Cardiovascular System Flashcards
What is Preload?
Preload is the force that stretches the cardiac muscle prior to contraction. This force is composed of the volume that fills the heart from venous return
Relaxation
What is Afterload?
The resistance the heart must overcome to circulate blood during systole
Contraction
What is Preload determined by?
- Blood volume
- Venous tone (capacity of the venous circulation to hold blood)
What is Afterload determined by?
- Tone in arterial circulation
What factors contribute to blood pressure?
Blood Pressure is the product of Cardiac Output and Peripheral Vascular Resistance
Cardiac Output determined by preload
PVR determined by afterload
What is the relationship between PVR and Afterload?
Afterload is increased when aortic pressure and peripheral vascular resistance are increased.
When afterload increases, there is an increase in end-systolic volume and a decrease in stroke volume
How can blood pressure be regulated
- Autonomic nervous system (mainly sympathetic (alpha-adrenoceptor))
- Circulating hormones such as adrenaline, angiotensin II and vasopressin
- Local control by endothelium derivative factors such as NO and PGI2
What is Cardiac Output?
Amount of blood pumped per unit time (5L/min for average human)
Product of heart rate and stroke volume
What is Stroke Volume?
The volume of blood ejected from the ventricle with each heart beat
What factors determine Stroke volume?
- Intrinsic factors regulate myocardial contractility via [Ca2+]I and ATP
- Extrinsic circulatory factors include the elasticity and contractile state of arteries and veins, and the volume and viscosity of the blood, which together determine cardiac load (preload and afterload) –> Venous return
Explain myocardial contractility
Similar to that in voluntary striated muscles
Involves binding of Ca2+ to troponin C; this changes the conformation of the troponin complex, permitting cross-bridging of myosin to actin and initiating contraction
Give a general outlook on the coordination of contraction
Normal sinus rhythm is generated by pacemaker impulse coming from the sinoatrial (SA) node
Impulse are conducted in sequence through the atria, the atrioventricular (AV) node, bundle of His, Purkinje fibres and the ventricles
Describe the action potential of a cardiac muscle cell
Divided into 5 phase
Phase 0, rapid depolarisation (similar to regular depolarisation
Phase 1, partial repolarisation when Na+ channel is inactivated
Phase 2, plateau resulting from inward Ca2+ current and low K+ conductance level
Phase 3, repolarisation when Ca2+ is inactivated and there is a rectifying K+ current
Phase 4, pacemaker potential: gradual depolarisation during diastole
Activation of T-type calcium channels during late diastole contributes to the pacemaker activity in the SA node.
What are the main sympathetic activity of the heart?
Increased force of contraction (positive inotropic effect),
Increased heart rate (positive chronotropic effect)
Increased automaticity –> the tendency to generate ectopic beats
Repolarisation and restoration of function following generalized cardiac depolarization
Reduced cardiac efficiency
Cardiac hypertrophy –> directly mediated by stimulation of myocardial α and β adrenoceptors
How does the kidney regulate blood pressure?
Pressure is detected in specialised juxtaglomerular cells, close to the afferent arteriole
Low pressure results in the secretion of renin
Describe the Renin Angiotensin Aldosterone System (RAAS)
- Renin is secreted in to the plasma
- Renin cleaves Angiotensinogen in to Angiotensin I
- Angiotensin I is converted into its active form (Angiotensin II) by an angiotensin-converting enzyme
- Angiotensin II acts to increase PVR and thus afterload by constricting smoot muscles
- Angiotensin II can also act on the adrenal cortex to release aldosterone to increase Na+ and water retention and thus increase blood volume and preload
NOTE: this pathway controls both pre and afterload
How do sympathetic nerves affect blood pressure?
Activation of β1 adrenoceptors and thus activation of adenylate cyclase. cAMP activates PKA which phosphorylates α1subunits of calcium channels. Increase contractility
Also stimulates Na+/K+ pump to repolarise. Restore function if asystole has occurred. Increase HR
How does parasympathetic nerves affect blood pressure?
Opposite to those of sympathetic activation.
These effects result from activation of muscarinic (M2) acetylcholine receptors which are negatively coupled to adenylate cyclase acting to inhibit the opening of L-type Ca2+ channels and reduce the slow Ca2+ current
Also open a type of K+ channel known as GIRK (G protein–activated inward rectifying K+ channel) via the production of G β/γ subunits. The resulting increase in K+ permeability produces hyperpolarising. Slows heart and reduce automacity
How does the baroreceptor reflex regulated blood pressure?
