Cardiovascular Disease & Risk Factors (2) Drugs used to treat hypertension Flashcards
- Diuretics - ACE Inhibitors and Angiotensin AT1 receptor antagonists - Calcium antagonists
Diuretics
Thiazide class of drugs
Affect TPR
>via local regulators (K-ATP channels)
Affect Preload
>intravascular volume via Na+/H2O retention
Kidneky - Long term fluid balance
Kidneys receive about 20-25% of blood flow
Kidneys play pivotal role in regulating [NaCl], [electrolyte], and fluid volume
(which then affects the rest of the organs in the body)
Principal functions:
>Filtration
>Reabsorption
>secretion
Reabsorption of fluid and solute in kidney
Na+ (mmol), 25,000 filtered/day, 150 excreted/day
99% reabsorbed
Diuretics affect salt reabsorption
>any small change in reabsorption of salt will affect plasma volume
Diuretics (1)
Early strategy for management of hypertension
>alter Na+ balance by dietary salt restriction
Pharmacological alteration of Na+ balance practical with development of orally active thiazide diuretics
>thiazides are main class of diuretics prescribed to most hypertensive patients
>Have hypertensive effects alone and enhance efficacy of virtually all other antihypertensive drugs
(often given in combination when PTs dont respond to a single agent)
>Very favourable experience with diuretics in randomised trials
> This drug class very important in treatment of hypertension
Diuretics (2)
Cause net loss of Na+ and water by action on kidney
Primary effect
>Decrease reabsorption of Na+ and Cl- from filtrate
>water loss follows via osmosis, secondary to the excretion of Na+
Results in decreased blood volume (which feeds into stroke volume > HR) and therefore, BP
Several groups of diuretics, each with different mechanisms and sites of action
Initial therapy - Thiazides
>e.g. hydrochlorothiazide
Nephron anatomy and sites of action of diuretics
Different classes of diuretics work at different parts of the nephron
>Thiazides work at Distal Convoluted Tubule
Might want to note: >Loop diuretics >act at loop of henle >most powerful class of diuretics >will cause torrential urine output (dont want this as our mainstay of a hypertensive drug, only used in emergency situations or plasma volume overload)
Thiazides - Mechanism (in distal convoluted tubule)
Na+ absorbed via apical membrane Na+/Cl- co-transporter (C3)
Transport driven by Na+/K+ ATPase in basolateral membrane
>less cytoplasmic [Na+} so Na+ enters cell from lumen down concentration gradient via C3
Thiazides inhibit C3, so increase Na+ excretion
>e.g. hydrochlorothiazide, moderately powerful diuretic
>K+ loss may be significant as K+ excretion is regulated by Na+ reabsorption (increased [Na+] to collecting duct)
»side effect you might see in patients
**Decrease amt of sodium reabsorbed, more remain in filtrate and excreted in urine
Thiazide antihypertensive mechanisms
Initially, decrease blood volume
>increase renal secretion of H2O and Na+
>Decrease venous return and so, CO
CO gradually returns to pre-treatment values, and blood volume to near normal due to compensatory responses such as activation of renin-angiotensin system
(Kidney is autoregulatory organ > if it receives less blood flow, it will activate renin-angiotensin system and produce more renin to get more blood flow - part of the homeostatic reflex mechanism)
Hypotensive effect maintained during long-term therapy because of decrease in TPR
Thiazides cause vasorelaxation in isolated arteries (smooth muscle)
>related to activation of K-ATP channels
This vasodilatory effect of thiazides complements the compensated volume depletion, leading to sustained BP decrease
Thiazides - Adverse Effects
Uric acid retention (Gout)
>Uric acid excretion decreased
>Thiazides compete for tubular secretion mechanisms (organic anion transporter)
Impaired glucose tolerance
>activation of K-ATP channels in pancreatic islet cells, so inhibition of insulin secretion
Allergic reaction (e.g. skin rashes)
Hypokalaemia (decreased K+)
Potassium Balance
Kidney excretion of K+ regulates extracellular [K+] >important, as small changes affect excitable tissues (brain, heart, skeletal muscle) >K+ loss with diuretics can cause problems if co-administered with cardiac glycosides or class III antidysrhythmic drugs whose toxicity is increase by low plasma K+ (clinically important drug interaction)
