Pharmacology of Hypertension Flashcards
What are the 4 anti-hypertensive drug classes?
- ACEi (angiotensin converting enzyme inhibitors)
- Calcium channel blockers
- Thiazide or thiazide-like diuretics
- ARB (angiotensin receptor blockers)
What are some examples of ACEi?
Ramipril
Lisinopril
Perindopril
What is the primary mechanism of action of ACEi?
Inhibit the angiotensin converting enzyme
Prevent the conversion of angiotensin I to angiotensin II by ACE
What is the drug target site of ACEi?
ACE (angiotensin converting enzyme)
What are the main side effects of ACEi?
Cough
Hypotension
Hyperkalaemia (care with K+ supplements or K+ sparing diuretics)
Foetal Injury (AVOID IN PREGNANT WOMEN)
Renal failure (in patients with renal artery stenosis)
Urticaria / Angioedema (fluid buildup and swelling under the skin)
What is some extra information about ACEi?
Most ACEi (not lisinopril) are pro-drugs - require hepatic activation to generate active metabolites
eGFR and serum potassium must be regularly monitored when prescribing ACEi
Most trials indicate that ARBs are not as effective as ACEi
What are some examples of calcium channel blockers?
Amlodipine
Felodipine
What is the primary mechanism of action of calcium channel blockers?
Block L-type calcium channels – predominantly on vascular smooth muscle
Results in a decrease in calcium influx = inhibition of myosin light chain kinase and cross-bridge formation
Results in vasodilation = reduces peripheral resistance
What is the drug target site of calcium channel blockers?
L-type calcium channel
What are the main side effects of calcium channel blockers?
Ankle oedema
Constipation
Palpitations
Flushing/Headaches
What is some extra information about calcium channel blockers?
Dihydropyridine type calcium channel blockers demonstrate a higher degree of vascular selectivity
What are some examples of thiazide or thiazide-like diuretics?
Bendro-flumethiazide (thiazide)
Indapamide (thiazide-like)
What is the primary mechanism of action of thiazide or thiazide-like diuretics?
They block the Na+, Cl- co-transporter in the early DCT = Na+ and Cl- reabsorption is inhibited
Osmolarity of the tubular fluid increases = decreasing the osmotic gradient for water reabsorption in the collecting duct
What is the drug target site of thiazide or thiazide-like diuretics?
Sodium/chloride cotransporter
What are the main side effects of thiazide or thiazide-like diuretics?
Hypokalemia
Hyponatremia
Metabolic alkalosis (increased hydrogen ion excretion)
Hypercalcemia
Hyperglycemia (hyperpolarised pancreatic beta cells).
Hyperuricemia
What is some extra information about thiazide or thiazide-like diuretics?
Thiazide and thiazide-like diuretics both lose their diuretic effects within 1-2 weeks of treatment
Continuing anti-hypertensive action appears to be due to vasodilating properties (these are more pronounced for the thiazide-like diuretics)
What are some examples of ARB?
Losartan
Irbesartan
Candesartan
What is the primary mechanism of action of ARB?
Act as insurmountable (i.e. non-competitive) antagonists at AT1 receptors (found on kidneys and on the vasculature)
What is the drug target site of ARB?
Angiotensin receptor
What are the main side effects of ARB?
Hypotension
Hyperkalaemia (care with K+ supplements or K+ sparing diuretics)
Foetal Injury (AVOID IN PREGNANT WOMEN)
Renal failure (in patients with renal artery stenosis)
What is some extra information about ARB?
Most trials indicate that ARBs are not as effective as ACEi
Losartan and candesartan are pro-drugs = require hepatic activation to generate the active metabolites
Case Study: Mrs Turner
64F - Rheumatoid arthritis for 9 years, in the last year her mobility is severely restricted, in pain even at rest
Pre-op for arthroplasty (replacement) revealed: BP = 149/93mmHg
GP measures 147/92mmHg and 145/91mmHg on 2 different occasions.
She is offered ambulatory blood pressure monitoring by her GP. Apart from RA pain, Mrs Turner feels well, although she does smoke (< 10 per day). She is 167cm and 85kg.
What is the patient’s problem?
BMI = 30.4
Pain from RA
Hypertension
What is a q-risk score?
What are the 5 biggest risk factors for cardiovascular-related events?
Large database from which the algorithm can find your risk for cardiovascular related diseases / conditions e.g. strokes, MIs, CVD
Hypertension Hypercholsterolaemia Family history Diabetes Smoking
What is Mrs Turner’s calculated q-risk score?
14.9
What is the therapeutic objective for Mrs Turner?
Lower her BP - to reduce risk of long term consequences e.g. cardiovascular related diseases
Pain management of her RA
Why is compliance lower for patients to take hypertension medication compared to e.g. inhalers?
Hypertension medications = no immediate effects
Short-term makes you feel worse due to everyday side effects
They offer future protection that patients sometimes do not realise
V. rarely patients sometimes have hypertensive encephalopathy (general brain dysfunction due to significantly high blood pressure), in which case the medication will have quick short term and long term effects
Whereas inhalers = feel better within a few hours
What would you do next for Mrs Turner?
Firstly, give her lifestyle modifications e.g. stop smoking, reduce her BMI etc.
Check for diabetes
Do an ambulatory 24-hr reading
Find out whether she has hypertension, and if she does - stage 1 or stage 2?
What are Stage 1 and Stage 2 hypertension?
When do you decide to treat (give hypertension medication to) patients?