Baroreceptors are located in the carotid sinus and aortic arch
They detect changes in BP caused by postural changes and adjust autonomic output to heart and blood vessels to correct for this change
What is angina?
Angina occurs when the oxygen supply to the myocardium is insufficient for its needs.
The pain has a characteristic distribution in the chest, arm and neck, and is brought on by exertion, cold or excitement
What is Myocardial Infarction?
Myocardial infarction occurs when a coronary artery has been blocked by thrombus.
Cardiac myocytes rely on aerobic metabolism. If the supply of oxygen remains below a critical value, a sequence of events leading to cell death ensues, detected clinically by an elevation of circulating troponin
What is the function of Beta-adrenoceptor antagonists in cardiovascular pharmacology?
Ex. Metoprolol (B1 selective)
They reduce cardiac output:
Reduce renin release from kidney, decrease RAAS Activation, therefore decrease preload and after-load
Have action in CNS to reduce bp
What are calcium-channel blockers?
Ex. nifedipine and verapamil
block L-type voltage-gated Ca2+ channels, Ca2+ entry and therefore muscle contraction
Can be divided into two classes
What are the two classes of calcium channel blockers?
- Dihydropyridines (ex. nifedipine) which are relatively selective for vascular smooth muscle and thus reduce AFTERLOAD
- Phenylethylalkamines (ex. verapamil) which are less selective and have more effects in the heart and may cause heart block. They reduce CONTRACTILITY
What can be said about Dihydropyridines function?
Dihydropyridines affect calcium-channel function in a complex way, not simply by physical plugging of the pore
Calcium channels exist in 3 different states and Dihydropyridine acting as an antagonist bind selectively to channels mode 0, thus favouring this non-opening state, whereas agonists bind selectively to channels in mode 2
List Drugs targeting at RAAS
- Angiotensin Converting Enzyme (ACE) Inhibitors (ex. enalapril and lisinopril) –> no active form, therefore, increase in vasodilation
- Angiotensin Receptor Antagonists (e.g. AT1 receptor anatgonist; losartan) –> no response
- Renin Inhibitor (e.g. aliskiren) –> completely block activation of system
All drugs cause a decrease in pre-load and after-load
Why does heart failure occur?
When the cardiac output is insufficient to meet the needs of the body
Results in impaired tissue perfusion, fluid retention, breathlessness, muscle weakness and arrhythmia
What are the two types of heart failure?
- Heart Failure with reduced ejection fraction (HFrEF) –> caused by impaired contractility and emptying of ventricle (Most common and drugs directed here)
- Heart failure with preserved ejection fraction (HFpEF) –> caused by impaired relaxation and filling of the ventricle
What are the common causes of Heart Failure?
- Myocardial Infarction
- Pressure Overload
- Volume Overload
- Cardiomyopathy
- Myocarditis
What is Digoxin?
Cardiac Glycoside that increases the force of contraction: positive inotrope therefore increase kidney perfusion and fluid loss
How do Cardiac glycosides work?
Most likely mechanism:
1. Glycosides inhibit the Na+/K+ pump.
- Increased [Na+]i slows extrusion of Ca2+ via the Na+/Ca2+ exchange transporter since increasing [Na+]I reduces the inwardly directed gradient for Na+ which drives extrusion of Ca2+ by Na+/Ca2+ exchange.
- Increased [Ca2+]i is stored in the sarcoplasmic reticulum, and thus increases the amount of Ca2+ released by each action potential
What are ARNIs?
ARNI, or an angiotensin receptor/neprilysin inhibitor, is made up of two drugs put together to treat heart failure. It contains an ARB (angiotensin II receptor blocker) and a neprilysin inhibitor.
Ex. Sacubitril/valsartan
How do ARNIs work?
Sacubitril/valsartan is a combination product.
Sacubitril is a pro-drug that, upon activation, acts as a neprilysin inhibitor. It works by blocking the action of neprilysin, thus preventing the breakdown of natriuretic peptides
Valsartan is an angiotensin receptor blocker, and it works on blocking the RAAS system.
Why can the neprilysin inhibitor not be used on its own?
Because neprilysin breaks down angiotensin II, inhibiting neprilysin will accumulate angiotensin II.
Leads to increase in preload and afterload
What is the Natriuretic Peptide System
Activated by stretch of cardiomyocytes
Natriuretic peptides are recognised by Natriuretic Peptide Receptor A which stimulates guanylate cyclase
Increase in production of cGMP
What is atherosclerosis?