Collecting duct: K+ leaks into tubule via ion channel
>K+ secretion regulated primarily by [serum aldosterone] and [Na+] delivered to distal nephron
>aldosterone binds to receptors in duct cells and stimulates Na+ reabsorption across luminal membrane via Na+ channel
> > NA+ reabsorption increases driving force for K+ secretion
K+ loss increased when more [Na+] reaches collecting duct e.g. with thiazides which decrease Na+ absorption in DCT (= hypokalaemia)
K+ loss decreased when less [aldosterone] e.g. with ACEIs or AT1 R antagonists, which decrease Ang II, so less Ang II-mediated aldosterone release (= hyperkalaemia)
(opposite is true with renin-angiotensin inhibitors)
Thiazides - Therapy
Thiazides recommended as primary therapy in uncomplicated hypertension
>clinical trials shown thiazides to decrease risks of stroke and heart attack associated with hypertension, and total mortality
> High oral bioavailability, and long duration of action
Particularly effective in older patients >55 years and those with volume-based hypertension
ACE inhibitors and AT1 receptor antagonists
Affect CO >via Na+/H2O retention >affects intravacular volume >affects preload >Affects SV (which affects CO)
Affects TPR
>Local regulators
>Circulating regulators
»Angiotensin II
Renin-angiotensin-aldosterone axis
Angiotensin (globulin secreted by liver)
>converted to Angiotensin I by Renin (enzyme made and secreted by kidney)
(amt is regulated by sympathetic nervous systems B1-ARs in kidney, and by the auto-regulation of the kidney - fall in GFR and pressure)
Ang I converted to Ang II by Angiotensin-coinverting-enzyme (ACE)
>40% made in lung epithelium, 60% elsewhere)
Angiotensin II acts on **1) Adrenal cortex >Stimulates release of aldosterone >mineralocorticoid that acts in kidney collecting ducts >increases renal NaCl reabsorption
2) Renal Proximal Tubule
>increases NaCl reabsorption
3) Renal efferent arterioles
>vasoconstriction and maintain GFR
*4) Systemic arterioles
>vasoconstriction and increases TPR
5) Hypothalamus
>thirst, increases ADH (anti-dqiuretic hormone - vasopressin)
Renin (enzyme)
Made and secreted by juxtaglomerular apparatus in kidney
>smooth muscle cells that line afferent and efferent arterioles of glomerulus
Renin release increased by
>fall in BP sensed by afferent arteriole
>sympathetic innervation of JG cells via B1-ARs
>Distal nephron fall in lumenal [Na+]
Angiotensin II Receptors
GPCRs: 2 types of receptor identified
>AT1 and AT2 (remember AT1)
AT1 receptors widely distributed
>vascular smooth muscle, myocardial tissue, adrenal cortex, kidney, brain
>important in ventricular and areteriolar smooth muscle remodelling
AT2 receptors mainly
>adrenal medulla, kidney, brain, foetus
>may play role in vascular development
MOST KNOWN ACTIONS OF ANG II MEDIATED BY AT1
Angiotensin II
Also affects cardiovascular structure
>hypertrophy (vasculature medial hypertrophy - increased tissue mass) and/or remodelling (redistribution of mass within a structure) e.g. in hypertension
»greater wall/lumen ratio in arterial vessels
»cardiac hypertrophy
Ang II is a direct mitogen
>directly cause morbid changes in structure due to increased cell migration, proliferation and hypertrophy
Conversion of Ang I into Ang II by tissue specific ACE of cardiac myocytes promotes cardiac remodelling, hypertrophy, and fibrosis
ACE Inhibitors: Mechanism
Inhibit bradykinin (potent vasodilator peptide) breakdown
>more vasodilation
>Fall in BP
Less Ang II formation
>all downstream effects of Ang II are inhibited (competitive inhibition)
>Less AT1 receptor mediated vasoconstriction
>Less aldosterone secretion
>less Na+/H2O retention
>Less preload and CO
>all decrease BP
ACE Inhibitors: Drugs
Captopril
>orally available, 75% bioavailability
>T1/2, 2h (short half life)
Enalapril
>inactive prodrug, 60% bioavailable
>Converted by hepatic hydrolysis to Enalaprilat
>T1/2 20h (once/day dosage = better compliance)
>Milder side effects
ACE inhibitors: Mechanism long-term
Over long-term
>less mitogenic influences of Ang II
>may inhibit or decrease morbid influences of Ang II on cardiovascular structure
»>i.e. prevent Ang II stimulation of arterial wall remodelling (greater wall/lumen ratio)
Hypertrophy can be reversed if BP is kept at a normal level
