Anti-hypertensives Part I (ACE-inhibitors, ARBs, CCBs, Vasodilators)

Part 1: ACE inhibitors/Angiotensin converting enzyme inhibitors

(a) Quinapril

(b) Perindopril

(c) Ramipril

(d) Fosinopril

(e) Moexipril

(f) Lisinopril

(g) Benazapril

(h) Enalapril

(i) Trandolapril

(k) Captopril

Acronym: QPR FML BET CAP

1.1 Mechanism of action

  • All of them block conversion of angiotensin I to angiotensin II.
  • They also inhibit the breakdown of bradykinin
  • Reduce the effects of angiotensin II-induced vasoconstriction, sodium retention and aldosterone release.
  • Reduce the effect of angiotensin II on sympathetic nervous activity and as a growth factor.

1.2 Clinical Indications

-Hypertension

-Heart Failure

-Diabetic Nephropathy (Type 1 Diabetes)

-Prevention of progressive renal failure in patients with persistant proteinuria >1g/day

-Asymptomatic left ventricular dysfunction

-Post Myocardial infarction (acute treatment or in patients with left ventricular dysfunction or heart failure)

-Reduction of risk of cardiovascular events in specific patients.

1.3 Side Effects/Adverse effects

*1. Angioedema (can be Heriditary, idiopathic or ACE-induced)

-ACE inhibitors increase risk of further episodes (use alternative class if possible or seek specialist advice)

-Isn’t dose related but may occur within first week of therapy

-Airway obstruction/respiratory distress may lead to death.

-Involves the accumulation of bradykinin (Angiotensin I resemblance) or inhibition of complement 1-esterase inhibitor (Complement cascade inhibitor)

-Once angioedema is gone, use anti-histamines and/or glucocorticoid to protect airways.

2. Fetotoxicity

-Angiotensin II Type 2 receptors expressed in placenta (Refer to precautions for more detail)

3. Skin Rashes (especially captopril), Itching

-Maculopapular rash (Conincally raised skin, coloured rash, may be pruritic)

-Occurs due to sulfhydryl group in captopril but occurs with other ACE inhibitors (less frequent)

*4. Acute Renal Failure

-Can induce acute renal insufficiency in patients with bilateral renal artery sternosis, stenosis of the artery to a single remaining kidney (Decreased perfusion to kidneys), heart failure, or volume depletion due to diarrhea or diuretics

-Care in elderly patients with CHF or particularly susceptible to ACE-induced acute renal failure.

*5. Cough (Induced by bradykinin)

-Occurs more frequently in women than men

-Once ACE-inhibitors stopped, cough disappears within 4 days

*6. Headache, dizziness, nausea, fatigue (Associated with Hypotension)

-Steep fall in blood pressure may occur following first dose of an ACE inhibitor in patients with elevated plasma renin.

*7. Hyperkalemia

-Retains K+, especially in patients with renal insufficiency or patients taking K+ sparing diuretics, K+ supplements, B-blockers or NSAIDs

8. Hypovolemia, dehydration

-Use of ACE-inhibitor increases risk of dehydration and first dose hypotension.

Others Not listed in Joe’s notes: Anaphylactoid reactions, palpitations, chest pain, flushing, fever, taste disturbances, vomitting, anorexia, diarrhea, constipation, stomatitis, dry mouth, sore throat, hoarseness, muscle cramps, elevated hepatic aminotransferases (AST/ALT) and bilirubin, abnormal dreams

*-Means common or infrequent side effects that occur

Rare side effects: Hepatitis (Cholestatic/bile cannot flow from the liver to the duodenum or hepatocellular), Pancreatitis, Proteinuria, Hyponatremia, Thrombocyptopenia, Neutropenia, Aplastic anemia, Agranulocytosis, Hemolytic anemia, Eosinophilia, Myalgia, arthralgia, neuropathy, paraesthesia, photosensitivity, psoriasis, pemphigus, toxic epidermal necrolysis, gynaecomastia, visceral angioedema

1.3 Precautions

(a) Angioedema (Could be hereditary, idiopathic or ACE-inhibitor induced)

-ACE inhibitors increase risk of future occurances (use alternative class if possible or seek specialist advice)

(b) Hypovolemia, Dehydration (e.g. taking a diuretic)

-Increases risk of first dose hypertension

(c) Primary Hyperaldosteronism

-ACE inhibitor is ineffective, use Spironolactone instead (drug of choice)

(d) Black, African or Caribbean descent

-Anti-hypertensive effect of monotherapy with an ACE inhibitor or sartan may be reduced (generally a calcium channel blocker or thiazide diuretic is more effective)

(e) Treatment with drugs that can increase potassium concentrations (e.g. potassium-sparing diuretics, spironolactone, cyclosporin)

-increases risk of hyperkalemia; avoid combination if there is no choice monitor potassium blood levels.

