Cardiovascular Flashcards
Chronotropy
Heart rate
Inotropy
Force of heart contraction
Adrenoreceptors
a1 - constrict vascular SM, inotropy
a2 - constrict vascular SM, reduce preganglionic NA release
B1 - chronotropy, inotropy, renin secretion (cAMP)
B2 - dilate arterioles, some chronotropy/inotropy (cAMP)
B3 - dilate coronary microvasculature, decrease inotropy
Propanolol
Inhibit B1 and B2
Metoprolol
B1 selective = no rest effects, decrease rate and force and renin secretion
Carvediol
B1, B2, a1 (some vasodilation)
Beta blockers activity
decrease cardiac output, decrease BP, decrease renal renin output, negative chronotropic (SA and AV nodes), negative inotropic, decrease work, decrease oxygen consumption
metabolised CYP2D6
Improve cardiac CA2+ storage and release via cAMP
B3
Nebivolol is agonist and B1 blocker
ARs - cardiomyocyte relaxation, decreased cAMP, eNOS activation -> relaxation of vascular smooth muscle, reduce remodelling
Baroreceptors
Detect initial drop in cardiac output with beta blockers, causing an initial increase in peripheral resistance (long term decreases)
Therapeutic uses of beta blockers
Hypertension - renin, cardiac output, decrease peripheral resistance (not used for this anymore due to low BP)
rate control - anti arrhythmic
Angina - reduce oxygen consumption
Heart failure - not a great effect, chronotropy, vasodilation
Anxiety - tremors and HR
beta blockers adverse effects
bronchospasm (B2 respiratory inhibition - asthma), withdrawal (taper), heart failure (too slow), low exercise tolerance, peripheral vasoconstriction, heart block (via conduction), CNS effects (cross BBB), worsening lipid profiles (lipoprotein lipase - increase bad cholesterol)
Type 2 diabetes - hypoglycaemia response inhibited
Atenolol
Only bblocker that is hydrophilic, does not cross BBB
Excreted in urine unchanged, longer half life
Ischaemic heart disease
Interruption of cardiac blood supply involving epicardial coronary vessels, block oxygen to heart. Caused by coronary artery disease (plaque)
Angina to myocardial infarction
chest pain, shortness of breath, exhausted, myocardial wall tissue dies
Treat decreasing ino and chrono, BP, oxygen demand, sympathetic stimulus
Sympathetic effect on adrenergic receptors
B1,2 a1 = myocyte death and increased arrhythmias
a1, B1 = vasoconstriction, sodium retention, fibrosis and scarring
Preload and afterload
Preload is the filling of the heart and is determined by the wall stretch
Afterload is down stream resistance affecting how the heart squeezes
Carvediol vs 2nd gen B-Blockers
Pros - greater drop in BP, no adverse decrease in HR, little impact triglycerides and glucose
Cons - no selectivity, bronchospasm, need twice a day dosing
ACE inhibitor example
Cilazapril
Good absorption and bioavailability 60%, half-life 9h, metabolised to active drug by liver, cleared through kidney
Decrease vascular resistance, BP, sodium retention, preload, blood volume return, decrease SM contraction, increase bradykinin vasodilator, downregulates sympathetic activity
AEs - bradykinin = leaky blood vessels, rash, hypotension, swelling of face
ARB example
Candesartan
Prodrug candesartan cilexetil via esterase in GI tract, low bioavailability, half life 9h, CYP2C9 inhibition, excreted in urine (less liver than other ARBs)
Selective to AT1, block all effects of Ang II (not just formation from one thing), no bradykinin accumulation, but lose vasodilator capability, angioedema, renin feedback loop?
