the hypothalamus and stored in the posterior pituitary gland. Factors that stimulate its physiologic release include increased serum osmolarity and hypotension. Its primary actions are therefore to increase body water to control osmolality and to increase blood pressure. A third action that it exerts is to help stop bleeding through platelet stimulation.
o Vasopressin binds two types of receptors: V1 and V2. V1 is subtyped into V1a and V1b. V1 receptors are found in many locations of the body, including endothelium and many other sites. V2 receptors are located in the collecting ducts of the nephron.
o At very low concentrations vasopressin acts on V2 receptors. Only at higher doses are the V1 receptors activated.
o Vasoconstriction effect: V1 receptors are located on vascular smooth muscle and produce a potent vasoconstrictor effect when stimulated. This occurs only at higher serum levels of vasopressin. Activation of V1 receptors results in increased intracellular calcium.
o Antidiuresis action: V2 receptors are located in the collecting duct of the nephron. When stimulated, they activate pores called aquaporins (e.g., aquaporin 2). These pores usually are stored in intracellular vesicles and when stimulated by vasopressin will fuse with the luminal membrane and facilitate the reabsorption of water from the nephron lumen back into the body. In the absence of the vasopressin and the aquaporins, the collecting duct is impermeable to water and will not absorb any water.
o Platelet Function: Factor VIII and von Willebrand‘s factor (vWF) bind together and then bind platelets, which causes platelet activation. A deficiency in either of these two factors will result in decreased platelet function and bleeding disorders
(hemophilia A and von Willebrand‘s disease). Desmopressin binds to V2 receptors, which are instrumental in endothelial release of factor VIII.
Anticholinergics
M3 Selective: (Darifenacin and solifenacin). Nonselective: (oxybutynin, tolterodine and trospium)
o The human bladder contains all five subtypes (M1 to M5) of muscarinic (M) receptors. Although M2 receptors are more abundant in this region, M3 receptors mediate contraction of the detrusor muscle in the bladder.
o Detrusor muscle contraction facilitates emptying of the bladder (micturition). Abnormal contractions of the detrusor, also known as hyperreflexia, can lead to incontinence, specifically urge incontinence. Anticholinergics that antagonize the M3 receptor inhibit these detrusor contractions, easing the symptoms of urge incontinence.
PST 05104 Pharmacology & Therapeutics 134 NTA Level 5 Semester 1 Facilitator Guide
Alpha-1 (α1) Antagonists:
Prazosin, terazosin, doxazosin and tamsulosin
o α1 Receptors are also found in the urinary sphincter (also smooth muscle) of the bladder. The sphincter controls the flow of urine out of the bladder.
o In patients with an enlarged prostate, pressure exerted by the prostate on the sphincter can interfere with normal urine flow. Therefore patients with an enlarged prostate experience hesitancy (difficulty starting urination) and typically do not urinate much at a time but experience urinary frequency.
o An α1 antagonist can relax the urinary sphincter, which facilitates the flow of urine.
5α-Reductase Inhibitors
Prototype: finasteride and dutasteride
o The 5α-reductase enzyme is the last step in the synthesis of DHT, the active form of testosterone. Prostate cells depend on stimulation by DHT for their growth. Reducing levels of DHT will therefore slow growth of the prostate.
o The 5α-reductase type II isoform is highly expressed in prostate epithelial cells. Selective or nonselective blockade of this enzyme results in decreased formation of DHT, inhibiting the growth-stimulating effects of this androgen.
STEP 3: Drug Interactions Associated with Drugs acting on Genital-Urinal System (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with drugs acting on genital-urinal system?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Most drugs in this group do not have significant interactions.
STEP 4: Side Effects of Drugs acting on Genital-Urinal System (20 minutes)
Diuretics
Thiazides Diuretics: (Hydrochlorothiazide, chlorothiazide, chlorthalidone) o Dehydration and decreased Na+ occur.
PST 05104 Pharmacology & Therapeutics 135 NTA Level 5 Semester 1 Facilitator Guide
Hypokalaemia or hypokalemic metabolic alkalosis: Thiazide diuretics enhance excretion of both K+ and H+ because of increased distal tubule delivery of Na+, and hence Na+ reabsorption, in the distal nephron.