1.4 Use of ACE-inhibitors in Special cases or conditions 

Cardiovascular condition

-Limited data to suggest that ACE inhibitors are beneficial in selected patients with aortic stenosis (theoratically they might cause coronary hypoperfusion, systemic hypotension, and reduced renal function)

Caution must be taken to avoid hypotension

-Patients with peripheral vascular disease or artherosclerosis (increased risk of renal failure)–>Avoid use of ACE-inhibitors

Renal impairment/failure

-Renal impairment increases risk of hyperkalemia and may affect the excretion of most ACE inhibitors, dosage may need to be adjusted

-Pre-existing renal impairment may worsen especially if the person is hypovolemic. Also concurrent use with NSAIDs will worsen renal function.

-ACE inhibitors increase risk of renal failure in bilateral renal artery stenosis.

-They may have a myelosuppressive effect  (causing bone marrow suppression) in end-stage renal failure, may require increased epoetin (Epoetin is a type of erythropoietin stimulator used to increase red blood cells count)

Relevance? -Hemodialysis with high flux polyacrylonitrile membranes may result in anaphylactoid reactions (a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation), similar reactions may occur in patients on low density lipoprotein apheresis with dextran sulfate (blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation)

Surgery

-Excessive hypotension may occur during anesthesia or surgery.

Elderly

-May be more predisposed to first dose hypotension, hyperkalemia and renovascular disease than younger patients. Start treatment with lower doses, monitor renal function closely.

Women

-Avoid in women who plan to conceive or who are using inadquate contraception.

Pregnancy (NOT ALLOWED IN PREGNANCY) and Breastfeeding

-Contraindicated. Use in first trimester may cause congenital malformations, use in second and third trimester MAY cause renal dysfunction and oligohydraminos (condition in pregnancy characterized by a deficiency of amniotic fluid. It is the opposite of polyhydramnios)

-Subsequent fetal death (CAT D)

-Breastfeeding: No adverse effects reported with captopril or enalapril. Not sure about others.

1.5 Counselling points/Comparative information/Practice points

-Most ACE-inhibitors except captopril can maintain an anti-hypertensive effect up to 24 hours and can be given once daily.

-Many are available as combination products with a diuretic (hydrochlorothiazides, indapamide), or a Calcium channel blocker

-Reserve for patients stabilised on similar doses of single ingredient products.

Therapeutic points:

-Might feel dizzy when you start taking this medicine. Get up gradually from sitting or lying down to minimise this effect, sit or lie down if patient becomes dizzy or light headed.

DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE TAKING THIS MEDICATION UNLESS DOCTOR INSTRUCTS OTHERWISE.

  • When starting ACE inhibitors, stop potassium supplements and potassium-sparing diuretics, stop other diuretics for 24 hours
  • Always start with low doses
  • Check renal function and electrolytes before starting ACE-inhibitor and review after 1-2 weeks.
  • Onset of ACE inhibitor associated angioedema may not occur for several years

Treatment with ACE inhibitors and ARBs

-In trials, the combination worsened renal function and increased risk of hypotension and hyperkalemia

-Combination DID NOT PROVIDE ADDITIONAL  benefit for post MI/left ventricular failure patients

-May be an option despite contradicting trial evidence. For patients chronic heart failure or non-responsive BP, seek specialist advice

1.6 Comparison between ACE-inhibitors (When and what to use for which patients)

1. Quinapril (Prodrug)

Indications: Hypertension (Combination with hydrochlorothiazide), Heart Failure

-Hepatic esterases transform prodrug quinapril into quinaprilat

-60% absorption

2. Perindopril (Prodrug)

Indications: Hypertension, Heart Failure, Reduction of risk of MI or cardiac arrest in people with established coronary heart disease without heart failure

  • Can be combined with amlodipine (Calcium channel blocker) for hypertension or stable coronary heart disease.