>By inhibiting Ang II, improves the rate of regression of remodelling
ACE Inhibitors: Side Effects
1st dose hypotension
>too much fall in pressure at the start, drug dosage needs to be titrated properly
HYPERkalaemia (increase in K+)
>less Ang II = less aldosterone = K+ retention
(usually only problem for patients on K+-sparing diuretics or with renal impairments)
*wouldnt normally prescribe a ACE inhibitor with a potassium-sparing diuretic
Acute renal failure (reversible)
>Usually in PTs with renal artery stenosis (narrowing) and renal function dependent on Ang II to maintain GFR
Persistent Dry cough (more bradykinin as ACE = kininase II)
>Because of the effects of the sensory nerve peptide bradykinin (lasts longer, irritates nerves in lungs)
ACEIs with sulfhydryl group (older ACEIs e.g. Captopril)
>altered/loss of taste (reversible)
>rash (reversible)
>more modern ACEIs such as Enalapril dont have these side effects
ACEIs: Advantages over other therapies
Cardiovascular reflexes less affected
Safe in asthmatics
Tend to enhance efficacy of diuretics
>as ACEI blunt increase in aldosterone in response to K+ loss, normal role of aldosterone to oppose diretic-induced natriuresis diminished
Fewer adverse effects on K+
Beneficial effects on cardiovascular remodelling
AT1 Receptor Antagonists
Selective for AT1 receptors
>generally >10,000 fold AT1 vs AT2
Non-peptide, orally-active
Examples: Lorsartan and irbesartan (*“sartans”)
Inhibit cardiovascular effects of Ang II
Similar efficacy to ACEI (antihypertensive)
Binding to AT1 receptor competitive, but in vivo, often insurmountable
»slow dissociation kinetics or receptor internalisation
»advantage of sustained receptor blockade (an advantage for this therapy in treating hypertension)
AT1 Receptor Antagonists: Mechanism
Block AT1 receptors on adrenal medulla
>inhibit aldosterone secretion
>reduced Na+/H2O reabsorption (more excreted)
>Lower BV and BP, preload, CO
Block AT1 receptors on blood vessels and cardiac
>No vasoconstrictive effects of Ang II
>decreased TPR
>decreased BP
*No effect on bradykinin
AT1 Receptor Antagonists: Adverse Effects
1st dose hypotension
hyperkalaemia
renal impairment
But no dry cough (no change in bradykinin)
Ca2+ channel Antagonists
Will focus on vascular selective Ca2+ channel antagonists
>dihydropuridines
>Decrease TPR directly
There are other Ca2+ channel antagonists that can affect contractility, but not used preferentially in treating hypertension
Voltage-gated Ca2+ channels
Comprosed of 4 subunits
>Alpha1 (4 homologous domians, each with 6 transmembrane segments - the pore forming subunit)
>Beta (intracellular)
>Gamma (4 transmembrane segments)
>Delta (1 transmembrane segment attached to extracellular A2 subunit via disulphide bond)
Identify of the A1 subunit defines the class of Ca2+ channel
Voltage-sensitive Ca2+ Channels
10 different genes encoding A1 subunits identified
> Nearly always talking about L-type Ca2+ channels
Cav 1.1-1.4 Family
Therapeutically-used modulators
>verapamil, diltiazem, nidefipine (DHPs)
(Dihydropuridines)
L-type voltage-gated Ca2+ channels
Ca2+ influx via L-type channel important determinant of vascular tone (all arteries) and cardiac contractility
>extracellular Ca2+ entry more important in initiating contraction of cardiac myocytes (Ca2+ induced Ca2+ release)
Basis for L-type Ca2+ antagonist use in hypertension is that high BP is due to increase in TPR
Vascular smooth muscle contraction is dependent on free [Ca2+]intracellular
Inhibition of transmembrane Ca2+ movement through L-type Ca2+ channels leads to decreased [Ca2+]intracellular and vascular smooth muscle relaxation (vasodilation)
*Remembering there is always a degree of vascular tone in our arteries so there is always a way to decrease tone via this mechanism
Sites of action of Ca2+ antagonists
Remembering Pousielle’s Law
(Resistance is inversely proportional to 1/r^4)
SA Node
>reduce automaticity
AV node
>Reduce conduction
Cardiac myocytes
>decreased afterload
>decreased myocardial O2 demand
Coronary arteries
>increased vasodilation
>increased myocardial o2 supply
Peripheral veins
>Minimal venodilation
(limited effect of Ca2+ channel antagonist on sympathetic (contractile) tone in veins)
Peripheral arterioles
>increased vasodilation
>decreased afterload
>Decreased myocardial o2 demand