Heart failure
damage decreases cardiac output and perfusion. Baroreceptors pick up drop and activate the nervous system and noradrenaline. -> salt and water retention, vasoconstriction, ion/chrono
RAAS
Release of angiotensin II and aldosterone from adrenal cortex
Control sodium excretion and fluid volume plus vascular tone
Liver -> angiotensinogen -> Ang I -> Ang II -> release aldosterone
Angiotension II
Vasoconstrictor, smooth muscle proliferator, fluid retention/hypertrophogenic, fibrogenic, apoptosis, NA and aldosterone release, remodelling via AT1 and 2 receptors
Aldosterone
mineralocorticoid receptor agonist
Anti-natriuretic peptide and fibrogenic, salt chloride and water retention, hypertrophy, damage arteries
RAAS inhibitors
Renin inhibitors - stop Ang II formation from angiotenisogen
ACE inhibitors - prevent Ang II from Ang I and bradykinin
AT1 blockers - at receptor (avoid AT2)
Renin
Released from juxtaglomerular cell on renal afferent arterioles
via stimulation of B1Rs on JG cells, low renal BP, low Na+ conc in distal tubule (glomerulus feedback)
ACE
Angiotensin converting enzyme
Ang I to Ang II
Extrinsic (vascular endothelial surface) and intrinsic (in cytosol of tissues)
AT1 vs AT2
AT1 - hypertensive effects (vasoconstriction, aldosterone, Na+ reabsorption, cell growth - fibrotic)
AT2 - beneficial (vasodilation, decrease BP, inhibit cell growth, anti-fibrotic)
Calcium channel blocker drug classes
Dihydropyridines, phenylalkylamines, benzothiazipines
Types of voltage gates calcium channels
L-type - long lasting in cardiac and vascular SM
T-type - transient in neurons and pacemaker cells
Heart conduction
SA node = pacemaker -> AV node = conduction -> cardiomyocytes
Via calcium currents, extracellular -> intracellular release
Phases of cardiac action potential
Na+ influx -> -> Ca2+ in (L-type) -> K+ out
NA/Adr causes CA2+ influx -> slow stroke
SA node -> atria -> AV node -> His bundles/Prkinje fibres -> ventricles
Calcium channel blockers
Inhibit calcium influx through L-type channels
Act on entry into vascular (vasodilation) cardiac (ino) muscle and SA/AV node (chrono)
CCB examples
Used in hypertension
Dihydropyridine = Amlodipine - vasodilator
Phenylalkylamines = Verapamil
Benzothiazipines = Diltiazem - depress cardiac contractility, SA/AV nodes (arrhythmias and angina)
Amlopidine
vasodilation in arterial smooth muscle, reduce afterload and arterial pressure, stabilises inactive L-type Ca2+ channel state (prevents change to active)
selective to arterial due to longer depolarisations in inactive channels
Good bioavailablity, peak 6-12h, CYP3A4, plasma bound = 30-50 hour half life
ADRs - decrease BP -> tachycardia, increased ino/chrono, increase oxygen demand = not used in angina
Varapamil
Binds to open L-type Ca2+ channels (more likely in myocardial cells)
suppress cardiac contractility, reduce LTCC recovery from inactivation
Decrease oxygen demand (angina), not used in heart failure as may cause heart block or with B-blockers
Rapid oral absorption, CYP3A4 inhibiton, lower bioavailability
Diltiazem
Cardiac LTCCs and some vascular LTCCs in sarcolemmal membrane of heart and vascular SM -> hypertension, angina (not first line) and arrhythmias
