LS5010 Cardiovascular Pharmacology Flashcards
define BP
force exerted on walls of arteries by circulating blood
define mean arterial pressure (MAP)
average arterial blood pressure during a single cardiac cycle
MAP=
CO X TPR
CO =
Heart rate X stroke volume
MAP =
DBP + 1/3(SBP - DBP)
whats normal BP
120/80
cardiovascular control centre is responsible for?
rapid, neural mechanism for the regulation of BP
inputs to CCC =
- higher brain centres (cerebral cortex, hypothalamus, limbic system)
- Baroreceptors (detect changes in BP) (most important)
- chemoreceptors (monitors blood levels of O2, CO2, H+)
- proprioreceptors (monitor joint movements)
where are baroreceptors found?
carotid sinus and in the aortic arch in heart
outputs from CCC?
- Heart: decrease HR (parasympathetic nerve (vagus))
- Heart: increase HR + Contractility (cardiac accelerator nerve (sympathetic))
- Blood vessels: vasoconstriciton (vasomotor nerves (sympathetic))
4 ways the sympathetic Nervous system (SNS) regulates BP
- Neurotransmitter released from sympathetic nerve endings is Noradrenaline (norepinephrine)
- Activation of β1 receptors in heart causes, Increased contractility, Increased heart rate
- α1 receptors in arteries/arterioles and veins/venules cause vasoconstriction
- Stimulates release of Renin from the kidney -> angiotensin II -> vasoconstriciton
Humoral control of BP
what converts angiotensinogen to angiotensin 1
renin
what converts angiotensin 1 to angiotensin 2
ACE (angiotensin conveting enzyme)
what is the other hormone that regulates BP (not renin or natri)
ADH (anti-diuretic hormone)
(vasopressin)
what stimulates ADH?
- hyperosmolarity
- angiotensin-II
- sympathetic stimulation
what are the 2 pathways ADH can work via?
V1 (receptors in blood vessels) = vasoconstriction -> increased TPR
V2(receptors in kidney) = increase fluid reabsorbtion -> increased blood volume
what is another hormone that regulates BP (not renin or ADH)
Natriuretic Peptides – Atrial natriuretic peptide (ANP)
B-type natriuretic peptide ( BNP)
whats stimulates Natriuretic Peptides?
Cardiac distension
SNS stimulation
Angiotensin-II
do Natriuretic Peptides – Atrial natriuretic peptide (ANP) and B-type natriuretic peptide ( BNP) increase or decrease BP?
decrease BP
how do Natriuretic Peptides – Atrial natriuretic peptide (ANP) and B-type natriuretic peptide ( BNP) decrease BP?
3 mechanisms
- decrease renin -> decreases aldosterone and A-II
- increase excretion of NA+/H2O in kidney
- vasodilation
define hypertension
Persistently elevated arterial blood pressure
with SBP > 140 mm Hg
DBP > 90 mm Hg
Complications of hypertension
list 5
– doubles risk of heart attack/failiure
- stroke
- eye damage
- endothelial damage
- kindey (hypertensive nephropathy)(chronic renal failure)
what is the target when treating hypertension?
reduce BP to less than 135/85 (lower if diabetes is present)
list the 7 classes of drug used to treat hypertension
- Thiazide diuretics
- Renin-angiotensin system inhibitors:
Angiotensin Converting Enzyme Inhibitors (ACEI)
Angiotensin receptor antagonists
Renin inhibitors
- Calcium channel blockers
- β-adrenoceptor antagonists (β blockers)
- α-adrenoceptor antagonists
- Directly acting vasodilators
-Centrally acting drugs
name to examples of thiazide diuretics
Bendroflumethiazide, hydrochlorothiazide
thiazide diuretics are the mainline treatment for hypertension.
What do these drugs do directly?
Inhibits Na+ /Cl- co-transporter, inhibiting Na+ reabsorption in distal tubule
how to thiazide diuretics reduce BP?
