Week 7 - Hypertension and Heart Failure

K= sparing diuretics

ex: amiloride used in combination with with thiazide inhibits the sodium ion pumps so that sodium is not replaced by potassium in the collecting duct

ACE inhibitor (ACEI) example

ex: enalapril (prodrug) active metabolite is enalaprilat. - predominatly eliminated by kidneys = reduce dose in renal impairment

example of a statin

ex: simvastatin Increase risk of myopathy, especially in renal insufficiency Myopathy is reversible (pain in muscles) Start with low does and increase dose gradually.

secondary hypertension

related to an underlying disease - treatment of disease = treatment of hypertension

What is hypertension

- Anything over 140 systolic/ 90 diastolic mm Hg - Most common Cardiovascular disease + incidence increase with age - Very common - No symptoms

ACE inhibitor mechanism of action

- Inhibits angiotensin 1 from turning into angiotensin 2 (potent vasocontrictor). - Inhibits bradykinin (potent vasodilator) from being turned into inactive bradykinin fragments Summary: decreased levels of angio 2 + decrease aldosterone (na+ and water retention hormone) + increased bradykinin

nitrovasodilators example:

1. Nirtovasodilators: - extensive first pass metabolism - t1/2 3 minutes - given sublingually or as a spray 2. nitroglycerin patches: - transdermal - slow release preparations 3. Isosoribide mononitrate: - no significant 1st pass liver metabolism - active metabolite - used to prevent angina attack

Pharmacological treatments

1. diuretics thiazide 2. K+ sparing diuretics 3. ACE inhibitor, 4. Angiotensin receptor 1 (AT-1) antagonist 4. Ca2+ channel blockers, 5. Alpha 1 adrenoceptor antagonist 6. Beta blockers

fibric acid derivatives examples

1. gemfibrozil - acts on (PPAR)a - is a nuclear receptor that regulates the gene expression = increase fatty acid oxidation (use), decrease in triglycerides and increase HDL indication: dyslipidaemia - most often in people who have diabetes liver metabolised + renal excretion contraindicated: renal insufficiency or liver disease. 2. Ezetimibe Inhibits transporter for cholesterol in GI tract Inhibits absorption of cholesterol Decreases LDL but no effect on HDL Pharmacokinetics: oral, only get enterohepatic recycling, used in people who have side effect to statins, used when effects of statins alone are not reducing LDL enough - reduced cardiovascular outcomes when added to statins.

drugs for HF

1. loop diuretics, 2. ACE inhibitor 3. AT-1 antagonist 4. aldosterone receptor antagonist, 5. beta blocker, 6. lipid modulation drugs - statins, 7. fibric acid derivatives,

ACE inhibitor for HF AT-1 antagonist for HF examples

ACE inhibitor - Enalapril AT-1 receptor antagonist - losartan

Ca2+ channel blockers example

Amlodipine - greater effect on the calcium channels in the blood vessels than heart. - once a day preparation - used in essential hypertension. Most common side effect = excessive vasodilation (headache, flushing, dizziness)

beta blocker mechanism of action for HF

B1 adr - are used to treat hypertension and angina but were contraindicated for HF Recently b1 adr antagonist have been shown to be beneficial in HF WHY? In a failing heart the B1 receptors is altered and b1 ADR = increase cardiac output

beta blocker for HF example

Bisoprolol - decreases mortality and morbidity in subjects with HF

Ca2+ channel blockers mechanism of action:

Effective against all vasoconstrictors ex: NA acting on adrenoceptors, 5-HT on 5-HT2 receptors

Aldosterone receptor antagonist example

Eplerenone: Aldosterone is a NA and water retention hormone Levels of aldosterone in HF are elevated Eplerenone - reduces the amount of na and water reabsorbed into the drug Adverse effects: hyperkalemia and hypoatremia

benefits of ACEI and AT-1 in HF

For HF benefits = venodilation and arteriolar dilation = reduce volume overload Venodilation: pooling of blood in veins = less fluid in lungs, reduced pulmonary resistance = better myocardial performance Arteriolar dilation: - normal heart: cardiac output is independent of peripheral arterial resistance. If resistance increases the heart adjust to cope - failing heart: heart is already working at maximum therefore it can not cope with increase resistance. Resistance can be reduced with ACE inhibitor /AT1 receptor antagonist = improved cardiac output.

Loop diuretics example for HF

Frusemide - - NA+K+2CI- co-transporter - transports those things from the urine back into the circulation - frusemide inhibits transport. (works in the thick scending limb of henle)

Lipid modulating drugs are indicated in what diseases?

