endocrine and kidney diseases - zacchetti

Vasopressin

• Vasopressin is important in central diabetes insipidus as replacement therapy for vasopressin deficiency.
• Vasopressin deficiency can result in the production of 10-15 L/day of urine, leading to dehydration and hypokalemia.
• LysVP (lysine vasopressin, derived from pigs) can be used instead of ArgVS (arginine vasopressin, derived from humans).
  • Acts on V1 receptors, causing vasoconstriction.
  • Has a short half-life.
• Desmopressin (DDAVP) is a modified vasopressin with two modifications:
  • D-Arg causes higher affinity for the V2 receptors without affecting V1, almost eliminating vasoconstriction.
  • Terminal cysteine is deaminated, increasing vasopressin's stability and prolonging its activity.
• Arginine Vasopressin can be used in septic shock to increase the pressure effect of catecholamines (norepinephrine).
• DDAVP (Desmopressin) can be used in diabetes insipidus of central origin, but not in cases originating in the kidney due to lithium toxicity.
• Desmopressin can distinguish between nephrogenic and central diabetes insipidus.
• Desmopressin can be used when there is inadequate vasopressin secretion.
• Desmopressin can be administered intranasally or sublingually with different doses.
• It can be used for nocturnal enuresis (intranasal) and bleeding disorders.
• Intranasal administration has better bioavailability, while sublingual requires higher doses.
• Administration to the mucosa of the mouth is being experimented with using modified patches inspired by octopus suckers to increase permeation.
• Desmopressin side effects include headaches, stomach pain, sickness, and running/bleeding nose (due to vasomotor activity).
• At high local concentrations, desmopressin can involve V1 receptors in the intranasal mucosa.
• Desmopressin can cause dizziness and weight gain due to water retention.
• Overdosage can lead to water intoxication.
• Systemic V1 receptor effects are valid only for vasopressin, not desmopressin.

Terlipressin

• This is a version of vasopressin that acts as both a V1 and V2 agonist.
• It is used mainly for V1 activity in conditions like septic shock, to support blood pressure when catecholamines are insufficient.

V2 Antagonists

• Vasopressin receptor antagonists, particularly for V2 receptors, are called aquatics.
• Aquatics increase renal-free water excretion, unlike diuretics that excrete sodium or sodium and water.
• Used for hyponatremia and hypo-osmolality, especially with excessive vasopressin secretion.
• Loop diuretics can mimic the aquaretic effect but require appropriate salt intake.

Vaptans

• These include Mozavaptan, Tolvaptan, Conivaptan, Lixivaptan, Nelivaptan and Relcovaptan.
• These are FDA-approved for hypervolemic and euvolemic hyponatremia.
• Tolvaptan is used for polycystic kidney disease and was approved in 2018.
• Research into V1 receptor antagonists for CNS effects was halted.
• Antagonists for V1A receptors are being explored for vasomotor issues like Raynaud’s disease.

Other Drugs Affecting Vasopressin

• Drugs that interfere with vasopressin secretion include psychotropic drugs, neuroleptics, antidepressants, and Vinca alkaloids.
• NSAIDs also interfere with vasopressin agonists.
• Aquaporin agonists have no reason to be administered as the wild-type protein is already at its highest activity.
• Aquaporin antagonists are in preclinical development.

Antihypertensive Drugs

• Used for severe-resistant hypertension and hypertensive crises.

Hydralazine

• Used in severe or resistant essential hypertension, especially during hypertensive crises.
• Can be given orally or intravenously.
• May involve potassium channels in arterial vasodilation.
• Causes reduction in peripheral resistance with baroreceptor activation.
• Beta-blockers can help manage baroreceptor reflexes.
• Can cause tachycardia, increased contractility, increased renin, and hydrosaline retention.
• Does not cause strong orthostatic hypotension.
• Administered orally and undergoes a first-pass effect.
• Side effects include tachycardia and hypotension (related to IV administration), “steal of blood flow” at the coronary level, and immunological reactions/peripheral neuropathies (sensitive to vitamin B6 administration).

