1.1.3. -> inhibition of Na+/K+ ATPase -> increased intracellular Na+, NXC reversal, increased Ca2+ -> increased vascular smooth muscle contraction -> vasoconstriction -> increased peripheral resistance -> hypertension

1.1.3.1. reversible sodium calcium exchanger - reversal leads to an accumulation od intracellular sodium and calcium --> increased smooth muscle contraction

1.1.4. --> positive inotropic effect -> increased cardiac output -> hypertension

1.1.5. --> potassium depletion -> hypokalaemia -> vasoconstriction -> hypertension

1.1.6. --> increased fluid retention -> ECFV expansion -> increased plasma volume

1.2. up to 2% of hypertensives

1.3. Causes

1.3.1. Glucocorticoid suppressible hyperaldosteronism

1.3.2. Mineralocorticoid secreting carcinoma

1.3.3. Aldosterone secreting adenoma

1.3.4. Benign adrenal hyperplasia

1.4. 70% unilateral adenoma, 30% bilateral hyperplasia

1.5. severe hypertension +hypokalaemia

2. Primary vs. Secondary

2.1. Primary (essential or idiopathic) - no obvious cause. Accounts for 90-95% of cases.

2.2. Secondary - arises through a specific identifiable cause.

3. Causes of secondary hypertension

3.1. acute stress

3.2. renal

3.3. endocrine

3.4. coarctation of the aorta

3.5. pregnancy

3.6. neurological disorders

3.7. alcohol and drug use

3.8. increased intravascular volume

3.9. acute stress

4. Features of secondary hypertension

4.1. onset before 20 years or after 50 years

4.1.1. secondary tend to be quite young

4.2. elevated pressure (e.g. >200/120mmHg)

4.3. Features indicative of secondary causes

4.3.1. unprovoked hypokalaemia

4.3.2. variable pressure

4.3.3. family history o renal or endocrine disease

4.4. poor response to usually effective therapy

5. Function of kidneys

5.1. control of EC fluid volume

5.2. blood pressure control

5.3. Achieved by ...

5.3.1. Glomerular filtration rate

5.3.2. reabsorption of Na+ and water

5.3.3. Renin-angiotensinogen-aldosterone system --> vasoconstriction

5.3.4. defects in inappropriate renin secretion / Na+ retention

6. Renin-angiotensin mediated hypertension

6.1. Renal artery stenosis - (most common)

6.2. renin-secreting tumours

6.3. Renal parenchymal disease (parenchymal - functional tissue of the organ)

6.4. Coarctation (narrowing) of the aorta (above pressure is high, below pressure is low)

6.5. Oestrogen induced hypertension

7. Renin artery stenosis

7.1. 50% of elderly have renal artery atheroma (>70 age)

7.2. 8-17% stenosis progress to occlusion (stenosis -narrowing, occlusion -blockage) in 3-4 years

7.3. 50% reduction in renal perfusion pressure stimulates renin release

7.4. other causes

7.4.1. Fibro-muscular dysplasia (enlargement)(young) - muscle becomes more fibrous

7.4.2. Takayasu's arteritis (Asian)

7.5. Obstruction can be seen in renogram

7.5.1. pinch point due to blockage

7.6. you can lose 50% of kidney function before it is noticeable

7.7. renin is the rate limiting step which initiates RAA system

8. Renal baroreflex control of GFR

8.1. Macula densa - closely packed of specialised cells, lining the wall of the cortical thick ascending limb of the loop of Henle at the transition to the distal convoluted tubule.

8.2. Plaque formation will impinge upon the vessel, pressure downstream is reduced as the vessel is the block

8.3. The pressure of the gomerula is reduced and the amount of filtered plasma is reduced

8.4. Angiotensinogen - acted on by renin (an enzyme)

8.5. Angiotensinogen II is biologically active

8.6. Constriction - effect of plaque will increase resistance to flow

8.7. It initiates RAA system to maintain GR

9. Unilateral stenosis vs Bilateral stenosis

9.1. Unilateral stenosis

9.1.1. Increased renin acts to maintain GFR

9.1.2. Hyperfiltration of contralateral kidney maintains renal function

9.1.3. salt + water balance is normal

9.1.4. AngII - increased proximal Na+ reabsorption on both sides

9.1.5. Aldosterone - increased distal Na+ reabsorption on both sides

9.1.6. Pressure natriuresis in contralateral kidney

9.2. Bilateral stenosis

9.2.1. Reduced renal plasma flow

9.2.2. Increased filtration fraction due to efferent arteriole constriction

9.2.3. Both renal arteries are blocked

9.2.4. Constriction of efferent arteriole, it compensated with blood becoming thicker, which could also increase pressure