Hypercholesterolemia + dyslipidaemia (diabetes, smoking, being male) = atherosclerosis = angina, HF, cerebrovascular disease + or myocardial infarction and Peripheral vascular disease, stroke - these problems lead up to upto half of all deaths

Which calcium channel are predominate on the heart and which are predominate on the blood vessels

L types CAv 1.2a - heart, CAv 1.2b - for blood vessels

Statins

LDL is collect up by the liver when there is not enough cholesterol in the dietary intake for the liver to use. It does this by stimulating the LDL receptors. STATINS inhibit HMG CoA reductase = makes the liver think there is not enough cholesterol = more cholesterol is bound in liver = excreted in bile = reduces LDL in blood.

drugs for angina attack

Nitroglycerin (NO) - acts on guanylate cyclase to convert GTP to cGMP that will result in a protein cascade that causes vasodilation On diseased coronary arteries the nitrovasodilators work to give venodilation therefore decreasing venous return = reduced work load on the heart = less oxygen demand

essential hypertension

Normal cardiac output exact cause unknown - combination of environement, stress, smoking, salt, obesity, genetic disease

A1- adrenoceptors antagonists example

Prazosin - Affects the sympathetic nervous system - stops noradrenaline binding to a1 adrenoceptors to reduce vasoconstriction and BP - Can bus used in combination in other antihypertensives - diuretics and B blockers.

Angina pectrois - typical angina (stable) What causes it?

Predictable - often from stress on the heart ex: exercise, emotional stress

Atypical angina - no plaque (rare - caused by coronary artery spasm)

Same symptoms as typical angina Treated with Amlodopine - Ca= channel blocker specific to blood vessels Cav1.2b = stops vasoconstriction

Role of cholesterol

Used in cell membrane, steroid hormones, bile salts Excess cholesterol is associated with atherosclerosis. High LDL = > or equal to 4.94% mmol/L Low HDL cholesterol <0.75mm Hypercholesterolemia + dyslipidaemia (diabetes, smoking, being male)

Define heart failure

anything leading to a reduced cardiac output = poor delivery of oxygen and nutrients = poor removal of carbon dioxide and waste from tissue

Beta-blockers example + mechanism of action

atenolol: o Heart: Stops NA from working on Beta 1 receptors to reduce heart rate and heart force. o Kidneys: Reduces NA from binding to Beta 1 receptors on kidneys = reduce RAAS o Beta blockers are contraindicated in asthmatics o Used in caution in diabetes = can cause hypoglycaemia o Pharmacokinetics • Oral administration • Hydrophilic • Elimination t1/2 of 5-8 er • Dosage adjusted in renal failure as it is excreted largely unchanged • Atenolol has little CNS effects in contrast propranolol (another beta-blocker) crosses into CNS causing nightmares.

Non- pharamacological treatments for hypertension

body weight reduction restrict Na+ diet exercise avoid excessive alcohol decrease stress

Angiotensin 1 antagonist (AT-1 antagonist) example

candersartans - available alone of in combination with a diuretic Levels of bradykinin are not changed by AT-1 receptor antagonists Adverse effects with ace inhibitors = dry cough and angioedema - these do not occurs with AT-1 receptor antagonists

Hypertension causes changes in

heart and blood vessels - thinckening of left ventricle wall, arteries, smooth muscle (hypertrophy and endothelial cell damage)

frusemide adverse effects

hypokalaemia, hypotension, hyponatremia (low levels of sodium), Hyperuricemia (high levels of uric acid - can be an issue for people with gout), ototoxicity - hearing loss (reversible), loss of magnesium

Angiotensin 1 antagonist (AT-1 antagonist)

inhibits angio 2 binds from binding to AT-1 to prevent vasoconstriction, hypertrophy, aldosterone secretion

Angina pectrois - typical angina (stable) what does it feel like?

o Feeling of suffocation and impending death o Imbalance between oxygen demand and supply o Heavy, pressing, substernal discomfort - often radiating to the shoulder

Congestive Heart failure

o HF occurs because of diseases that weaken the heart ex: CAD o Congestion in right side of the heart because of left heart failure. oSymptoms 1. oedematous legs - swollen legs 2. acites - fluid build up in the abdomen 3. Fluid in lungs - often makes it hard to breath when lying down Treatment goals: reduce fluid No cure only can treat symptoms

Angina pectrois - typical angina (stable) pathophysiology

o stress + exercise activate Sympathtic NS = release of noradrenaline which stimulate the b1 adrenoceptors = increase heart rate, force and work = increased oxygen and nutrient demand o angina in a diseased coronary is caused by an inadequate ability to meet oxygen and nutrient demand.

Typical angina - unstable what causes it?

o this often happens when stable angina worsens o occurs in rest o increase thickening and plaque formation

pharmacokinetics of frusemide

oral or intravenous, readily absorbed in GI tract - diuretic effect in 30 mins. IV - good for emergency situation effects in 2 - 10 minutes. Actively secreted into proximal tubule - duration of action 4-8hrs. Excreted in urine - GREATER maximum effect then thiazide

ACEI and AT-1 receptor antagonists can't be used in...

pregnant women

Thiazide diuretics

works on distal tubules na+CI- co-transporter from reabsorbing na+CI- from urine