12.1 Pharmacology of hypertension Flashcards
What is hypertension & the stages
- Persistently raised arterial blood pressure (~25% adults)
- Normal is a range
- Systolic 90-120 mmHg
- Diastolic 60-80 mmHg
- Abnormal is a range
- Stage 1: 140/90
- Stage 2: 160/100
- Stage 3: SBP > 180 or DBP > 120
What are the causes of hypertension & types?
- >90%: ESSENTIAL hypertension (primary)
- Cause unknown
- <10%: SECONDARY hypertension
- Renal disorders
- Endocrine
- 1° hyperaldosteronism → (fluid regulation)
- Pheochromocytoma (is a rare, usually noncancerous (benign) tumor that develops in an adrenal gland)
- ↑ adrenaline → ↑HR, ↑CVP, ↑vasoconstriction
- Cushing’s syndrome → (INCREASE in cortisol)
-
Drug-induced
- Abuse: e.g., cocaine → (sympathetic NS)
- Iatrogenic: e.g., combined oral contraceptive
- Pregnancy = pre-eclampsia
What are the consequences of hypertension?
- Increased risk of many cardiovascular disorders
- Coronary artery disease
- Stroke
- Heart failure
- Peripheral arterial disease
- Vascular dementia
- Chronic kidney disease
- Lowering hypertension → ↑↑ health benefits
What is the pathophysiological mechanism of hypertension?
- Cardiac output
- Peripheral resistance
- Autonomic nervous system
- Endothelium
- Vasoactive peptides
- Renin-angiotensin-aldosterone system
What is the equation to work out arterial blood pressure? (ABP)
Arterial Blood Pressure = Cardiac Output × Total Peripheral Resistance
ABP = CO × TPR
What is the equation to work out force?
Force = Flow × Resistance
What is the equation to work out volts?
Volts = Current × Resistance (V = IR)
What is the equation to work out cardiac output?
Cardiac output = Stroke volume × Heart Rate
What is stroke volume proportional to?
Central venous pressure
Explain the role of the autonomic nervous system of hypertension (e.g. receptors & control)
-
Heart function
- β₁ → ↑heart rate, ↑force → CO
-
Vessel function
- Arteriolar tone regulates TPR
- Venular tone regulates CVP
- α₁ → vasoconstriction
- β₂ → vasodilation
- Short-term regulation of pressure & flow
- Baroreceptor reflexes
- Little evidence to implicate adrenaline and noradrenaline as causes of essential hypertension
- Sympatholytic drugs lower ABP and have a role in therapy, even if ANS dysfunction is not the cause
Endothelium effect on hypertension
- Dysfunction implicated in essential hypertension
- Endothelial cells produce vasoactive agents
- Nitric oxide (NO) → vasodilator
- ↑guanylyl cyclase → ↑cGMP → ↑PKG sm. muscle relaxation
- Atheroma → ↓NO production
- Sodium nitroprusside (↑NO) used in hypertensive emergencies
- Sildenafil inhibits phosphodiesterase V (PDEV) → ↑cGMP
- Prostacyclin (PGI₂) → vasodilator
- Endothelin → vasoconstrictor
Give examples of some vasoactive peptides & what they do
-
Bradykinin → vasodilator
- ACE inhibitors block bradykinin inactivation
-
Natriuretic peptides (A, B & C)
- ANP = Atrial: secreted by atrium
- BNP = Brain: secreted by ventricles
- CNP = C-type
- What do they do?
- → ↑Na⁺ & H₂O excretion
- NPR1 is a guanylyl cyclase → ↑cGMP → smooth muscle relaxation → vasodilation
- Dysfunction may → fluid retention & hypertension
-
Vasopressin = anti-diuretic hormone (ADH)
- Vasoconstrictor, ↑BP & ↑H₂O reabsorption
What is the difference between renin & rennin?
Renin
- Produced by juxtaglomerular cells
- Regulates ECF volume & blood pressure
Rennin
- Found in the stomach of baby ruminants
- Used to make cheese
From the RAAS system what do essential (primary) hypertension patients have low levels of?