Atherosclerosis is a potentially serious condition where arteries become clogged with fatty substances called plaques, or atheroma.
What does endothelium typically regulate?
- Vessel tone
- Leukocyte adhesion and platelet aggregation
- Tendency for thrombus formation
What are the causes of endothelial dysfunction?
- Elevated and modified low-density lipoproteins (such as in hypercholesterolemia)
- Oxygen free radicals
- Infectious microorganisms such as herpes virus and H.pylori
- Physical damage and gene activation by turbulent flow and high blood pressure `
How is a fatty streak formed?
Accumulation of foam cells
Foam cells are formed when macrophages take up Low-density lipoproteins that have been oxidised by the interaction of with oxygen free radicals
Explain the formation fo advanced complex lesions
Occurs due to the additional influx of different inflammatory cell types and extracellular lipids.
This continued influx of cells results in the formation of a fibrous cap, which consists of recruited smooth-muscle cells and extracellular matrix (ECM) deposition.
At this stage, the center of the core can become necrotic as a result of apoptotic macrophages as well as other succumbing cells
What are statins?
Ex. Simavastatin
Statins work by competitively blocking the active site of the first and key rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase.
Inhibition of this site prevents substrate access, thereby blocking the conversion of HMG-CoA to mevalonic acid.
What is the mechanism of action of fibrates?
Ex. Gemfibrozil and Fenofibrate
Activate peroxisome proliferator-activated receptors (PPARα) and increase expression of genes associated with lipid clearance (such as lipoprotein lipase and apoA1)
What is the action of ezetimibe?
It blocks transport of cholesterol in gut, without affecting absorption of fat-soluble vitamins, triglycerides or bile acid
Added to statin where response is inadequate alone
What are PCSK9 inhibitors?
Proprotein convertase subtilisin/kexin type 9 binds to and degrades the receptor for low-density lipoprotein particles
Inhibitors increase LDL receptor recycling and availability on the cell surface and therefore increase LDL clearance
Ex. Evolocumab (monoclonal antibody) and Inclisiran (siRNA)
What is the action of Nicorandil?
Nicorandil is an anti-angina medication that has the dual properties of a nitrate and ATP-sensitive K+ channel agonist
Nitrate moiety allows NO release. It is also able to open ATP sensitive K+ channels that hyperpolarise the cell and thus reduce intake of Ca2+
Reduces preload and afterload and dilates coronary arteries
What are anti-thrombotic drugs?
Taken prophylactically to reduce the risk of thrombus if atherosclerotic plaque ruptures
Usually anti-platelet (aspirin, clopidogrel) but can also be anti-coagulation (warfarin)
Describe haemostasis
Damage exposes platelets to ECM in the vessel wall. This ECM releases inflammatory markers that lead to adhesion of the platelets and their aggregation at that site – > platelet plug :
Platelets that have adhered undergo very specific changes. They release their cytoplasmic granules that include ADP. Also change shape.
Fibrin binds platelets into stable clump. Platelets express glycoprotein IIb/IIIa receptors for attachment of fibrin
Where can anti-platelet drugs target with examples?
- Cyclooxygenase inhibitor (e.g. aspirin) –> irreversible inhibition of COX, prevents formation of TxA2 and platelet activation
- P2Y12 Inhibitor (e.g. clopidogrel) –> blocks effect of ADP and prevent platelet activation
- Thrombin Receptor antagonist (e.g. voripaxar) –> prevent activation of PAR-1 receptors on platelets
Describe the coagulation cascade
Blood vessel damage causes conversion of Factor X to Factor Xa
Xa acts on Factor II (prothrombin) to produce IIa (thrombin)
Thrombin acts on fibrinogen to produce fibrin and will also act on Factor XIII to produce XIIIa that can now stabilise fibrin
What is the action of warfarin?
Warfarin competitively inhibits the vitamin K reductase
The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulatory factors protein C and protein S, require the presence of vitamin K.
What are the unwanted effects of warfarin?
It has a narrow optimal range, with a high risk of bleeding
Broken down in liver, enzymes are induced by other drugs and thus can be difficult to control the concentration
Blood levels must be checked regularly
What other anti-coagulants can be used instead of warfarin?
- Rivaroxaban and Apixaban: binds directly to factor Xa. Blocks the amplification of the coagulation cascade, preventing the formation of a thrombus.
- Dabigatran: direct inhibitor of thrombin (factor II) enzyme activity (comp; rev)