Not used in heart failure or with B-blockers, does not cause AV block, hypertension or bradycardia
Rapid, 1st pass metabolism, CYP3A4/2D6 and esterases
CCB ADRs
Relaxed smooth muscle, facial flushing, constipation, bradycardia, hypotension, AV block, HF
Anti-lipidaemics benefits
Dyslipidaemias -> CV disease, endothelial lesions, thrombotic occlusion
Hypercholesterolaemia -> coronary heart defects, HTN
CV disease + kidney disease cycles -> fucked
Cholesterol synthesis
Acetyl coenzyme A -> HMG CoA -reductase> mevalonate (MVA) -> cholesterol
In liver and diet, LDL receptors regulate
Transported by lipoproteins
Types of cholesterol lipoproteins
HDL (picks up used cholesterol), LDL, IDL, VLDL, chylomicrons
HDL 2 and 3 = ApoA-I (the rest are ApoB)
LDL receptors
Bind apoplipoprotein B100 from LDL -> internalisation of LDL -> recycled receptor, LDL degraded to aas and free cholesterol
Cholesterol -> decrease HMG CoA reductase, increase ACAT, decrease LDL Rs
Atherosclerosis
Increase in plasma cholesterol, deposition of fatty materials in arteries, low LDLRs, uptake of oxidised LDL by macrophages -> foam cells -> deposition in arteries, calcification, thrombus, occlusion, ulceration
Anti hyperlipidaemics
Endogenous Cholesterol Esterase attenuators, LDL receptor degradation inhibitors, exogenous CE uptake inhibitors
Endogenous CE attenuators
Statins - atorvastatin
Fibrates - bezafibrate
Nicotinic acid
LDL receptor degration inhibitors
PCSK9 inhibitors - alirovumab
Exogenous CE uptake inhibitors
Cholesterol uptake inhibitors - ezetemibe
Bile acid binding resins - colestipol and cholestyramine
Statins
Atorvastatin
Treatment for dylipidaemia
Reversible, competitive HMG CoA reductase inhibitors, increase LDLR synthesis, LDL clearance = low LDL in blood, slight HDL increase
Pleiotropic = effect on mavalonic acid
Atorvastatin
Decrease hepatic cholesterol synthesis
Rapid absorption, long half life - 14h, plasma protein binding, poor bioavailability, CYP3A4
Pleiotrophy
Inhibit MVA pathway = no isoprenylation = decrease cell growth, increase eNOS, decrease ROS = anti-inflammatory via NFkB
Statins adverse effects
myopathy and rhabdomyolysis = release of myoglobin into plasma and kidney
Pain from damage to skeletal tissue via mitochondrial function creating ROS?
Interact w CYP3A4, 2C9, OATP1B1, glucoronidation
Ezetimibe
reduce reuptake of cholesterol from diet into bile
Alirocumab
PCSK9 inhibition = decrease LDLR destruction via preventing binding of LDLR
2-4 weeks subcutaneous, 4-6h onset
Types of diuretics
Osmotic, loop, thiazide, K+ sparing
Kidneys
?
Osmotic diuretics
Mannitol
Not metabolised = filtered in glomerulus -> pulls water into nephron
Causes osmotic stress in proximal tubule lumen limited water reabsorption, sodium retention in urine, draws water out of cells increase extracellular fluid volume (pulmonary oedema and increase renal blood flow)
IV for acute emergency, some hypersensitivity reactions
Loop diuretics
Frusemide - most potent
Organic acid transporter (proximal tubule) -> NKCC2 transporter inhibitor on thick ascending loop (sodium/potassium channel on inner lumen surface)
Block sodium influx through NKCC2 to compensate for ATPase activity.