-Perindopril erbutamine is a prodrug (30% to 50% transformed to perindoprilat by hepatic esterases)

-Biphasic elimination, slow dissocation from tissue

-Not affected by food, bioavailability 75%

3. Ramipril

Indications: Hypertension (Ramipril in combination with felodipine) , Post MI in patients with heart failure, Prevention of MI, stroke, cardiovascular death,

Need for revascularisation procedures in patients >55 years with:

Coronary artery disease, stroke or periphearl vascular disease, diabetes and 1 or more risk factors (Low HDL cholesterol, Previous vascular disease, smoking, microalbuminuria, high total cholesterol, smoking, hypertension)

4. Fosinopril

Indications: Hypertension (in combination with hydrochlorothiazide), heart failure

-Absorbed incompletely (36%), not reduced by food

5, Moexipril

-Not listed in AMH 2012

6. Lisinopril

Indications: Hypertension, Heart failure, Post MI acute treatment

Lys analogue of enalaprilat, lisinopril itself is active.

-Absorbed incompletely 30%, not affected by food

7. Captopril

Indications: Hypertension, Heart Failure, Post MI in patients with left ventricular dysfunction, Diabetic nephropathy (Type 1 Diabetes)

Precautions: Collagen vascular disorders (e.g. scleroderma, systemic lupus erthymetosus/SLE), severe renal impairment-may be predisposed to neutropenia or agranulocytosis.

-Bioavailability 75%, reduced by food to 30%

8. Enalapril

Indications: Hypertension (in combination with hydrochlorothiazide or lercanidipine), Heart failure, Asymptomatic left ventricular dysfunction

-Enalapril maleate is the prodrug hydrolysed by esterases to active enalaprilat

-Bioavailability 60%, not reduced by food

9. Benazepril

-Nost listed in AMH 2012

10. Trandolapril

Indications: Hypertension (in combination with verpamail), Post MI in patients with left ventricular dysfunction

*Precautions: Hepatic impaired patients (Use a lower starting dose in those with hepatic impairment)

Trandolapril metabolised into trandolaprilat

-10% bioavailable as trandolapril and 70% as trandolaprilat

***Biphasic elimination kinetics (slow dissociation from tissue)

****Excretion mostly by kidneys except fosinopril (excreted in urine and bile), quinapril (urine 61% and feces 37%), trandolapril (33% in urine, 66% in feces) 

Drug interactions:

1. NSAIDs-Reduce anti-hypertensive effects of anti-hypertensives (PGI2, PGE2 inhibited, no more compensatory vasodilation)

-Increased risk of renal impairment and hyperkalemia.

-Avoid combination in elderly or if renal hypoperfusion/impairment occurs.

2. Loop Diuretics

-Increased risk of hypotension. Withhold loop diuretic for at least 24 hours before starting ACE-inhibitor.

-Begin with low doses of ACE-inhibitor in the evening (under supervision)

*Combination avoided due to the increased risk of renal impairment

3. Thiazides

-increased risk of severe hypotension

*Begin with a low dose in the evening

* Use with caution in the elderly, renal impaired (combination with other anti-hypertensives should be avoided)

4. Lithium

-Lithium excretion decreases when ACE-inhibitors used (Insidious toxicity may occur)

*5. Digoxin

-Increased levels of digoxin, reduces excretion, reduced GFR

6. K+ supplements, K+ sparing diuretics-Result in hyperkalemia

*7. Antacids (Reduce oral bioavailability of ACE-inhibitors)

8. Capsaicin (Worsen bradykinin-induced cough)

*9. Allupurinol

-Increased hypersensitivity reactions to allupurinol

*-Not listed in AMH 2012

NOTE: Monitor Li+/K+ concentration, renal function every 1-2 weeks. Reduce Li+ by adjusting dose if necessary. Alternatively, use other classes of anti-hypertensives.