9.2.5. Salt and water retention

9.2.6. Aldosterone increases distal Na+ reabsorption on both sides

9.2.7. No pressure natruiresis

9.2.8. Pulmonary oedema, ventricular failure, hypokalaemia

9.2.9. more serious condition than unilateral

9.3. Both

9.3.1. increased blood volume inhibits renin secretion

9.3.2. hypertension is maintained by SNS

9.4. Renin suppression

9.4.1. Suppression of renin depends if it is uni or bilateral

9.4.2. Natruiresis - the balance between NP and salt loss

10. Antihypertensives

10.1. beta andrenergic blockers

10.2. diuretics

10.3. Ca2+ channel blockers

10.4. alpha-adrenergic bockers

10.5. angioplasty or by-pass graft

11. Pressure Natruiresis

11.1. Increased excretion of sodium along with water when there is an increase in arterial pressure

12. Hypertension of adrenal origin

12.1. Adrenal cortex

12.1.1. Steroids

12.1.1.1. mineralocortcoids (aldosterone)

12.1.1.2. glucocorticoids (cortisol)

12.2. Adrenal medulla

12.2.1. Catecholamines

12.2.1.1. adrenaline

12.2.1.2. noradrenaline

13. Cushing's Syndrome

13.1. Harvey Cushing -first clinical description in 1932

13.2. Cause

13.2.1. Prolonged exposure to free circulating glucocorticoids

13.2.2. Therapeutic misuse of glucocorticoids or adrenocorticotrophin (ACTH)

13.2.3. ACTH-dependent (83%) or ACTH-independent (17%)

13.2.4. 'Diabetes of a bearded woman'

13.3. Typical features

13.3.1. Thinning of the skin

13.3.2. Weight gain

13.3.3. Central obesity

13.3.4. Moon face

13.3.5. Backache

13.3.6. Malaise

13.3.7. Depression / psychosis, euphoria

13.3.8. Hirsuitism

13.3.9. Striae - stretch marks

13.3.10. HYPERTENSION

13.3.11. Buffalo hump

13.3.12. Sexual dysfunction

13.4. Increased cortisol

13.4.1. --> decreased vasodilators (kinins/PGs) --> increased total peripheral resistance --> hypertension

13.4.2. --> decreased catecholamine metabolism --> vasoconstriction --> increased peripheral resistance --> hypertension

13.4.3. --> increased sensitivity to vasoconstrictors -> vasoconstriction -> increased total peripheral resistance -> hypertension

13.4.4. increased renin substrate -> increased plasma renin activity (PRA) --> increased Ang II --> vasoconstriction --> increased peripheral resistance --> hypertension

13.4.5. --> increased ICFV to ECFV shift -> ECFV expansion -> increased plasma vol. -> increased CO -> hypertension

13.4.5.1. cortisol will bind to the same receptor as aldosterone, promoting shift between IC and EC fluid

13.4.6. --> increased PNMT (converts noradrenaline to adrenaline) activity in adrenal medulla -> increased adrenaline -> increased CO -> increased hypertension

13.4.7. Mineralocorticoid receptor (MR) increased activity --> increased Na+/fluid retention --> plasma volume --> increased CO --> hypertension

13.4.8. cortisol activated methyl transferal

13.4.9. elevated phenylethanolamine N-methyl transferase activity seen in hypertension.

13.5. Treatment

13.5.1. life expectancy < 5 years if not treated

13.5.2. adrenal adenoma + ectopic tumours

13.5.2.1. surgery

13.5.3. Adrenal carcinoma

13.5.3.1. pharmaceutical (adrenolytic drugs)

13.5.4. pituitary tumour

13.5.4.1. transphenoidal surgery

13.5.5. adrenalectomy

13.5.5.1. requires lifelong steroid replacement therpay

14. Adrenal medulla - Pheochromocytoma

14.1. Medulla secretes catecholamines (Adr/NAdr)/ dopamine

14.2. Up to 4Kg 100g normal

14.3. Chromafin cell tumours

14.3.1. Pheochromocytoma

14.4. Treatment

14.4.1. alpha-adrenergic antagonist (e.g. phenoxybenzamine) prior to surgery

14.5. severe adrenaline and / or noradrenaline

14.6. severe hypertension

14.6.1. increased peripheral resistance

14.6.2. increased cardiac output

14.7. continuous or episodic

14.7.1. induced by compression of tumour

14.7.2. frequency - several times a week for 15 minutes

15. Summary

15.1. Secondary hypertension is rare but usually severe

15.2. Common causes

15.2.1. Kidney

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