Ca2+ Channel Antagonists - Mechanism
Inhibit L-type Ca2+ channels
>decrease Ca2+ entry in vascular smooth muscle so lower [Ca2+]intracellular
>decrease vascular contractile tone
>decrease TPR - especially due to arteriolar (resistance vessel) dilation
»decrease BP
L-type Ca2+ antagonists: 3 classes
1) Dihydropyridines (DHPs)
>”dipines”
>all vascular selective forms of Ca2+ antagonists
>e.g. nifedipine, felodipine, amlodipine
2) Benzothiazepines
>e.g . diltiazem
3) Phenylalkylamines
>e.g. varapamil
> > > Site specificity of each class
Confers distinctive pharmacological effects
> Different drug binding sites on channel
bind to a1 pore-forming subunit of channel
interaction is allosteric, no direct competition
Selectivity of L-type Ca2+ antagonists
L-type antagonists
> “slow” Ca2+ channel inhibition
>Myocardium = negative inotropism (weaker contractile force)
>Nodal tissue = slowed HR
>Vasculature = peripheral and coronary dilation
**Vascular selectivity of DHPs (e..g nifedipine) at therapeutic doses
The other 2 classes have marked depressive effects on cardiac contractility, and depression on heart rate (SA node) and depression of conduction (AV node), not something you want in treatment of hypertension
L-type Ca2+ channel antagonists
Myocardium and nodal/conductive tissue
- Verapamil > diltiazem > nidefipine (DHPs)
Arterial smooth muscle
- Nifedipine»_space; verapamil > diltiazem
**Vascular selective dihydropyridines preferred for treatment of hypertension (map = co x TPR) in patiwnts with stable angina, atherosclerosis, pregnancy
L-type Ca2_ antagonist therapeutics
ALL L-type Ca2+ antagonists relax arterial smooth muscle so decrease TPR
Little effect on veins, so no effect on preload (means no effect on postural hypotension)
Little effect on skeletal muscle contraction (more reliant on sarcoplasmic reticulum Ca2+ pools)
Oral bioavailability
>but limited by high first pass metabolism in gut and liver
L-type Ca2+ antagonists: Adverse Effects
Dihydropyridines
>reflex tachycardia, palpitations, nausea, flushing, headache
>Less problems with sustained-release formulations (more modern drugs reduce speed at which BP falls)
(depends on how initial dose is titrated, any drug that lowers BP will initially trigger baroreceptor reflex -> reflex tachycardia to bring BP back to setpoint which can be altered over time)
Diltiazem
>bradycardia, AV block
>especially if combined with beta blocker or patient has SA node dysfunction
Verapamil
>Bradycardia, AV block
>Blocks P-glycoprotein drug transporter
>renal and hepatic elimination of e.g. digoxin is inhibited
(reduce elimination of drugs that cause heart failure)
Dont normally give Diltiazem and Verapamil for hypertension
Treatment of Hypertention - Overview
Benefits are unequivocal (can add years to life)
Diverse group of drugs
>choice depends on severity of hypertension, presence of other disorders, and acceptability of side effects to patient
Aim to normalise BP
Adverse effects (depending on PT co-morbidities) may preclude use
Up to 50% of patients will no respond adequately, or comply to monotherapy
»combination therapy used
Combination therapy guiding principles
Use drugs from different classes with complementary actions
Aim for at least additive effects, e.g.
>B1-AR antagonist and thiazide diuretic
>Thiazide and ACEI or AT1 receptor antagonist
>ACEI and Ca2+ channel blocker
>B1-antagonist and DHP Ca2+ channel blocker
AVOID combinations such as:
>B1-AR antagonist and verpamil/diltiazem
(compromise cardiac function)
>B1-AR antagonist and methyldopa(or clonidine)
(Centrally acting antihypertensives, a2-ar agonists)
»cause bradycardia and heart blcok
»their abrupt withdrawal would lead to hypertensive crisis
Dual/Triple combination single-pill therapy now common
Single-pill 3 drugs
1 pill a day, 3 agents combined within
>Much easier for PTs to remember to take, considering most of them are elderly, 1 pill is much easier to comply with
ExforgeHCT
>Amlodipine (DHP)
>Valsartan (AT1 receptor antagonist)
>Hydrochlorothiazide (thiazide diuretic)
Efficacious for moderate to severe hypertension
(more BP fall than dual regimens)
Well tolerated with adverse effect profiles similar to dual regimens
Fixed-dose combinations used as a single pill improve patient adherence leading to better long-term BP control