Na+/water excretion → reduced blood volume → reduced cardiac output→ ↓ BP
what are RAASIs
renin-angiotenin-aldosterone system inhibitors
name the 3 typres of RAASIs
with examples
- renin inhibitor (Aliskiren) (not for clinical use, more experimental)
- ACE (angiotensin converting enzyme) (enalapril,captopril) (clinical use)
- ARB (Angiotensin receptor blockers) (clinical use)
add RAASIs to this table
list the 5 benefits of ACEI and ARBs in HT
- Vasodilatation - reduces peripheral resistance (TPR), reduces afterload & ↓ BP
- Salt & water excretion - decreases blood volume & hence BP
- Depress SNS activity
- Inhibit cardiac and vascular hypertrophy
- Inhibit ADH secretion
list the 4 Clinical uses of ACEI and ARBs:
- hypertension
- heart failure
- post-myocardial infarction (secondary prevention)
- Diabetic nephropathy
list the 5 Unwanted effects of ACEI and ARB
Generally well tolerated – particularly ARB
- Cough (ACEI) – due to excess bradykinin (replace ACEI with ARB)
- Hypotension (both)
- Urticaria / Angioedema (ACEI - v. rarely)
- Hyperkalaemia (because aldosterone formation is reduced)
- Foetal injury (both)
what are the third major class of drugs used to treat hypertension?
Calcium Channel Blockers (CCBs)
what is the Mechanism of Action of CCBs?
Block Ca2+ entry through L-type calcium channels in heart and arteries
what are the 3 classes of CCB?
- Dihydropyridines (DHP): nifedipine, amlodipine –vascular selective
- Phenylalkylamines (verapamil): cardiac selective – rate slowing
- Benzothiazepine (diltiazem): intermediate selectivity
what is the mainstay CCB given to treat hypertension?
Dihydropyridines(DHP) - Mainstay treatment in hypertension
Vasodilatation – reduce TPR and BP
Given orally, readily absorbed
S/E of Dihydropyridines
Ankle Oedema
Headache / Flushing
Reflex tachycardia
what is a negative inotropic effect?
decrease contractility of heart
what is a negative chronotropic effect?
decreases heart rate
are beta blockers a firstline treatment for hypertension
No
- used in patients with evidence of increased sympathetic drive
- used when patients are intolerant to ACEI and ARBs
what are the 3 types of beta blockers?
Cardioselective - β1 block (Atenolol )
Non-selective α and β block (Labetolol)
Non-selective β1 and β2 block (Propranolol )
4 mechanisms
How do Beta blockers reduce BP?
4 ways
- negative chronotropic
- negative inotropic. Reduce cardiac output
- Reduce renin release by the kidney → ↓ A-II
- Lipophilic agents (e.g. metoprolol, propranolol) exert central sympatho-inhibitory actions.
Uses of β-blockers:
Hypertension
Angina
Post-myocardial infarction
Heart Failure
Arrhythmias
(outside CV system used in anxiety, glaucoma, thyrotoxicosis)
Adverse Effects of β-blockers:
Worsening of cardiac failure in patients with poor LV function
Bradycardia
Bronchoconstriction
Fatigue
Cold extremities
CNS effects (lipophilic agents) e.g. nightmares, hallucinations
lowering of HDLs and increases Triglycerides
name a common second/third line drug used to treat hypertesnion that causes vasodilation
α1-adrenoceptor blockers - prazosin, doxazosin
Name 2 drugs less commonly used for treatment of hypertension via vasodilation
Minoxidil
Hydralazine
name a potassim sparing diuretic used to treat hypertension
spironolactone
name 2 centrally active drugs used to treat hypertension
clonidine
moxonidine
define coronary Artery disease (CAD)
(Ischaemic heart disease (IHD), coronary heart disease)
Impedance of one or more coronary arteries that supply blood to the heart
Usually due to atherosclerosis
name the 3 classes of CAD
- Stable angina
- Unstable angina
- Myocardial Infarction (Heart Attack) :
define Atherosclerosis
Can be defined as a focal fibroproliferative disease of the intimal layer of a blood vessel.
Risk factors for coronary artery disease:
Name 3 Modifiable risk factors
- High BP
- Physical inactivity
- Obesity, Diabetes
- Decreased HDL
- High total blood cholesterol & increased LDL
- High Triglyceride (TG)
- Smoking ↓HDL and ↑LDL
↑carbon monoxide in the blood, risk of endothelial injury
Risk factors for coronary artery disease:
List 3 non modifiable factors
Non modifiable:
- Age
- Gender Men > women
- Genetics – eg; familial hypercholesterolaemia
define Stable angina (angina pectoris)
Chest pain or discomfort due to reversible ischaemia of the myocardium
In stable angina Why is there pain only in exertion or stress ?
