Secondary hypertension Flashcards
What are some causes of secondary hypertension?
- renal disease (salt/H2O imbalance)
- adrenal tumours (aldosterone)
- aortic coarctation (narrowing of aorta)
- Steroids, drugs, Rx
What are 6 determinants for secondary hypertension?
- Renal diseases (e.g. Glomerulonephritis, diabetic nephropathy)
- Vascular causes (e.g. Renal artery stenosis)
- Hormonal abnormalities (e.g. Conn’s syndrome, Cushing’s syndrome, Pheochromocytoma)
- Drugs (Contraceptive pill; liquorice)
- Pregnancy (Pre-eclampsia)
- Genetic disorders
What is glomerulonephritis?
Inflammation of glomeruli
• Can be acute or chronic
• Kidney becomes contracted and granular – due to cortical atrophy
• Some diseases induce this
• Causes fluid imbalance and swelling in the lower limbs
What are the causes of endocrine hypertension?
In the Adrenal cortex
• Adrenal adenoma producing aldosterone (Conn’s syndrome) – can be due to benign tumour
• Adrenal hyperplasia – can be due to benign tumour
• Cushing’s syndrome excess cortisol increasing adrenalin’s vasoconstrictive effect
Adrenal medulla
• Pheochromocytoma (adrenalin secreting tumour)
How can endocrine hypertension be treated?
Tumours can be removed and patients can be cured of secondary hypertension
What drugs can induce hypertension?
- NSAIDs
- Oral contraceptives
- Alcohol
- Cocaine
- Erythropoietin
- Glucocorticoids
- Ginseng, yohimbin
- Tyramine and MAO inhibitors (antidepressants)
- Angiogenesis inhibitors
What does kidney cancer do (in terms of blood vessels) and what drugs are used for it?
- It’s highly angiogenic and metastatic tumour – induce blood vessel growth
- Antiangiogenic drugs inhibit growth of new vessels
How does angiogenesis take place in tumours?
- Angiogenesis - formation of new blood vessels is essential for solid tumour growth and metastasis
- Regulated by proangiogenic soluble mediators such as vascular endothelial growth factor (VEGF – vascular endothelial growth factor)
- Tumours secret VEGF and they act on nearby capillaries causing them to grow and form new vessels
How do antiangiogenic drugs stop angiogenesis?
Antiangiogenic drugs that block the VEGF signalling pathway prolong progression free survival in several cancers and are now in broad clinical use
What is a side effect of antiangiogenic drugs?
Hypertension is the most common CVS toxicity of this therapeutic class affecting between 19%-67% of patients
What is the evidence that VEGF is involved in maintaining vascular tone?
- Hypertension - Low VEGF/VEGF inhibited
* Hypotension - High VEGF
What are the primary receptors in the VEGF signalling pathway?
- Primary receptors: VEGFr1, VEGFr2, VEGFr3
* Sit on endothelial cells with co-receptors
What is the most common VEGF?
- VEGFA the most common VEGF but VEGFB/C/D also exist
* They bind to receptors and initiate blood vessel growth/formation from old vessels
What does VEGF-A binds to?
VEGF-A is the main component that binds to VEGFR-1 and VEGFR-2 with VEGFR-2 having predominant role in cell signalling
What are VEGF co-receptors?
Neuropilins (NRP1, NRP2) are VEGF co-receptors but can also signal independently
What are the functions of VEGF-B, VEGF-C and VEGF-D?
- VEGF-B has restricted angiogenic activity e.g. in heart
* VEGF-C and VEGF-D involved in vasculogenesis and lymphangiogenesis
What happens when VEGF binds to VEGF-2?
Through binding to its receptor there’s multiple pathways activated
- Endothelial cell induces relaxation effect through NO – causes vasodilation
- Angiogenesis induced through PIP2 calcium signalling
- Protein Kinas B pathway activated – cell survive increased, apoptosis reduced
- RAS/RAF/MEK/MAPKinaes pathway activated – increases gene expression, transcription and cell proliferation of endothelial cells, can induce angiogenesis
What happens when VEGF is blocked?
Blocking VEGF binding blocks a lot of the processes – NO induction prevented, vascular tone increases
What are different anti-angiogenic therapies?
- Anti-VEGF
- Receptor tyrosine kinase inhibitors
- mTOR blocker
Mechanism of anti-VEGF?
- Binds to VEGF molecule
* Prevents from binding to receptor
Mechanism of receptor tyrosine kinase inhibitors?
Small molecule inhibitors that target the receptors
Mechanism of mTOR blocker?
- mTOR is a protein in tumour cells that makes VEGF
* blocking it prevents VEGF synthesis
Which drug causes the most/highest frequency of hypertension as a side effect?
- VEGF inhibitors e.g. axitinib – 90% incidence of hypertension, cause the most hypertension
- because they’re very potent
- This side effect is known as an on-target effect (as opposed to off target side effect) – the drugs effects are specifically because of its target.
- Also known as mechanism-dependent on-target toxicity – cause the effect is due to the mechanism of the drug
How can hypertension induced by antiangiogenic drugs be treated?
Removal of anti-angiogenic leads to rapid decrease of blood pressure
What are the mechanisms of antiangiogenic drug induced hypertension?
Not yet known!
Possibly:
• Downregulation of NOS/NO ↓ vasodilation
• Increase ET-1 ↑ vasoconstriction
• Increase bioavailability of ROS ↑ vasoconstriction, vascular remodelling
• EC dysfunction/apoptosis/rarefaction ↑ peripheral resistance
What are the different pregnancy related hypertension?
Most common complication of pregnancy and leading cause of morbidity and maternal mortality
- Chronic hypertension (already before pregnancy)
- Gestational hypertension or pregnancy-induced hypertension (PIH): New onset without the presence of protein in the urine
- Preeclampsia: Hypertension and proteinuria (have protein in urine)
- Eclampsia: Hypertension induced onset of seizures
What is nail bed capillaroscopy?
- Capillary density as a measurement of vascular rarefaction
* Reduced density could be correlated with pregnancy induced hypertension
What is capillary rarefaction associated with?
- Capillary rarefaction is associated with preeclampsia
- Associated with soluble circulating decoy receptors for VEGF (sFLT-1), and others (e.g. sENG) – they prevent VEGF from binding to its receptor (thus increase hypertension)
What is VEGF associated with?
maintenance of normal vascular homeostasis
What happens if there is impaired VEGF signalling?
Impaired VEGF signalling mediated by presence of antiangiogenic factors leads to EC dysfunction
• May lead to reduction in cell numbers and cell death
What is found in maternal plasma?
In maternal plasma there’s potential mediators that may increase soluble decoy receptor – may be from plasma
- AT1-AA
- TNF-a
- HIF-1a