Minoxidil

• Vasodilator used orally for severe or resistant hypertension.
• Activates potassium channels, causing smooth muscle relaxation.
• Causes a reduction in peripheral resistance (similar to hydralazine).
• Frequent side effect: hypertrichosis.
• Can cause ECG changes and has a black box warning for pericardial effusion/cardiac tamponade.
• Minoxidil is administered gradually, and diuretics/beta-blockers can help manage hydrosaline retention/tachycardia.
• May cause cardiac ischemia and reduced glucose tolerance.

Diazoxide

• Strong drug given orally or intravenously for acute or severe hypertension.
• Potassium channel activator that inhibits insulin secretion.
• Can cause hyperglycemia (50% of patients).
• Use for excessive insulin secretion (insulinomas or congenital hyperinsulinemia).
• May produce hydrosaline retention, myocardial ischemia, and cerebral ischemia (hypotension).

Sodium Nitroprusside

• Molecule of cyanide with iron and a nitric oxide donor, metabolized to NO.
• Used IV in acute hypertensive crises to produce rapid and controlled hypotension.
• Activates guanylate cyclase in smooth muscles, causing vasodilation.
• Affects both arteries and veins, reducing peripheral resistance and preload.
• Reduces oxygen consumption and can be used in myocardial infarction.
• Side effects include hypotension and cyanogenesis (overdose).
• Antidotes for cyanide poisoning: hydroxocobalamin, sodium thiosulfate, and sodium nitrate.
• Can cause methemoglobinemia and non-specific side effects like nausea, asthenia, dizziness, and psychosis.

Uricosuric Agents

• Increase uric acid excretion for hyperuricemia and gout.
• Hyper-uricosuria can produce kidney stones.
• Hydration and diluted urine are important.
• Some uricosuric agents interfere with other drugs' excretion.

Gout Treatment

• Lifestyle re-evaluation is very important.
• Xanthine oxidase inhibitors reduce uricosuric acid by inhibiting the enzyme xanthine oxidase.
• Allopurinol and oxypurinol (for patients with poor kidney function) are examples.
• Febuxostat is another xanthine oxidase inhibitor.
• Benzbromarone was withdrawn due to hepatotoxicity.

Febuxostat

• Xanthine oxidase inhibitor, considered more potent and effective than allopurinol.

Probenecid

• Uricosuric agent that competes with penicillin excretion, prolonging penicillin's half-life.
• Interferes with the organic anion transporter (OAT).
• Can interfere with penicillins, weak acids, NSAIDs, methotrexate, zidovudine, and lorazepam.

Rasburicase

• Recombinant urate oxidase given parenterally to reduce uricosuric acid in hyperuricemia (e.g., tumor lysis syndrome).
• Half-life is 8 hours; hypersensitivity reactions may occur.
• Can produce hemolysis in G6PD deficiency.

Pegloticase

• Pegylated uricase given intravenously every two weeks.

Drugs with Uricosuric Properties

• Include amlodipine, losartan, atorvastatin, and fenofibrate.
• Losartan can inhibit URAT1 (transporter).

Drugs with Anti-Uricosuric Action

• Loop diuretics and thiazide diuretics produce hyperuricemia.

URAT1 (SLC22A12)

• Specific urate transporter involved in uric acid reabsorption.
• SNPs in URAT1 might explain some cases of hyperuricemia.

Lesinurad

• URAT1 inhibitor approved in 2015/16.
• Administered orally with lots of water.
• Given with allopurinol or Febuxostat to avoid kidney failure.
• Was withdrawn from the market for commercial reasons, but safety concerns likely played a role.
• AR882 is another URAT1 inhibitor in phase 3 clinical trials.

Drugs and Dialysis

• Dialysis can change the pharmacokinetic properties of drugs.
• Monitor dialysis patients for clinical efficacy and toxicity.
• Drug effect can indicate dialysis effectiveness.
• Dialyzability is related to drug dosage.

Determinants of Drug Dialysis

• Molecular size.
• Protein binding.
• Volume of distribution.
• Water solubility.
• Plasma clearance (metabolism vs. excretion).

Molecular Weight

• Hemodialysis uses synthetic membranes with fixed pore sizes, and drug movement depends on molecule size vs. pore size.
• Peritoneal dialysis is more permissive.

