PHARM - Drugs for the Treatment of Hypertension - Week 4 Flashcards
What do diuretic drugs do?
Decreases plasma volume, which decreases TPR.
In what way do diuretics affect cardiac output (4)?
Lowers stroke volume by lowering preload.
This is done by lowering intravascular volume by affecting Na+/H2O retention
Name three factors that affect Na+/H2O retention, and the effect they have.
Sympathetic system - increase
Aldosterone - increase
ADH - increase
When are diuretics used in a hypertnesion treatment therapy?
Early strategy for hypertension management - after Na+ balance by dietary salt restriction.
What kind of drug is viable as a diuretic, and does this class have other effects?
Orally active thiazide diuretics - have antihypertensive effects alone, and enhance efficacy of all other hypertensive drugs.
What is the primary effect of a diuretic?
Decreases reabsorption of Na+ and Cl- from filtrate, increasing water loss, and increasing excretion of salt.
It decreases blood volume and therefore BP.
Where on a nephron do thiazide diuretics act?
Distal convoluted tubule.
Briefly describe in 2 steps the mechanism of Na+ reabsorption in the distal convoluted tubule, and how thiazides act here.
Na+ is absorbed apically by Na+/Cl- co-transporter (C3) down its concentration gradient.
It is pumped out basolaterally by Na+/K+-ATPase.
Thiazides inhibit C3, increasing Na+ secretion.
How do thiazides affect K+?
K+ loss may be significant because K+ excretion is regulated by Na+ reabsorption.
Name 4 adverse effects of thiazides, and their mechanisms.
-Uric acid retention (gout) - uric acid excretion is decreased because thiazides compete for tubular secretion mechanisms
-Impaired glucose tolerance - activation of Katp channels in pancreatic islet cells, inhibiting insulin secretion
-Allergic reaction
-Hypokalaemia (decreased K+)
In what case does K+ loss with diuretics cause problems?
If thiazides are co-administered with:
-cardiac glycosides/antidysrhythmic drugs whose toxicity is increased by low plasma K+
How does Na+ reabsorption affect K+ secretion?
Na+ reabsorption increases driving force for K+ secretion.
K+ loss increases when more Na+ reaches the collecting duct.
What effect do ACE inhibitors and AT1 receptor antagonists have on blood pressure, and how?
They decrease blood pressure by decreasing total peripheral resistance.
What is renin and what is its action?
An enzyme made and secreted by the kidney.
It converts angiotensinogen to angiotensin I.
What is angiotensinogen, and where is it made and secreted?
A globulin made and secreted by the liver.
What is ACE, where is it found (2), and what does it do?
An enzyme found 40% in lung endothelium, and 60% elsewhere.
It converts angiotensin I to angiotensin II.
What effect does angiotensin II have at the adrenal cortex?
Aldosterone production
What effect does angiotensin II have at the renal proximal tubule?
Increases NaCl reabsorption
What effect does angiotensin II have at the renal efferent arterioles?
Vasoconstriction to maintain GFR
What effect does angiotensin II have at systemic arterioles?
Vasoconstriction, increasing TPR
What effect does angiotensin II have at the hypothalamus?
Thirst, and increased ADH
What effect does aldosterone have?
Increased renal NaCl reabsorption
How many receptors for angiotensin II are there?
Where are they found (9)?
2 - AT1 and AT2
AT1 - vascular smooth muscle, myocardial tissue, adrenal cortex, kidney, and the brain
AT2 - adrenal medulla, kidney, brain, and foetus
By which angiotensin II receptor are most of its known actions mediated by?
AT1
What is renin made and secreted by?
The juxtaglomerular apparatus.
Where are juxtaglomerular apparatus found?
Smooth muscle cells that line afferent and efferent arterioles of glomeruli
What three factors increase renin release?
Fall in BP sense by afferent artioles
Sympathetic innervation of juxtaglomerular cells by B1 adrenoceptors
[Na+] decrease in the distal nephron lumen
In addition to inhibitng ACE, what else do ACE inhibitors inhibit, and what effect does this have?
Inhibits bradykinin breakdown, which results in vasodilation, decreasing TPR, and therefore BP
Give two examples of ACE inhibitors.
Captopril
Enalapril - better compliance due to 1 per day dose and less side effects
Name 4 side effects of ACE inhibitors, and their mechanisms.
1st dose hypotension
Hyperkalaemia - less AngII, less aldosterone, and more K+ retention
Acute renal failure - in patients with renal artery stenosis
Dry cough - more bradykinin
Describe two side effects of ACE inhibitors with sulfhydryl groups.
Altered/loss of taste
Rash
Consider AT1 receptor antagonists. Do they affect bradykinin levels?
Noh
Name three side effects of AT1 receptor antagonists.
1st dose hypotension
Hyperkalaemia - less AngII, less aldosterone, and more K+ retention
Acute renal failure - in patients with renal artery stenosis
No dry cough due to no change in bradykinin levels
Name the four different types of voltage operated calcium channels.
L, N, P, and T
How many subunits do voltage operated calcium channels have?
4
What is the basis for using L-type Ca2+ channel antagonists to treat hypertension (3)?
-BP increase is due to an increase in TPR
-Vascular smooth muscle contraction is dependent on free [Ca2+]
-Inhibition of transmembrane Ca2+ movement through L-type Ca2+ channels leads to decreased [Ca2+] and vascular smooth muscle vasodilation
What effect do Ca2+ channel antagonists have at the SA node and AV node?
SA node - decreased automaticity
AV node - decreased conduction
What effect do Ca2+ channel antagonists have at cardiac myocytes and coronary arteries (2 each)?
Cardiac myocytes - decreased afterload, decreased myocardial O2 demand
Coronary arteries - increased vasodilation, increased mycardial O2 supply
What effect do Ca2+ channel antagonists have at peripheral arteries and veins (4)?
Arteries - Vasodilation, decreased afterload, increased myocardial O2 demand
Veins - minimal vasodilation
In 5 steps, briefly describe the mechanism of action for Ca2+ channel antagonists.
-Inhibit L-type Ca2+ channels
-Decrease Ca2+ entry to vascular smooth muscle
-Decrease cascular contractile tone
-Decrease TPR - especially due to arteriolar dilation
-Decrease BP
Name the three classes of Ca2+ channel antagonists.
Dihydropyridines
Benzothiazepines
Phenylalkylamines
Do Ca2+ channel antagonists affect preload?
Noh
Do Ca2+ channel antagonists affect skeletal muscles? Why is this so?
Little effect, because the sarcoplasmic reticuli have Ca2+ pools.
What is the preferred class of Ca2+ channel antagonist to treat hypertenstion and why?
Vascular-specific dihydropyridines as it lowers TPR
Name 5 side effects of dihydropyridines.
Reflex tachycardia, palpitations, nausea, flushing, headache
Name 2 side effects of benzothiazepines.
Bradycardia, AV block
Name 2 side effects of phenylalkylamines.
Bradycardia, AV block
Do AT1 receptor blockers target cardiac output or total peripheral resistance?
Cardiac output
What percentage of patients will not respond adequately to hypertension treatment, and what is done in these cases?
Up to 50%, combination therapy is used.
Name three general guidelines for combination therapy for treating hypertension.
Use drugs from different classes with complimentary actions
Aim for the least additive effects
Avoid combinations such as B-adrennoceptor antagonists and phenylalkylamines (compromises cardiac function)