Inability of coronary blood flow to increase sufficiently to meet increased metabolic demands of the heart (increased O2 requirement during exercise, excitement)
show the change in O2 demand and O2 supply in Angina or myocardial ischaemia compared to normal heart
Imbalance between O2 demand and O2 supply
Increased demand
define Myocardial infarction
Severe chest pain due to irreversible ischaemia of myocardium
Angina Treatment aimed at:
- Increasing coronary blood flow (O2 supply to myocardium)
- Reducing O2 demand/cardiac workload
list the 6 Antianginal drugs
- Nitrovasodilators (organic nitrates)
- β-adrenoceptor blockers
- Calcium channel blockers
- Potassium channel openers
- Ivabradine
- Ranolazine
give an example of an Organic nitrates
Glyceryl trinitrate (GTN),
Isosorbide mononitrate (IMN),
isosorbide dinitrate (IDN)
what is the Mechanism of action of organic nitrates treating angina
Converted to Nitric Oxide → activates guanyl cyclase → ↑cGMP → vasodilatation
what are the Beneficial actions of nitrates in alleviating angina
- Venodilatation - reduces venous return → reduces preload→ reduce cardiac workload and O2 demand
- Arterial dilatation → Reduces afterload → reduce cardiac workload and O2 demand
- Coronary artery dilatation - increase myocardial O2 supply
- Increase blood flow through collateral arteries - increases blood flow to ischaemic area
Nitrate pharmacokinetics
what are the adverse effects of organic nitrates
- Postural hypotension (venodilatation)
- headaches and flushing as a result of vasodilation
list the 3 classes of β-adrenoceptor antagonists used to treat angina, with example drugs
- cardioselective - β1 block (Atenolol )
- non-selective α and β block (Labetolol)
- non-selective β1 and β2 block (Propranolol )
β-adrenoceptor are found where?
α-adrenoceptors are foudn where?
- heart
- blood vessels
Calcium Channel Blockers (CCBs) block?
Ca2+ entry through L-type calcium channels in cardiac and vascular smooth muscle cells
CCBs
Ca2+ entry is important for?
- Contractility (inotropy) of heart
- Vasoconstriction
name the 3 classes of CCBs
- Phenylalkylamines (verapamil) – more heart selective
- Dihydropyridines (nifedipine, amlodipine) – vascular selective
- Benzothiazepines (diltiazem) (intermediate selectivity)
Beneficial effects of CCBs in angina
- Arteriolar dilation (DHP) → reduce afterload → ↓ cardiac workload & ↓ O2 demand
- Coronary artery dilatation- improves myocardial O2 supply
- Reduces heart rate (Negative chronotropic) (verapamil): → ↓ cardiac workload &↓ O2 demand
- Reduces contractility (Negative inotropic) (verapamil): → ↓ cardiac workload &↓ O2 demand
Nicorandil is an Anti-Anginal drug which has dual mode of action, what are these?
Nitrate like action
potassium channel opener
a newer antiangianl drug, Ivabradine, works via what mechanism?
- blocks If channel (cardiac pacemaker current)
- this Slows heart rate →reduce cardiac workload/O2 demand
Ranolazine is used to treat angina by?
- Ranolazine inhibits the late inward Na current in the ischaemic myocardium
- this prevents any furth ischaemia
what is the result of ranolazine
Ranolazine prevents accumulation of Ca2+ in ischaemic myocardium.
- improves relaxation
- improves coronary blood flow (note: coronary blood flow is greatest during diastole)
How does Increased aortic resistance increase myocardial oxygen consumption
Narrowing of aorta increases ventricular afterload which increases the O2 deamnd of myocardium.
Decrease HR and decreased contractility will reduce O2 consumption
Decreased venous return will reduce preload and hence reduce O2 consumption
Main action of Glyceryl Trinitrate in treatment of angina is:
venous dilatation
Nicorandil is a :
potassium channel opener
Define Heart failure
Cardiac output (CO) is inadequate to meet the metabolic demands of the body
define acute Heart failure
- sudden loss of cardiac function (eg due to myocardial infarction)
define Chronic HF
progressive
list the 6 causes of
- Ischaemic heart disease/ Myocardial infarctions (heart attack)
- Cardiomyopathies (disease of heart muscle )
- Chronic hypertension
- Abnormal valves – congenital defects, aortic or mitral valve stenosis, regurgitation
- Myocarditis, pericarditis, endocarditis
- Metabolic disease eg/ thyrotoxicosis, DM
heart failure can be divided into 2 types, what are they?
systolic failure
diastolic failure
left sided failure/impaored LV contractility can lead to what condition?
pulmonary oedema
Right sided failure/impaired RV contractility can lead to what?
