Anti-hypertensives Flashcards
List the classes of major anti-hypertensive agents
There are multiple classes of anti-hypertensive agents. These include:
1. Alpha Blockers (1 and 2 receptor blockers)
2. Beta-blockers
3. ACEI/ARB
4. Calcium channel blockers
5. Diuretics including Aldosterone antagonists
6. Vasodilators
The different classes of drugs target different pathways and can be used together to produce a synergistic effect.
All are ^[mostly] equally important.
Combination doses are rare but can be used if the patient cannot tolerate drugs in full doses.
Describe the action of alpha-1 adrenoceptors
- The alpha-1 adrenoceptors are involved in vessel wall dilation/contraction
- The receptors predominate in the peripheral vascular system
- Binding of adrenaline to alpha-1 receptors leads to vascular smooth muscle cell contraction
- Alpha-blockers prevent this interaction leading to vasodilation
- Block post-ganglionic alpha-1 receptors
Describe and provide examples of alpha-1 blockers
- Examples: Prazosin, doxazosin, terazosin
- Adverse effects: orthostatic hypotension, reflex tachycardia, nasal congestion, [oedema]
- First dose effect
- Special examples (only to be aware that they exist, not clinical)
- Phentolamine: Non-selective, reversible alpha blocker
- Phenoxybenzamine: Non-selective, irreversible alpha blocker
- Only real use is in phaeochromocytoma management
Describe the actions of alpha-2 adrenoceptors and alpha2- receptor blockers
Alpha-2 adrenoceptors
- Clonidine
- Alpha-2 agonist
- Inhibits sympathetic vasomotor centres leading to reduced sympathetic outflow -> Reduced vasomotor tone
- Methyldopa
- Alpha-2 agonist
- Long-standing use in pregnancy
Alpha-2 adrenoceptors
- Act in the brainstem to reduce SNS outflow
- Leads to reduced peripheral vascular resistance, and reduced synaptic transmission
- Adverse effects: sedation, dry mouth (nightmares and drowsiness)
- Rebound hypertension (due to receptor upregulation) ^[not at all specific to this class of drugs]
- Presumed secondary to receptor up-regulation
- Less common with methyldopa
Describe beta adrenoceptors
- Beta adrenoceptor blockers are responsible for blocking sympathetic activity
- The beta adrenoceptors are located in the central nervous system ^[thus can exert neurological side effects including nightmares and drowsiness]
- Beta-1: heart (and kidney, increasing RAAS activity and sodium/water retention)
- Beta-2: lungs, peripheral vessels ^[given bronchoconstriction risks, better to prescribe block beta 1 receptors]
- Pacemaker cells in the atrium of the heart (B1) and cardiac myocytes
- Sympathetic vs parasympathetic input
- Stimulation of B1
- Chronotropic and inotropic effects
- Bradycardia, bronchoconstriction, peripheral vasoconstriction, depression, nightmares
- Contraindicated in peripheral vascular disease
Describe beta blockers
- The affinity for beta-receptor subtypes (and alpha-1 receptors) leads to further subcategories
- Cardioselective (predominantly beta-1)
- Atenolol, metoprolol, bisoprolol
- Mixed receptor agents (also block alpha-1)
- Labetalol, carvedilol
- Esmolol
- Rapidly metabolized by red cell esterases
- Other uses
- Anti-anginal, anti-dysrhythmic, tremor, anxiety, glaucoma (eye drops)
Note: side effects are largely associated with older generations of drugs, as they often crossed the blood brain barrier.
Note 2: pharmacogenetics set to change how these drugs are prescribed.
- Anti-anginal, anti-dysrhythmic, tremor, anxiety, glaucoma (eye drops)
Describe the importance of the RAAS system and why it is therapeutically targeted
The RAAS system is heavily therapeutically targeted.