Part 2: ARBs

1.1 Types of ARBs

Losartan

Olmesartan

Valsartan

Eprosartan

Irbesartan

Candesartan

Telmisartan

Acronym: Love I can Tell

1.2 Mechanism of Action

  • Competitively (but often this inhibition is insurmountable) blocks binding of angiotensin II to type I angiotensin II receptors (ATII Type 1 receptors). Max response cannot be restored.
  • Inhibits most biological effects of AngII (e.g. Prevent contraction of vascular smooth muscle, rapid+slow pressor response, thirst, ADH release, Aldosterone secretion, Release of Adrenal catecholamines, Enhancement of NAdr transmission, increases in sympathetic tone, changes in renal function and cellular hypertrophy/hyperplasia).
  • Reduce angiotensin-induced vasoconstriction, sodium reabsorption and aldosterone release
  • ARBs are renoprotective in Type 2 Diabetes mellitus-How?

(RAAS causes systemic and glomerular capillary hypertension as well as injury to vascular endothelium and glomerulus.

-Direct profibrotic and pro-inflammatory actions of Ang II and aldosterone may promote kidney damage.

-AngII–>Increases reactive oxygen species and renal damage. Thus, both ARBs and ACE-inhibitors lower proteinuria and serum creatinine. This improves response of renal vasculature to Nitric Oxide (an indicator of endothelial and renal endothelial health).

1.3 Indications

  • Hypertension
  • Heart Failure in patients unable to tolerate ACE-inhibitors (i.e. start with ACE-inhibitors first for CHF)
  • Reduction of Renal Disease Associated with Type 2 diabetes.

*Note all ARBs are indicated for hypertension. However, only some are used in heart failure and reduction of renal disease associated with Type 2 diabetes.

1.4 Precautions

1. Peripheral vascular disease

-In these patients, they are likely to have arterial renal stenosis (Decreased renal perfusion)

2. Volume or sodium depletion

-May activate the renin-angiotensin system leading to excessive hypotension when an ARB is started; correct the dosage accordingly and/or monitor carefully

3. Aortic stenosis

-ARBs may theoretically cause coronary hypoperfusion, systemic hypotension and reduced renal function (However apart from ARBs, ACE-inhibitors have limited therapeutic use patients with aortic stenosis, thus ARBs are preferred.)

4. Primary hyperaldosteronism

-Spironolactone is the drug of choice, ARBs may be ineffective, seek specialist advice

5. Black African, Carribean descent

-Anti-hypertensive effect of monotherapy with ARB or ACE-inhibitor may be reduced (Generally, Calcium channel blocker or thiazide diuretic is more effective)

6. Treatment with drugs that can increase potassium concentration

-K+ sparing diuretics e.g. spironolactone, cyclosporin (ARBs increase risk of hyperkalemia; avoid combination or monitor potassium concentration regularly)

1.4 Use of ARBs in Special Conditions

Renal

-Renal impairment may worsen, increased risk of hyperkalemia. Use lower initial doses and monitor potassium.

-ARBs increase risk of renal failure in bilateral renal artery stenosis.

Women

-Avoid in women planning to conceive or who are using inadequate contraception.

Pregnancy

-Contraindicated. use in first trimester may cause congenital malformations, second trimester and third trimester may cause fetal renal dysfunction and oligohydroaminos (lack of aminotic fluid), subsequently fetal death (CAT D-AUS)

Breastfeeding

-Avoid breastfeeding while on ARBs.

1.5 Adverse effects/Side effects

*1. Dizziness, Headache

*2. Hyperkalemia

*3. Fetotoxicity

*4.  Caution when used in Patients highly dependent on renin-angiotensin system

-In such patients, ARBs can cause hypotension, oliguria (low urine output), progressive azotaemia (Increase in urea and Nitrogen levels in blood due to low renal excretion) or acute renal failure.

