Urinary Tract Pharmacology

Question 1

Proteinuria and effect if excessive?

Answer 1

Loss of protein in the urine.
If excessive amounts, can lead to hypoproteinaemia (hypoalbuminaemia and oedema) and/or progressive kidney disease.

Question 2

1. Quantitative test to measure protein in the urine?
2. Disease of what part of the kidney is associated with severe proteinuria?
3. Basic treatment principles of proteinuria?

Answer 2

1. Urine protein : creatinine ratio (UPC).
2. Glomerular disease - normally immune-mediated or due to amyloid deposition.
   Glomerular filtration pressure associated with degree of protein loss.
3. Treat underlying glomerular disease but also reduce protein loss.

Question 3

What controls the transglomerular filtration pressure?

Answer 3

Renin-angiotensin system.
- angiotensinogen converted to angiotensin I by renin.
- angiotensin I converted to angiotensin II by angiotensin converting enzyme.
- angiotensin II stimulates aldosterone secretion.
- aldosterone increases water and sodium retention.
– increases preload.
- aldosterone also constricts vascular smooth muscle.
– increases afterload.

Question 4

Angiotensin II action.

Answer 4

Acts preferentially on glomerular efferent arteriole.
Maintains GFR and transcapillary pressure in glomerulus.
Use this for pharmacological intervention.

Question 5

Blocking angiotensin II.

Answer 5

Prevents efferent vasoconstriction (effectively vasodilation).
Reduces transcapillary pressure in glomerulus.
Reduces degree of proteinuria.

Can influence renin-angiotensin pathway at 2 points:
- ACE – w/ inhibitors (ACEi).
- angiotensin receptor blockers (ARB).

Question 6

1. Indications for ACE inhibitors.
2. Examples of ACE inhibitor drugs.
3. ACE inhibitor excretion.

Answer 6

1. To reduce glomerular pressure and proteinuria.
   To reduce afterload and preload in heart failure.
   To mildly reduce BP (systemic hypertension).
2. Benazepril (biliary excretion).
   - Benefortin, Nelio, Fortekor, Benazecare.
   - Fortekor Plus - with Pimobendan.
   - Cardalis - with spironolactone.
3. Primarily biliary excretion so kidney disease does not affect its excretion.

Question 7

ACE inhibitor warnings.

Answer 7

Drops BP a little bit, can result in mild azotaemia, can impact sodium retention, so… Contraindicated in hypovolaemia, hypotensive states, hyponatraemia and AKI.
Use with care in azotemic patient, monitor urea and creatinine.

Question 8

1. Indications for angiotensin receptor blockers (ARBs).
2. Licensed for?
3. Drug example?
   - advantages.
4. ARB warnings.

Answer 8

1. To reduce proteinuria associated with CKD.
   To possibly help avoid ACE escape following chronic ACEi use.
2. Licensed for cats.
3. Telmisartan (Semintra).
   - Easy to give.
   - Liquid.
   - Easy to titrate correct dosage.
4. Care with hypotensive and hypovolaemic states.
   Monitor urea and creatinine over time in patients with CKD.

Question 9

Velagliflozin (Senvelgo).

Answer 9

Recently licensed for management of feline DM.
Alternative to insulin injections.
Sodium-glucose co-transporter 2 (SGLT-2) inhibitor.
- blocks SGLT-2 in proximal tubule, thus blocking around 90% of glucose reabsorption (do not go hypoglycaemic as remaining 10% reabsorbed via different co-transporter).
- thus reducing hyperglycaemia and associated clinical signs; excess glucose excreted in urine.

Question 10

1. Which arm of the ANS controls the contraction of the detrusor muscle which causes bladder emptying?
2. Which arm of ANS controls contraction of the muscles responsible for storing urine in the bladder?

Answer 10

1. Parasympathetic.
2. Sympathetic.

Question 11

Drug that acts on the detrusor muscle of the bladder.

Answer 11

Parasympathomimetics e.g. bethanechol.
- promotes function of acetyl choline.
- used in bladder atony.
– e.g. following obstruction that has caused bladder to stretch over time, decreasing elasticity in bladder wall.
–> helps patient to void while bladder recovers.
- cholinergic side effects (DUMBBELS).
- Defaecation/diarrhoea.
- Urination.
- Miosis (pupillary constriction).
- Bradycardia.
- Bronchoconstriction.
- Emesis.
- Lacrimation.
- Salivation.

Question 12

What is the urethra comprised of?

Answer 12

Smooth muscle internal sphincter proximally.
Skeletal muscle of the urethra more externally and distally.

Question 13

Filling phase.

Answer 13

Urine storage.
Sympathetic control.

Internal urethral sphincter under sympathetic NS control.
Skeletal muscle of urethra under voluntary control.
During filling phase, detrusor muscle relaxes and urethral sphincter remains closed.
Bladder fills and afferent impulses come from stretch receptors in bladder to the spinal cord and also telling somatic efferent to contract external urethral sphincter.
Sympathetic NS inhibits detrusor muscle from contracting and causes contraction of the internal urethral sphincter.

Question 14

Micturition (urination) phase.

Answer 14

Bladder stretch receptors stretch to point of signalling time to empty bladder.
Parasympathetic NS results in contraction of bladder smooth muscle - detrusor muscle contraction.
Switch off external urethral sphincter and internal urethral sphincter, with inhibition of sympathetic NS.
- urethral sphincter opens to allow urine out.

Question 15

Urinary sphincter mechanism incompetence (USMI).

Answer 15

Commonest in spayed bitches.
- some evidence that more collagen and less muscle in the sphincter.
- oestrogen potentiates the activity of the receptors that help to control the urethral sphincter.
Decreased urethral closure pressure.
Typically leak urine when at rest, lying down or asleep.
Need to improve urethral sphincter tone.

Question 16

Drugs used to treat USMI.

Answer 16

Alpha-adrenergic agonists.
- e.g. phenylpropanolamine.
– e.g. Propalin
- sympathomimetic.
– can cause side effects associated with this.
–> behavioural changes e.g. aggression.
–> tachycardia.
–> GI upsets.
- oral syrup formulation.
Oestrogens (Incurin).
- increase responsiveness of adrenergic receptors (Propalin).
- side effects associated with hormone
– vulval swelling, attraction to male dogs, mammary hypoplasia.
Testosterone in male dogs.

Question 17

Urethral spasm.

Answer 17

Seen in cats with FLUTD and dogs with reflex dyssynergia.
No physical obstruction.
Functional spasm.
- can occur after attempting catheterisation, causing urethral damage.
Try to relax both smooth muscle and skeletal muscle.

Question 18

Drugs to treat to urethral spasm.

Answer 18

Smooth muscle:
- Prazosin (alpha 1 antagonist, fast onset).
– Alpha-adrenergic antagonists.
– also act on vascular smooth muscle leading to vasodilation and hypotension - monitor and care w/ anaesthesia.
- Phenoxybenzamine (alpha 1 antagonist, slower onset).
Skeletal muscle.
- Dantrolene.
– uncouples excitation contraction process.
- Diazepam.
– enhances GABA activity.
– risk of idiosyncratic hepatic necrosis, (avoid in cats).
– very short half-life in dogs.
– good to give to dogs with reflex dyssynergia around 20mins before a walk.
Adjunctive treatment.
- prevention of recurrence and management of the environment.
- analgesia – NSAID –> care in kidney cases.
- glycosaminoglycans supplements.
- stress relief (nutraceuticals e.g. Zylkene, feline pheromone analogues e.g. Feliway).
- water intake – maximise.