Impaired glucose tolerance is caused by impaired insulin release and diminished use of glucose.
Hyperlipidemia: Thiazide diuretics increase cholesterol and low-density lipoprotein (LDL); the mechanism has not been established.
Hyperuricemia: Thiazides compete with uric acid for secretion into the PT, reducing the excretion of uric acid. This can lead to attacks of gout.
Impotency (rare) is likely a result of reduced volume.
Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and reduced blood pressure. This is typically only seen in patients with already reduced GFR.
Loop Diuretics: (furosemide, ethacrynic acid, torsemide, bumetanide)
Hypokalaemia is caused by Na+ reabsorption in exchange for K+ excretion at the distal tubule.
Metabolic alkalosis (increased HCO3−)
Increased exchange of Na+ in the lumen for H+ in the cell, resulting in H+ loss.
Other electrolytes disturbances: Given the large number of ions (Na+, Cl−, and so on)
that are affected by these agents, electrolytes should be monitored.
Ototoxicity: Reversible hearing loss occurs most often in those with reduced renal
function or who are receiving other ototoxic agents such as aminoglycoside antibiotics. The mechanism has not been established, although the Na+/K+/2Cl−
transporter is also found in the inner ear. High-dose furosemide can cause permanent deafness.
Hyperuricemia: The reduction in volume induced by the potent actions of loops elicits a compensatory increase in uric acid reabsorption in the PT. Loop diuretics also compete with uric acid for secretion into the PT. Increased levels of uric acid may precipitate attacks of gout.
Potassium-Sparing Diuretics: (Triamterene, amiloride, Spironolactone and Eplerenone)
Hyperkalemia can be exacerbated if the patient is taking another drug that raises potassium or is supplementing with potassium from the diet or from supplements. Patients with impaired renal function are also at higher risk for developing severe hyperkalemia.
Metabolic acidosis occurs via decreased secretion of H+ through the Na+ channel.
Spironolactone Specific: Antiandrogenic actions mainly gynecomastia, menstrual disorders and testicular atrophy.
Carbonic anhydrase inhibitors : (Acetazolamide, Dorzolamide, methazolamide )
Hyperchloremic metabolic acidosis occurs because of reduction in bicarbonate stores.
Renal stones: Renal output of phosphates and calcium increases with CAI use. Chronic use of CAIs may also reduce excretion of solubilizing factors and, coupled
PST 05104 Pharmacology & Therapeutics 136 NTA Level 5 Semester 1 Facilitator Guide
with the alkalinization of the urine (Ca+2 salts are relatively insoluble at alkaline pH), creates an ideal environment for stone development.
Hypokalemia: Additional NaHCO3 in the collecting tubule stimulates the secretion of K+ because of maintenance of the ion gradient.
Osmotic Diuretics: ( Mannitol )
Extracellular volume expansion: Osmotic diuretics rapidly distribute to the extracellular compartment, extracting water from cells.
Before onset of the diuresis, this can lead to expansion of the extracellular space.
Frank pulmonary edema can arise in patients with heart failure or pulmonary
congestion.
Dehydration and hypernatremia: Excess use without fluid replacement can lead to dehydration. Composition of serum ions and fluid balance should be monitored.
Antidiuretic Hormone (Vasopressin) Analogues
Vasopressin, Desmopressin and Terlipressin
o Vasopressin side effects: Excessive vasoconstriction. The use of vasopressin should be restricted to physicians trained in critical care.
o Desmopressin side effects: Water intoxication (hyponatremia): This is caused by the
antidiuretic action and results in water retention leading to dilution of electrolytes, specifically Na+. Hypotension (paradoxical to other analogues): If administered by the intravenous route, desmopressin must be given slowly.
Anticholinergics
M3 Selective: (Darifenacin and solifenacin). Nonselective: (oxybutynin, tolterodine and trospium)
o Typical anticholinergic side effects: Dry mouth, constipation, blurred vision, erythema and pruritus.