*Denotes common adverse effects found in Joe’s notes

  • Other infrequent adverse effects found in AMH 2012: First dose hypertension, rash, diarrhea, dyspepsia (indigestion, is a condition of impaired digestion), abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin, renal impairment, pharyngitis, nasal congestion
  • Rare side effects found in AMH 2012: Cough, Uticaria, Angioedema, Henoch-Schonlein purpura, hepatitis, taste disturbance, migraine

*Note: ARBs are far less likely to induce cough (rare), angioedema far less common than ACE-inhibitors

1.6 Comparative information for ARBs

Hypertension

-Effect of ARBs is similar to that of other major anti-hypertensive drug classes

-Both losartan and irbesartan are marketed to reduce progression of renal disease in patients who have type 2 diabetes, hypertension and proteinuria (+microalbuminuria for irbesartan)

-ALL except Losartan are available in combination products with hydrochlorothiazide. Olmesartan, telmisartan and valsartan also available combined with amlodipine (CCBs)

High cardiovascular risk, heart failure, post MI

*Currently, recommendations are to use ACE-inhibitors as first line agents for treatment of CHF (cheaper)

-ARBs have not been shown to be superior to ACE-inhibitors for CHF, vascular disease, high-risk diabetes or left ventricular failure/dysfunction post MI.

-However, they improve prognosis and are an alternative in patients unable to tolerate or unresponsive to ACE-inhibitors.

Candesartan and Valsartan marketed for CHF and valssartan for left ventricular failure/dysfunction after MI.

Should we combine ARBs and ACE-inhibitors?

-At present, there is conflicting evidence regarding the benefit of combining an ARB with an ACE-inhibitor in CHF (combinations may worsen renal function, increase side effects such as hypotension and hyperkalemia-AMH 2012).

– Combination did not provide additional benefit in patients at high risk of vascular disease nor improve survival in patients with left-ventricular failure/dysfunction or post MI.

-Despite conflicting trial results, it may be an option for non-responsive patients or CHF. However, seek specialist advice.

-ARBs are superior to B1 blockers in reducing stroke in hypertensive patients with left ventricular hypertrophy.

Important differences between ARBs and ACE-inhibitors

1) ARBs reduce activation of ATII Type 1 Receptors more effectively than ACE-inhibitors. ACE-inhibitors inhibit production of Angiotensin II but there are alternative pathways where Ang II is generated.

2. ARBs permit activation of ATII Type 2 Receptors.

3) Both ACE-inhibitors and ARBs enhances renin-release. ARBs increase renin release resulting in increased levels of circulating Angiotensin II thus allowing Angiotensin II Type 2 receptors to be activated. ACE-inhibitors increase renin release but since they block the conversion of AngI to AngII, there will be decreased levels of Angiotensin II.

4) ACE-inhibitors may decrease Ang (1-7) levels more than do ARBs (side effects?)

5) ACE-inhibitors result in the accumulation of ACE-substrates, namely bradykinin whereas ARBs do not.

1. 7 Counselling points

-Patient may feel dizzy when started on ARBs. Get up gradually from sitting or lying down to minimise this. Sit down or lie down if patient becomes light headed or dizzy.

-DO NOT TAKE POTASSIUM SUPPLEMENTS while on this medicine unless told by doctor to do so.

1.8 Practice Points

-Before starting an ARB, stop potassium supplements and potassium-sparing diuretics

-Check Renal function and electrolytes level regularly.

-Unlike ACE-inhibitors, ARBs do not inhibit breakdown of bradykinin. Thus if ACE-inhibitor is not well-tolerated (i.e. cough occurs or angioedema history), ARBs are a better alternative.

-Maximum anti-hypertensive effects occurs about 4-6 weeks after starting treatment (Effects not immediate)

-If initial response to monotherapy with a low maintenance dose of ARBs is insuffficent, consider adding second anti-hypertensive (e.g. thiazide) instead of increasing ARB dose.

1.9 Comparison between ARBs (When and what to use for which patients)

1. Losartan (14% of dose losartan converted to metabolite EXP3174 which is more potent than losartan as a ARB)

Indications: (a) Hypertension (Not used in combination with hydrochlorothiazides), (b) Reduction of renal disease progression in patients with type 2 diabetes, hypertension and proteinuria (urinary albumin to creatinine ratio greater than or equal to 300mg/g or proteinuria >500mg per 24 hours)

-Precautions in hepatic patients (lower dose required), Children (may be used under specialist supervision for children unable to tolerate ACE-inhibitor induced cough).

*Drug interactions specific for Losartan-Rifampicin

-Rifampicin (antibiotic) (CYPC29 inducer) increases metabolism of losartan (uses CYP2C9 and CYP3A4) to EXP3174. Thus, rifampicin potentiates Losartan’s effects (Monitor clinical effect and adjust losartan dose accordingly).