Protein Binding

• Protein binding reduces dialyzability, but uremia can decrease protein binding.

Volume of Distribution

• High volume of distribution decreases protein dialyzability.

Plasma Clearance

• High hepatic or metabolic clearance reduces the impact of dialysis.

Dialysis Membrane

• Dialysis data is based on specific membranes.
• Changes in membrane technology can affect dialysis characteristics.

Flow Rate

• This is another factor affecting drug dialysis.

Urinary Tract Infections (UTIs)

• Very frequent in women and can lead to recurrent infections.
• Management includes antibiotics, especially for recurrent infections.
• Long-term antibiotic use can cause GI symptoms.

Na+ Bicarbonate

• Sodium bicarbonate (baking soda) can be used to make urine more basic.
• Can impair bacterial attachment to the mucosa.
• Risk of poisoning and electrolyte imbalance.

Coping with Recurrent UTIs

• Increase water intake.
• Avoid bladder irritants like caffeine, alcohol, spicy food, nicotine, carbonated drinks, and artificial sweeteners.

Traditional Remedies

• Uva Ursi and Goldenseal may help but can cause liver damage and drug interactions.

Cranberry Juice

• It was determined that there was no real efficacy to the therapy.

Antibiotics

• The spectrum of drug activity and bacterial sensitivity are important.
• Adequate drug concentration in urine is necessary.
• Quinolones, cotrimoxazole, and trimethoprim/sulfamethoxazole have been used.
• Agents that concentrate in urine include Nitrofurantoin, fosfomycin, and methenamine

Treatment for Simple UTIs

• Include trimethoprim/sulfamethoxazole (Bactrim), fosfomycin (Monurol), and nitrofurantoin.
• Cephalosporins may be used, but fluoroquinolones are not commonly recommended.

Reasons Against Fluoroquinolones

• Increased bacterial resistance.
• Relevant side effects.

Treatment for Frequent UTIs

Two Philosophies

• Full-dose antibiotics at symptom onset.

• Low-dose antibiotics over long periods (prophylaxis).

• Post-coital prophylaxis can be used.

• Hormonal replacement therapy may help reduce relapses in menopause.

Common Drugs

• Trimethoprim and sulfamethoxazole are used due to high urine concentrations.
• It is a first choice for uncomplicated UTIs and bacteria resistant to beta-lactamases or fluoroquinolones

Nitrofurantoin

• It is used for uncomplicated UTIs and prophylaxis due to high urine concentrations and low systemic effects.
• This drug has poor tissue penetration.
• Is a first-line agent for uncomplicated UTIs.
• It has a short half-life (20–60 minutes) and accumulates in the urine.
• Has a Wide-spectrum activity against gram-positive and gram-negative bacteria.

Considerations for Kidney Level

• A decrease in renal function needs an adjustment in Dosage.
• Issues with liver

Fosfomycin

• Is given orally or intravenously for multiresistant bacteria.
• Inhibits UDP-N-acetylglucosamine-3-enolpyruvyl transferase, with a bactericidal effect similar to beta-lactams.
• Not recommended for children under a certain age.

Beta-lactams

• Has high concentration in urine to have an antibacterial effect,
• cephalosporins, can rach good concentration if eliminated in the kidney

Pivmecillinam

• new drug approved to uncomplicated UTIS .

Cefepime/enme-tazobactam

• A combination used to treat UTI.

Fluroquinolones

• Shown increase amount of bacterial resistance and side effect.

General way to treat UTI

• moxifloxacin helps too reach high concnetration in the urine

Other types

• Tetracyclines, Macrolides,

Support aganist for gram+

• add vancomycin for resistance against multbacteria

Uromune

• A bacteria to treat UTI for three months and has long lasting effect.

SGLT2 inhibitors

• Can treat with cardiovascular and renal issues
• Canaglifozin, Dapaglifozin, Empaglifozin, and Bexaglifozin
• Can side effect the drug
• Can cause gangrene, osmotic uresis

Sotaglifozin

• An inhibitor with dual action for both type 1 and 2 diabetes.