Low levels of renin & AT-II
Step by step brief what happens in RAAS
- (LOW) ABP
- Renin
- Angiotensinogen
- Angiotensin I
- Angiotensin II (by Angiotensin-converting enzyme)
- Aldosterone
- Mineralocorticoid receptor e.g.
- Epithelial sodium channels
- Na+/K+ ATPase
Where Na⁺ goes, water follows osmotically → ↑ECF → ↑preload → ↑Stroke Volume → ↑Cardiac Output → ↑ABP
Explain renin (RAAS) and mechanism of making it
- Circulates in blood
- Cleaves angiotensinogen
- Secreted by granular cells of JGA into blood mechanism:
- ↓BP → ↑Symp. activity & ↓GFR
- ↑Symp. → β₁ receptors on GC (granular cells)→ ↑renin
- MD (macula densa cells) detects Na⁺/Cl⁻ in DCT
- ↓GFR → ↓Na⁺/Cl⁻ load at MD → dilation of AFF & constriction of EFF → ↑GFR (= autoregulation)
- ↓Na⁺/Cl⁻ load at MD → ↑renin
Explain angiotensinogen
- Produced by liver and secreted into blood
- Renin substrate → forms angiotensin I
Explain angiotensin I
- Cleaved from N-terminal of angiotensinogen by renin
- Converted to Angiotensin II by angiotensin-converting enzyme (ACE)
- ACE is widely expressed: lung, kidney..
Explain angiotensin II
- Produced by cleavage of C-terminal by ACE (cleaves 2 amino acids)
- Full agonist at AT₁ receptors (GPCR) → release of aldosterone (mineralocorticoid) from adrenal cortex → ↑ECF → arteriolar vasoconstrictor → ↑BP → ↑vasopressin (ADH) release from pituitary
Explain the role of ACE 2 (angiotensin-converting enzyme 2)
- Cleaves 1 amino acid from AT-II → AT (1-7)
-
AT (1-7)
- Is a physiological antagonist of AT-II
- LOWERS BP & is a vasodilator
Explain Angiotensin 1 receptors (AT₁)
- GPCR (Gᵢ & Gq signalling)
- Widely expressed, esp. liver, kidney, adrenal, lung
- Activation by AT-II
- → smooth muscle contraction → vasoconstriction
- → central & peripheral sympathetic stimulation
- → aldosterone release (adrenal: zona glomerulosa)
- → ADH release (pituitary)
- → tubular Na⁺ reabsorption (PCT in kidney)
- → endothelin release (endothelial cells) -> vasoconstrictor
Explain aldosterone (in RAAS)
- Steroid > mineralocorticoid
- Full agonist at intracellular mineralocorticoid receptor in tubular cells of the DCT
Explain mineralocorticoid receptors (in RAAS)
- Expressed in epithelia with high electrical resistance
- e.g. distal kidney tubular cells
- → selectively changes transcription:
- ↑ ENaCs
- ↑ Na⁺/K⁺-ATPase
- Spironolactone = competitive antagonist
Explain epithelial sodium channels in RAAS
- Widely expressed
- in distal kidney tubules, also in lung & resp. tract, reproductive tracts
- In principal cells of late DCT/early CD:
- ↑ENaC expression on apical membrane →
- ↑Na⁺ permeability →
- ↑Na⁺ reabsorption from tubule lumen into cell
- This is the rate-limiting step for salt reabsorption in this part of the nephron
- They are NOT voltage-gated channels
- Amiloride = channel blocker
Explain Na⁺/K⁺-ATPase (Na⁺ pump) in the RAAS system
- Expressed everywhere
- For each ATP hydrolysed, 3Na⁺ out & 2K⁺ in
- Preserves Na⁺/K⁺ gradient across membranes
- In DCT ↑Na⁺/K⁺-ATPase on basolateral side → ↑Na⁺ from cell into interstitial fluid (ECF) → this preserves low [Na⁺]ᵢ and gradient for Na⁺ entry from lumen
- Cardiac glycosides (e.g., digoxin) = inhibitor
What is Liddle syndrome?