2. Olmesartan (Given as olmesartan medoxomil, inactive ester prodrug, active absorbed in gut)

-Indications: Hypertension (In combination with hydrochlorothiazide or amlodipine)

-Precaution: Renal Impaired (Contraindicated if Creatine Clearance is <30ml/min), hepatic (contraindicated if biliary obstruction, partially eliminated in bile), severe hepatic impairment (Child-Pugh Score 10-15). Concentration increases in moderate impairment (Child-Pugh Score 7-9)

*Child-Pugh Score: Assessment of chronic liver disease especially cirrhosis. Scoring system which depends on serum albumin levels, PT/INR, Ascites, Hepatic Encephalopathy

3. Valsartan

-Indications: (a) Hypertension (In combination with hydrochlorothiazide and/or amlodipine) (b) Heart Failure (NYHA class II-IV) if unable to tolerate an ACE-inhibitor (c) Left ventricular failure/dysfunction after MI, when clinically stable

*NYHA class: New York Heart Association functional classification for the extent of heart failure.

-Precaution: Renal impaired (Manufacturer recommends a lower maximum dosage if CrCl<30ml/min). Hepatic impaired (Mostly excreted unchanged in bile. Contraindicated in cholestasis (bile cannot flow from liver to duodenum), biliary cirrhosis and severe hepatic impairment.

-Valsartan concentrations are increased in mild-to-moderate impairment, manufacturer recommends a lower max dose.

4. Eprosartan (In combination with hydrochlorothiazide)

-Precautions: Hepatic impaired (Lower dosage required)

5. Irbesartan

-Indications: (a) Hypertension (In combination with hydrochlorothiazide) (b) Reduction of renal disease progression in patients with Type 2 diabetes, hypertension and microalbuminuria (>30mg/24 hours) or proteinuria (>900 mg/24 hours)

6. Candesartan (Candesartan cilexetil-Inactive prodrug, absorption in gut)

-Indications: (a) Hypertension (In combination with hydrochlorothiazide) (b) Heart failure in patients unable to tolerate ACE inhibitors or with ACE-inhibitor in patients with low ventricular ejection fraction (May require combination with ACE-inhibitor)

-Precautions: Renal (Lower doses required if Creatine Clearance <30ml/min)

7. Telmisartan

-Indications: (a) Hypertension (In combination with amlodipine or hydrochlorothiazide) (b) Prevention of cardiovascular morbidity and mortality in patients with coronary artery disease, peripheral artery disease, high-risk diabetes, previous stroke or TIA (transient ischemic attack)

-Longest half life of all ARBs.

Acronym: LOVE I can tell.

***All these drugs have >90% protein binding. All have oral bioavailability of <50%. Candesartan and Olmesartan both renal and biliary excreted. Telmisartan is only bile excreted (hepatic affected but not renal insufficiency). Irbesartan excreted as a glucorinide conjugate, parent compound is excreted in urine (20%) and 80% in bile. Losartan is metabolised to EXP3174 by CYP2C9 and CYP3A4 (clearance affected only by hepatic insufficiency). Valsartan is converted into inactive metabolite by CYP2C9, excreted in feces via bile route.

1.10 Drug Interactions for ARBs

1. Lithium

-ARBs may reduce excretion of lithium and increase risk of toxicity (onset may be insidious)

*Monitoring of lithium concentrations, renal function is necessary. Reduce lithium dose if necessary (consider using alternative classes)

2. Loop Diuretics

-Increases risk of excessive hypotension first dose of ARB due to volume depletion. Withhold loop diuretic (or reduce dosage) for at least 24 hours before starting ARBs. *Begin with low dose of ARBs (or give the first dose in evening under supervision)

3. NSAIDs

-May Reduce antihypertensive effect and increase risk of hyperkalemia or acute renal failure. *Avoid combination if not monitor BP, weight, serum creatinine and potassium regularly. Limit daily dose of aspirin to 100-150mg daily.

4. Thiazide Diuretics

-If High dose of thiazides used in combination with ARBs, risk of excessive hypotension after the first dose of ARBs may occur due to volume depletion. Withhold thiazide diuretic for at least 24 hours before starting ARBs. *Begin with low dose of ARB (or give first dose in the evening under supervision).

