W2 Blood Pressure Control (Pharmacotherapeutics) Flashcards
AKA Antihypertensive Drugs 1 (41 cards)
What is the pathway for antihypertensives for an individual with hypertension with type 2 diabetes?
- ACEi or ARB
2.ACEi or ARB +++ CCB or thiazide-like diuretic - ACEI or ARB + CCB + thiazide-like diuretic
- Confirm resistant hypertension: confirm elevated BP with ABPM or HBPM, check for postural hypertension and discuss adherence
- Consider seeking expert advice or adding a:
- Low-dose spironolactone if blood potassium level is <4.5mmol/l
- Alpha-blocker or beta-blocker if blood potassium level >4.5 mmol/l
See expert advice is BP is uncontrolled on optimal tolerated doses of 4 drugs
What is the pathway for antihypertensives for an individual with hypertension without type 2 diabetes/ Age 55 or over or Black-African-Caribbean family origin (any age)?
- CCB
- CCB + ACEi OR ARB or thiazide-like diuretic
- CCB + ACEi OR ARB + thiazide-like diuretic
- Consider seeking expert advice or adding a:
- Low-dose spironolactone if blood potassium level is <4.5mmol/l
- Alpha-blocker or beta-blocker if blood potassium level >4.5 mmol/l
See expert advice is BP is uncontrolled on optimal tolerated doses of 4 drugs
Monitoring treatment:
Measure standing and sitting BP in people with..?
Measure standing and sitting BP with
1. Type 2 diabetes
2. Symptoms of postural hypertension
3. Aged 80 and over
What is a pro-drug?
A prodrug is a compound that has little or no activity on a desired pharmacological target but is converted to an active, or more active, entity by an endogenous metabolic reaction.
What is Angiotensin ll?
At1 receptor activation ( Gq coupled receptor) leads to what…?
A peptide hormone, that acts at AT1
receptors, stimulating both vasoconstriction ( inc peripheral resistance) and aldosterone release ( Inc CO by inc blood vol)
=This leads to increasing blood pressure which we want to prevent
Vascular smooth muscle: vasoconstriction
Adrenal Cortex: aldosterone release
Adrenergic innervations: adrenaline release and inhibit reuptake (synergistic effect on heart and blood vessels)
Pituitary gland- Antidiuretic hormone (ADH) release
ACEi:
(Angiotensin-converting enzyme inhibitors)
What is ACE? (structure)
Where is is localised?
- ACE is a zinc-containing dipeptidyl
carboxypeptidase enzyme (150 to 180 kDa,
also known as kininase II) - ACE is primarily localised on the luminal side of the vascular endothelium. The lung, which has a vast surface area of vascular endothelium, is rich in ACE. It is also present in other organs including the kidney, heart, brain, and striated muscle skin, as it is a part of local RAASs
- ACE cleaves the terminal histidyl-leucine from angiotensin I (decapeptide) to form the octapeptide angiotensin II
What are the mechanisms of ACE inhibitors?
- Arterial and Venous vasodilation (no vasoconstriction)
* Reduction in arterial & venous pressure
* Reduction in ventricular preload & afterload - Decrease blood volume (no aldosterone release)
* Natriuresis
* Diuresis - Downregulation of sympathetic activity
- Suppression of hypertrophy (cardiac and vascular
ACE is inhibited so Angiotensin ll is unable to be converted into Angiotensin ll to act at AT1 receptors so vasoconstriction and aldosterone release does not occur so a dec in peripheral resistance and dec in cardiac output so leads to blood pressure reduction
ACE inhibitors lower blood pressure by reducing the vasoconstriction induced by angiotensin II, thereby decreasing peripheral resistance.
Consequently, the lower Ang II level reduces the sodium and water reabsorption and cardiac output.
What are examples of ACE inhibitors?
( name ending…?)
‘pril’ drugs
*Captopril (first marketed, not a pro-drug, shorter half-life)
*Enalapril (more recent, longer duration of action)
*Fosinopril
*Imidapril
*Lisinopril (not a pro-drug)
*Perindopril
*Quinapril
*Ramipril (More recent, longer duration of action)
*Trandolapril
Pharmacokinetics of (ACE) inhibitors
What are the ADME processes of ACE inhibitors?