- Rare genetic (autosomal dominant) disorder
- Severe hypertension, manifesting at early age
- Mutations in β & γ subunits prevent channel internalization and degradation
- Overexpression of ENaCs → excess Na⁺ reabsorption
- Treat with ENaC channel blockers e.g., amiloride
List some anti-hypertensive drugs
-
Diuretics
- Thiazide
- Loop
- K⁺-sparing (acetazolamide)
- Renin inhibitor (-kiren)
- ACE inhibitors (-pril)
- Angiotensin Receptor Blockers (ARB) (-sartan)
- β blockers (-lol)
- Calcium channel blockers (-dipine)
- Centrally acting α₂ agonists (e.g., clonidine)
-
Vasodilators
- Nitroprusside = nitric oxide (NO) donor
- Phentolamine = non-selective α-adrenergic antagonist
- Prazosin = selective α₁-adrenergic antagonist
- Hydralazine
- Minoxidil = potassium channel opener (KCO)
What is the class, pharmacology, physiology, clinical of aliskiren
- CLASS: renin inhibitor
-
PHARMACOLOGY:
- Target: renin
- Activity: competitive inhibitor
- PHYSIOLOGY: ↓production of AT-I → ↓RAAS activation
- CLINICAL: Essential Hypertension
What is the class, pharmacology, physiology, clinical of enalapril?
-
CLASS: ACE inhibitor (ACEI)
- Pro-drug: converted to active metabolite → enalaprilat
-
PHARMACOLOGY:
- Target: ACE
- Activity: competitive inhibitor
-
PHYSIOLOGY:
- ↓production of AT-II
- ↓breakdown of bradykinin (vasodilator)
-
CLINICAL:
- Essential hypertension
- Heart failure
What is the class, pharmacology, physiology, clinical of valsartan?
- CLASS: angiotensin receptor blocker (ARB)
-
PHARMACOLOGY:
- Target: AT₁ (receptor)
- Activity: competitive antagonist
-
PHYSIOLOGY:
- ↓ effects of AT-II
- No effect on bradykinin → no cough
- CLINICAL:
- Essential hypertension
- Heart failure
What is the class, pharmacology, physiology, clinical of atenolol?
- CLASS: Selective β₁ blocker
-
PHARMACOLOGY:
- Target: β₁ receptor
- Activity: competitive antagonist
-
PHYSIOLOGY: (is not understood)
- ↓cardiac output
- Alter baroreceptor reflexes
- ↓renin secretion
- ↓sympathetic outflow (central)
-
CLINICAL:
- Essential hypertension
- Angina
- Arrhythmias
What class of drugs are atenolol, propranolol, isoprenaline?
Atenolol = SELECTIVE β₁ antagonist
Propranolol =NON-SELECTIVE β antagonist
Isoprenaline = β adrenergic agonist (in asthma)
In what clinical situations should adrenaline be used in?
- CPR
- Acute hypotension
- Anaphylaxis
What is the class, pharmacology, physiology, clinical of amlodipine?
- CLASS: Calcium channel blocker
-
PHARMACOLOGY:
- Target: L-type voltage-gated calcium channels
- Activity: gating inhibitor
-
PHYSIOLOGY:
- smooth muscle > cardiac muscle
- ↓Ca²⁺ mobilisation in sm. muscle
- →vasodilation
-
CLINICAL:
- Essential hypertension
- Angina
Explain voltage-gated calcium channels (hypertension)
- Large protein
- All open in response to depolarisation
- Types:
-
L-type: once open, remain open for a long time, inactivate slowly
- In excitable cells, cardiac, smooth & skeletal muscle
- Phosphorylated by action of adr/NA
- P/Q-type: Purkinje neurons (brain)
-
N-type: Neural (CNS & PNS)
- Neurotransmitter release
- R-type: Resistant to blockers
- T-type: open transiently (very short period of time), inactivate rapidly
-
L-type: once open, remain open for a long time, inactivate slowly
What are the treatment steps of someone with hypertension?