*Drug interactions specific for Losartan-Rifampicin

-Rifampicin (antibiotic) (CYPC29 inducer) increases metabolism of losartan (uses CYP2C9 and CYP3A4) to EXP3174. Thus, rifampicin potentiates Losartan’s effects (Monitor clinical effect and adjust losartan dose accordingly).

***********************************************************This incomplete portion will be updated soon*********************************************

Part 3: Calcium Channel Blockers (CCBs)

3.1 Types of CCBs

-Dihydropyridines, Benzothiazepines, Phenylalkylamines

Diltiazem and Verapamil (Phenylalkylamines), Amlodipine, Felodipine, Lercanidipine, Nifedipine (DHP)

3.2 Mechanism of action

-Lower BP by inhibiting Calcium channel influx through voltage-sensitive L-type calcium channels in arteriolar smooth muscle.

-Leads to smooth muscle relaxation and decreased TPR (peripheral resistance).

3.3 Physiological Effects

  • Decreased TPR. Thus, baroreceptor reflex might be evoked, resulting in tachycardia (especially DHPs)

-Tachycardia is minimal to absent with verapamil and diltiazem because of direct negative chronotropic effects of these two drugs.

3.4 Adverse effects

1. Headache, flushing, dizziness (Hypotension related)

2. Constipation (Especially with verapamil)

3. Gingivial Hyperplasia

*Requires flossing and good hygiene care

4. Pulmonary edema

5. Peripheral edema (Occurs due to increased hydrostatic pressure in lower extremities)

6. Cough

7. Arrhythmias (Lead to SA node arrest/dysfunction)

8. Gastro-eosophageal reflux (Lower sphincter inhibited)

*(Due to oscillation in blood pressure and reflex tachycardia, nifidepine or other DHP with short half lives are not suitable for long-term hypertension treatment)

3.5 Drug interactions

  • Concurrent use of B-blockers with non-DHPR (non-peripheral CCBs) will magnify the negative chronotropic and inotropic effects –>Resulting in cardiac block
  • Verapamil blocks the P-glycoprotein drug transporter in kidneys so drugs that use this transporter are affected (e.g. digoxin etc)
  • CCBs also are substrates of CYP 450 Enzyme, thus the metabolism is affected by many drugs (Verapamil substrate 1A2, 3A4, inhibitor of 3A4) (Felodipine Sub 3A4)

Part 4: Vasodilators

-Hydralazine, Dioxide and minoxidil

4. 1 Mechanism of action

-Causes direct relaxation of arteriolar smooth muscle, possible secondary to a fall in calcium concentration

Does not dilate epicardial coronary arteries or relax venous smooth muscles

-Hydralazine induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, likely due to baroreceptor-mediated reflexes (Increased chronotropy, inotrophy), increased plasma renin and fluid retention (Counteracts anti-hypertensive effects of hydralazine)

-Preferential dilation of arterioles, postural hypotension is not common.

-Hydralazine lowers BP equally in supine or upright positions.

4.2 Pharmacokinetics

-Absorption, metabolism and excretion (hydralazine is well absorbed through GI tract but systemic bioavailabliity is low)

-Hydralazine is N-acetylated in the bowel and/or liver.

-Half life is around 1 hour, systemic clearance is about 50ml/kg/min.

-Rate of acetylation is genetically determined.

-Acetylated compound is inactive, thus dose necessary to produce systemic effect is larger in fast acetylators.

4.3 Adverse effects and precautions (Hydralazine only)

1. Headache, Nausea, Flushing, Dizziness (Hypotension related)

2. Tachycardia, Palpitations, Angina Pectoris (Baro-receptor reflex mediated)

-Angina pectoris (effect of myocardial ischemia) may occur because of increased oxygen demand induced by baro-receptor reflex induced stimulation of sympathetic nervous system

-Hydralazine does not dilate epicardial coronary arteries, thus the arteriolar dilation it produces may cause a ‘steal’ from blood flow from ischemic region.

-If hydralazine drugs used alone, there may be salt retention with development of CHF.

-When combined with a B-blocker and a diuretic, hydralazine is better tolerated. 

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