Peripheral oedema
list the 6 Symptoms and signs of heart failure
- Contractile dysfunction - reduced ejection fraction (<45%)
- Pulmonary Oedema (~90% patients) : Dyspnoea, Orthopnoea, Rales
- Hypotension - Decreased cardiac output causes low blood pressure.
- Hypoperfusion
- Peripheral Oedema (70% patients)– ankles , sacral region, abdomen (ascites)
- Exercise intolerance: Ability of heart to work harder during exercise is impaired
define Congestive heart failure
Heart failure principally due to L heart failure which affects performance of R heart. Both pulmonary and systemic venous pressure rise. Most patients have failure on both sides concurrently.
fill in/choose the red highlighted sections
what are the aims f drug treatment of HF
- Reduce symptoms
- Increase survival
- Reduce fluid volume
- Improve contractility
- Reduce cardiac oxygen demands
list 6 types of Drug used in treatment of HF
- Diuretics
- RAAS inhibitors
- Beta blockers
- Positive inotropic drugs
- Vasodilators eg nitrates
- Ivabradine
Standard drug therapy for HF includes
a diuretic and ACEI
name the 3 classes of diuretic used to treat HF, with examples, and in what circumstance theyre used
Thiazide duretic e.g. hydrochlorothiazide, bendroflumethiazide. Used in mild heart failure
Loop diuretics (Furosemide, Bumetanide). Used for moderate-severe HF
Potassium sparing diuretics: Amiloride, Triamterine OR Spironolactone, Eplerenone
how to thiazide diuretics work in HF?
Inhibits the Na+/Cl- co-transporter in the distal convoluted tubule
how to loop diuretics work?
Inhibit the Na+/K+/2Cl- co-transporter in the thick Ascending Limb of loop of Henle
how do the potassium sparring diuretics Amiloride, Triamterine work in HF?
- Blocks epithelial Na+ channels (ENaC) in distal tubule and collecting ducts
- Increases Na+ excretion & decreases K+ excretion
how to the potassim sparring diuretics Spironolactone, Eplerenone work in HF
- Antagonises aldosterone receptor
- Act in in DCT & CD: ↓ Na+ reabsorption (increased excretion), ↓ K+ excretion
Diuretics:
How do they benefit heart failure patients?
- Increase excretion of water and Na+ by action on kidney
- Decrease fluid volume (Counteract actions of angiotensin-II & ADH)
- Reduce preload and O2 demand
- Reduce pulmonary oedema (relieves dyspnoea)
- Reduce peripheral oedema (reduces swelling)
A-II causes what 3 things, resulting in progression of HF and worsening symptoms.
fluid retention, vasoconstriction, cardiac remodelling
Give one example of an
ACE Inhibitor ( ACEI) - ?
and a
Angiotensin receptor 1 blockers (ARB) - ?
captopril
valsartan
list 4 benefits of ACEI/ARBs in HF
name the 2 types of beta blockers used in HF and give examples
Atenolol, metoprolol (β1 selective)
Carvedilol, labetalol (β/α1)
list the 4 actions of B-blockers in HF
- ↓ Heart rate, ↓ contractility, ↓ cardiac workload
- Protects from ischaemia (due to ↓ cardiac workload)
- Inhibits activation of RAAS (↓ vasoconstriction , ↓ fluid retention)
- Prevents abnormal heart beat and rhythms (arrhythmias) in HF patients
what are the 2 classes of Positive Inotropes, and the 4 unique positive inotropes used in HF. Give exmaples for the classes
- Cardiac glycosides (Digoxin, Digitoxin)
- Phosphodiesterase (PDE3) inhibitors: (milrinone)
- Dobutamine
- Levosimendan (new inotrope)
- Istaroxime
- Omecamtiv Mecarbil
what 2 vasodilators are used to treat HF
- Nitrates: Isosorbide dinitrate
- Hydralazine
what heart rate lowering drugs (also used in Angina) is used to treat HF?
Ivabradine (coralan): Blocks If channel, Slows heart rate
what is the name of the new drug, Combined Angiotensin receptor Inhibitor + Neprylisin(NEP) Inhibitor
Valsartan + Sacubitril (Entresto)