Alpha-1 (α1) Antagonists:
Prazosin, terazosin, doxazosin and tamsulosin
o Orthostatic hypotension is common and can be quite significant, usually occurring within 90 minutes of the first dose of the drug. It can lead to dizziness and falls.
o Headache might be caused by cerebral vasodilation. o Somnolence may occur.
o Nasal congestion is caused by dilation of vessels in the nasal passages, causing mild swelling.
o Palpitation is a result of reflex tachycardia.
o Cardiovascular events: Although these agents are typically well tolerated, results of a recent study suggest that they may be associated with an increased risk, summarized in the Antihypertensive section.
PST 05104 Pharmacology & Therapeutics 137 NTA Level 5 Semester 1 Facilitator Guide
5α-Reductase Inhibitors
Prototype: finasteride and dutasteride
o Sexual dysfunction: Decreased libido, ejaculation disorders, and erectile dysfunction are caused by the antiandrogenic effects.
STEP 5: Contraindications of Drugs Acting on Genital-Urinal System (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of drugs acting on genital-urinal system? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Diuretics
Thiazides Diuretics: (Hydrochlorothiazide, chlorothiazide, chlorthalidone)
o Sulfa allergy: Thiazide diuretics should be used with extreme caution (or not at all) in patients reporting hypersensitivity reactions to sulfa-containing drugs.
Loop Diuretics: ( furosemide, ethacrynic acid, torsemide, bumetanide ) o Hypovolemia is a contraindication.
o Severe K+ abnormalities are contraindications because these drugs decrease K+ level. o Sulfa allergy: Furosemide, bumetanide, and torsemide may be cross-reactive in those
who have an allergy to sulfonamides.
Potassium-Sparing Diuretics: ( Triamterene, amiloride, Spironolactone and Eplerenone )
o Severe K+ abnormalities: Not used in patients with hyperkalaemia.
Carbonic anhydrase inhibitors : (Acetazolamide, Dorzolamide, methazolamide ) o No major contraindications
Osmotic Diuretics: ( Mannitol )
o Active cranial bleeding: If bleeding is occurring into the brain, then the mannitol will be directly added to the brain and will raise the osmotic pressure in the brain and lead to water being added to the brain, which is the opposite of what the mannitol is being given for.
o Continuous administration of mannitol should not occur, because the drug will accumulate in the tissues and result in osmotic-induced tissue edema, including in the brain.
PST 05104 Pharmacology & Therapeutics 138 NTA Level 5 Semester 1 Facilitator Guide
Antidiuretic Hormone (Vasopressin) Analogues
Vasopressin, Desmopressin and Terlipressin
o Desmopressin only: patients at risk for unregulated water consumption (psychogenic polydipsia), because they can develop hyponatremia
Anticholinergics: Bladder
M3 Selective: (Darifenacin and solifenacin). Nonselective: (oxybutynin, tolterodine and trospium)
o Conditions in which cholinergic blockade would exacerbate an already serious condition, or patients at risk for the following:
o Urinary retention
o Gastroparesis, gastric obstruction
o Narrow-angle glaucoma (uncontrolled)
5α-Reductase Inhibitors
Prototype: finasteride and dutasteride
o Pregnancy: Women of childbearing age should not use 5α-reductase inhibitors. They are strictly contraindicated in pregnancy.
o Testosterone is essential for development of genitalia in males; therefore these agents can lead to abnormal development.
o Pregnant women are advised not only to avoid taking the medication but also to avoid even handling the pills.
STEP 6: Key Points (5 minutes)
Metronidazole and Tinidazole are common medicines in amoebiasis
Metronidazole and Tinidazole should not given to patient who have taken alcohol
Long term use of Metronidazole and Tinidazole need clinical and laboratory monitoring
Long course and higher dose is required in liver abscess
STEP 7: Evaluation (5 minutes)
What are the indication of Metronidazole and Tinidazole
What is the dose of Metronidazole
Which adult dose Tinidazole
What is the common adverse effect of Metronidazole and Tinidazole
PST 05104 Pharmacology & Therapeutics 139 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 140 NTA Level 5 Semester 1 Facilitator Guide
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