A: 40-66% bioavailable depends on the
drug
D: Binds to tissue and plasma protein
M: Metabolised in the liver
E: Eliminated through the kidney
What is the ADME processes of Captopril?
Captopril= absorbed and eliminated rapidly (not a prodrug)
A: 40-66% bioavailable depends on the
drug
D: Binds to tissue and plasma protein
M: Metabolised in the liver
E: Eliminated through the kidney
What is the ADME processes of Enalapril?
Enalapril, like most of the later ACE inhibitors, is an inactive pro-drug that requires hydrolysis during or active absorption to generate the active acid form, enalaprilat.
A: 40-66% bioavailable depends on the
drug
D: Binds to tissue and plasma protein
M: Metabolised in the liver
E: Eliminated through the kidney
What is the ADME processes of Lisinopril?
Lisinopril is an analogue of enalapril and is itself active. Lisinopril is not metabolized and is excreted as an unchanged drug. Lisinopril is entirely eliminated exclusively in the urine.
A: 40-66% bioavailable depends on the
drug
D: Binds to tissue and plasma protein
M: Metabolised in the liver
E: Eliminated through the kidney
What is the most common side effect of ACEi and why?
Dry, irritant cough in about 15% (10% of men and 20% of women) is attributable to
the accumulation of bradykinin.
- ACE metabolises bradykinin but is inhibited
What is Bradykinin?
Bradykinin is a potent vasodilator peptide that exerts its vasodilatory action through stimulation of specific endothelial B2 receptors. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict.
ACE inhibitors block the breakdown of bradykinin and increase bradykinin levels, which can contribute to the vasodilator action.
What is Accumulation Bradykinin?
- Accumulation bradykinin induces sensitization of airway sensory nerves via rapidly adapting stretch receptors and C-fiber receptors that release neurokinin A and substance P.
- This causes airway smooth muscle to constrict leading to bronchoconstriction and persistent dry cough. (most common adverse effect, 10-20% of patients)
What is bradycardia?
A low heartbeat
SE of a medicine
Adverse effects of ACEi:
Most common?
Rare (but potentially detrimental)
Most common:
Dry, irritant cough in about 4-35% is attributable to the accumulation of bradykinin.
Rare (but potentially detrimental)
* Hyperkalaemia (due to potassium retention is mediated by the reduction of aldosterone)
* Taste disturbance (ACE inhibitors affect the Zinc of the ACE protein in the salivary gland cells)
* Hypotension (due to renin-angiotensin system)
* Renal impairment (vicious cycle)
* Angioedema (kinin potentiation); Skin rashes, Urticaria
What are the clinical considerations of ‘prils’? (3)
(General scheme SE)
- Cough is not dose-dependent and is a class effect (dose titration isn’t helpful)
- Hypotension: combine with low-dose diuretics.
- Dehydration (diarrhoea, vomiting, postural hypotension and acute kidney disease):
suspend temporarily.
Renal risk assessment
- ACE inhibitors are beneficial for patients with chronic renal failure and hypertension
- Monitor serum creatinine and potassium (shouldn’t be raised 20% more than the reference range)
- Periodically assess renal structure and function
- Discontinue ACE inhibitors for patients with bilateral renal artery stenosis
What is angiotensin ll?
Where does it act?
Angiotensin II is a peptide hormone, that acts at AT1receptor
ACE inhibitors are either not prescribed or avoided as the first-line option for which categories of patients?(3)
- 55 or above years (natural ageing of renal function)
- Caribbean or black African ethnic origin (less response to renin-dependent BP regulation)
- Pregnant and breastfeeding women
How do ARBs work?
- ARBs are receptor antagonists that
block type 1 angiotensin II (AT1) receptors on blood vessels and other tissues such as the heart. - AT1 receptors are coupled to the Gq-protein and IP3 signal transduction pathway that stimulates vascular smooth muscle contraction
- The outcome/effect is similar to ACEi’s
Angiotensin II
List some examples of ARB’s
‘sartan’ drugs
Candesartan
(prodrug)
irbesartan
Losartan (prodrug)
valsartan
olmesartan
What are the ADME Properties of ARBs?
A: Readily absorbed, 20-66% bioavailability
depending on the drug
D: Binds to plasma protein (>90%)
M: Metabolised in the liver (CYP450 2C9)
E: Eliminated through the kidney