- Low BP sensed as a decrease in blood flow and thus a decrease in GFR
- Decreased in sodium/chloride levels by the macula densa
- The macula densa causes an increase in Na+ and water reabsorption
- Juxtaglomerular cells sense the decrease in blood pressure and release renin
- Converts angiotensinogen to angiotensin I
- Angiotensin II produced by ACE (itself produced in the lungs)
- Angiotensin II is a potent vasoconstrictor and causes an increase in the release of aldosterone from the adrenal glands (among other things)
- Aldosterone further increases the Na+ and H2O reabsorption in the distal convoluted tubule of the nephron
Briefly describe the mechanism of action of ACE inhibitors and Angiotensin II receptor blockers
- ACEI inhibit the activity of ACE to prevent the formation of the active angiotensin II from the inactive angiotensin I.
- Reduction in blood pressure secondary to vasodilatation following ACE inhibition is greatest when the renin-angiotensin system is stimulated (e.g., with salt restriction or diuretic therapy)
- ARBs selectively antagonize the action of angiotensin II at the angiotensin II AT1-receptor
- The AT1-receptor mediates all the classical effects of angiotensin II
- Vasoconstriction
- Aldosterone release
- Sympathetic activation
- Etc
- AT2-receptor is less well understood but broadly mediates effects opposite to the AT1-receptor
Note: use of both drugs can lead to bad renal side effects
Discuss how ACEI and ARBs link to glomerular haemodynamics
- Prostaglandins
- Angiotensin II (acting on efferent arteriole)
- Renin released from JG cells
- SNS activation leads to renin release and vascular smooth muscle contraction
Provide examples of ACE inhibitors and their side effects
ACE Inhibitors
- Examples of ACEI: Captopril, Enalapril, Perindopril, Ramipril, Trandolapril, etc.
- Bradykinin effects
ACEI Adverse effects:
- C – Cough
- A – Angioedema
- P – Postural dizziness
- T – Taste changes
- O – Hypotension
- P – Contraindicated in Pregnancy
- R – Rashes/renal impairment*
- I – Increased serum potassium
-
L – Low Ang II and aldosterone
(*Especially with bilateral renal artery stenosis)
List examples of angiotensin receptor blockers
Angiotensin receptor blockers
- Candesartan
- Irbesartan
- Olmesartan
- Telmisartan
- Valsartan
- Etc
- Reduced adverse effect profile
Discuss advantages and disadvantages of using ACEIs or ARBs
- Recommended as first-line treatment of hypertension, especially those with DM, heart failure, CVD/IHD, or proteinuric chronic kidney disease
- No rebound hypertension
- Long-term benefits on cardiac remodelling and kidney disease with proteinuria
Explain why calcium channels are therapeutically targeted
- Calcium channels allow movement of calcium across cell membranes
- Influx of calcium leads to smooth muscle cell contraction
- Ca2+ can enter the cell from the extracellular space or be released from the sarcoplasmic reticulum
- Also important in cardiac pacemaker cells
- Extracellular Ca2+ influx is mainly mediated by the opening of voltage-dependent L-type Ca2+ channels
Describe the mechanism of action of calcium channel blockers and their side effects
- Block inward Ca++ currents in myocardium, cardiac conduction system, and smooth muscle (L-type channels) by blocking cross bridge cycling, leading to vasodilation
-
Dihydropyridines (which targets peripheral vessel, and are most common CCBs used for hypertension)
- Amlodipine, felodipine, lercanidipine, nifedipine, etc
- Mainly act on vascular smooth muscle (reduce peripheral resistance)
- Flushing, headache, dizziness, palpitations, peripheral edema
-
Phenylalkamines
- Verapamil
- Mainly cardiac effects (reduce HR, conduction, and contractility)
- Affect contractility and hence not for CCF
- Bradycardia, AV conduction delay
-
Benzothiazepine
- Diltiazem
- Effect on both cardiac muscle and vascular smooth muscle
NOTE: non-DHPs can also be used as anti-arrhythmic agents
Describe briefly how diuretics work
Renal sodium handling
Note: diuretics can act on any portion of the nephron, but predominantly target DCT and collecting duct. Drugs that target the DCT are most effective.
Diuretics work by increasing sodium excretion thus preventing blood pressure rise.