Stage 1 = 135-150 systole
Stage 2 = 150+ systole
Stage 2 = get treated
Stage 1 = only get treated if they also have target end organ damage, renal disease, 10 year risk of greater than 10%, CVD or left ventricular hypertrophy
Why would Mrs Turner be treated with calcium channel blockers instead of ACE inhibitors?
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker - >55 y/o and ethnicity (black)
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 2.5mg once daily as a starting dose)
What is the mechanism of action of calcium channel blockers in the treatment of hypertension?
Calcium channel blockers prevent calcium from entering the heart muscle cells
Leads to less contractility of the heart and vasodilation
Relaxes smooth muscle, reduces resistance of the blood vessels, reduces cardiac output
What is meant by the term clearance in general?
Clearance = the measure of the ability of the body to eliminate a drug
Clearance by means of various organs of elimination is additive
Elimination of drug may occur as a result of processes that occur in the liver, kidney, and other organs
What is meant by plasma clearance?
What is elimination half-life?
What is meant by time to peak plasma levels?
Plasma clearance = how much blood goes through the kidney in a given time to filter out the drug
Elimination half-life = time it takes for the concentration of the drug in the body to half
Peak plasma levels = time it takes for the medication in the blood plasma to accumulate and reach peak concentration, the faster the absorption rate the lower the time to peak plasma concentration
What is the relationship between plasma clearance and elimination half-life?
As plasma clearance (ml/min/kg) decreases elimination half life increases
Time to peak plasma levels increase
Conc. of drugs with a long half life remains fairly stable
Felodipine:
Plasma clearance (mL/min/kg) - 38
Elimination half-life (hrs) - 6-8
Time to peak plasma levels (hrs) - 1-3
Amlodipine:
Plasma clearance (mL/min/kg) - 11
Elimination half-life (hrs) - 35-50
Time to peak plasma levels (hrs) - 6-12
What are the differences between amlodipine and felodipine?
So which is more suitable between Felodipine and Amlodipine?
Felodipine = cleared faster, quicker accumulation of the medication in the blood plasma
Amlodipine = cleared slower, effects last longer and more or less consistently, but takes longer to accumulate in the blood to cause the effects
Amlodipine = more suitable = stays in the blood longer and more consistently throughout the day
Mrs Turner = suffering with swollen ankles since she started on amlodipine, too painful on her knee.
GP mentions the angiotensin converting enzyme (ACE) inhibitors.
What is the mechanism of action of ACE inhibitors in the treatment of hypertension?
Targets ACE - mainly in the lungs and some in the renal endothelium
Stops conversion of angiotensin-1 to angiotensin-2
Angiotensin-2 is a very potent vasoconstrictor, so if this is inhibited, the peripheral vessels remain vasodilated
Angiotensin-2 also induces aldosterone, which increases Na+ absorption resulting in increased H2O absorption, which increases blood volume. So lack of angiotensin-2 leads to increased urine output = lowered blood volume = lowered BP
What are ARBs?
Angiotensin receptor blockers - block the action of angiotensin-2
Why do ACEi cause a cough, but ARBs do not?
ACE = has functions other than converting angiotensin-1 to angiotensin-2, it also breaks down bradykinin, which accumulates and can lead to a cough
ARBs block angiotensin-2 action directly, so ACE are still free to break down bradykinin
If Mrs Turner were to start an ACE inhibitor, the advice would be to check renal function (eGFR), serum electrolytes (especially blood potassium) and blood pressure 1-2 weeks after starting treatment
Why might ACE inhibitors have a negative effect on eGFR and serum potassium?
Afferent arteriole needs to be more open than the efferent arteriole to produce the pressure in the glomerulus that filters out the blood
Lack of angiotensin-2 = lack of constricted efferent arteriole = lowered pressure = lowered eGFR
Lack of angiotensin-2 = lack of aldosterone = more Na+ and water in the urine output = more K+ remains in the blood = hyperkalaemia. Increased K+ in the blood = can affect the heart
Mrs Turner and her GP decide against the ACE inhibitors as increase in serum K+ = cancellation of her knee replacement
Mrs Turner agrees to switch to a thiazide-like diuretic – indapamide (1.25mg orally once a day)
What is the mechanism of action of indapamide?
Block the sodium chloride co-transporter in the distal tubule
More Na+ remains in the filtrate, which leads to increased water passed in the urine output
For the first few weeks it leads to reduced cardiac output due to reduced venous return (due to lowered blood volume)
But long term, reduces peripheral resistance
How is there Na+ excreted into the filtrate if sodium chloride channels are blocked in the kidneys?
Earlier on in the distal tubule, the sodium chloride channel is blocked - preventing reabsorption of Na+ and Cl-
But in the later part of the distal tubule, it is a different set of sodium transporters, which eliminate Na+ from the blood at the expense of K+ (As in K+ reabsorbed as Na+ excreted)
This increases water reabsorption in the distal tubule
Increased urine output
Decreased cardiac output
What happens after you take thiazide diuretics for a while?
After a while a mechanism adapts to overcome the reduction in cardiac output
Cardiac output goes back to normal
So in reality they work by decreasing total peripheral resistance
Indapamide (and other thiazide-like diuretics) are excreted unchanged in the urine
Why is this a vital part of the therapeutic action of thiazide-like diuretics?
These drugs work in the kidneys, therefore must remain unchanged as they pass through the liver, when they reach the kidneys so they can have their therapeutic effect?
(I think)