Hypertension (decrease BP), oedema, hyperkalaemia, hypercalcaemia
Frusimide
4-6h duration, rapid absorption, plasma protein binding, CYP/glucoronidation
ADRs - hypovolemia, dizziness, syncope, hyponatraemia, hypokalaemia, Mg2+ and Ca2+ depletion, uric acid retention
Thiazide diuretics
Bendroflumathiazide - mild diuretic
Inhibit Na+/Cl- transporter (eNCC1) in distal cortical diluting segment = prevent NaCl reabsorption, increase sodium and water excretion
Hypertension (decrease BP, peripheral resistance and plasma volume), can be used in renal disease if GFR is maintained
Bendroflumathiazide
Oral, 1h onset, variable elimination kinetics, compete w uric acid transporters (OATs), renal elimination
Dehydration, alkalosis, uric acid retention, hypokalaemia, dehydration, hyponatremia
K+ sparing diuretics
Spironolactone and amiloride
At late distal/collecting duct
Spironolactone
Aldosterone antagonist at mineralocorticoid receptor (stops promotion of sodium reabsorption and potassium loss via ENaC pump synthesis)
First pass metabolism, binds to basolateral surface receptors
oral = 70% absorbed, prodrug -> canrenone
ADRs - hyperkalemia, GI disturbances
Amiloride
ENaC inhibitor, inhibits sodium flux (weak effects on sodium balance)
OAT at proximal tubule
ADRs - hyperkalaemia
Use - drug resistant hypertension, chronic liver failure
Antiarrhythmic drugs
Metoprolol, amiodarone, diltiazem, digoxin
Arrhythmias
Abnormal rhythm can cause sudden death. Originate in atria/AV node or ventricles
Caused by defect in pulse generation via automatic tissue/ectopic beats (tacky/Brady), defect in impulse generation (drops beats)
Abnormal depolarisation - Na+ channel effect
Classes of antiarrythmics
Class I - interfere with Na+ channel (lignocaine)
Class II- B blockers (metoprolol)
Class III - decrease potassium efflux (amiodarone)
Class Iv - Ca2+ blockers (diltiazem)
Class I antiarrythmic
Block fast Na+ channels in use-dependant way -> upstole/phase zero -> plato phase
Lignocaine binds to Na+ channels in open and inactivated states, increasing rate and magnitude of depolarisation
Class II antiarrythmics
Block NA/A
Decrease increasing firing at SA node, slow conductor velocity at AV node
Rate control, stress/exercise tachycardias, decrease mortality post-MI
Adverse = non-selective, bronchospasm, negative inotropic, fatigue, insomnia, depression
Class III antiarrythmics
Block K+ efflux, increase AP duration and refractory period (to repolarisation), decrease Na+, Ca2+ flux
Decrease chance of reentry arrythmias, rate control, no pro-arrhythmic action
10-100 day accumulation, can cause pulmonary fibrosis, rashes, thyroid abnormalities
Class IV antiarrythmics
Decrease Ca2+ in nodal cells and cardiomyocytes
Binds to open state -> promote inactivated channel
LTCCs = decrease rate of discharge in SA node, decrease conduction, increase refractory period in AV node and decrease myocardial contraction
Don’t use with B-blockers
Digoxin
Doesn’t fit Vaughan Williams classification
Increase inotrophy and decrease chronotrophy
Cardiac glycoside = inhibit cellular Na+/K+ATPase -> increase inotrophy, decrease sympathetic tone, increase urine, decrease renin release
Increase vagal activity of ACh = decrease SA node firing rate, decrease AV conduction velocity, decrease ventricular rate
Narrow therapeutic range, oral or IV, lots of interactions, can cause arrhythmias
Intravascular thrombi
Can lead to angina, MI, deep vein thrombosis, pulmonary embolism, stroke
Prostacyclin (PGI2)
endothelial cells -> inhibit platelet aggregation and secretion, increase cAMP release, decrease COX activity on platelets, decrease prothrombotic trombone production
Thrombus formation
Cholesterol -> endothelial boundary -> plaque -> rupture into vessel -> decreased PGI2 synthesis-> thrombin -> release collagen, TXA2, ADP -> platelets can adhere to ECM proteins
Thrombin
GPCR agonist -> Ca2+ entry = change platelet shape -> ADP and TXA2 = platelet activation
Fibrin
Made from fibrinogen
Stabilised platelets, forming polymers in matrix
Antiplatelet examples
Aspirin and clipodogrel
Anticoagulants examples
LMWH - enoxaparin
VKAs - warfarin
NOACs - dabigatran
Asprin
Broken down in liver to inactive form
Inhibit COX irreversibly via acetylation (selective to COX1)
Stops COX from forming TXA2
Beneficial for vascular disease
Risk = haemorrhage and GI ulceration
Clopigodrel
ADP non comp inhibitor on P2Y receptors -> prevent GPIIb/a activation
Reduce platelet activation and synergistic with aspirin
Warfarin
VitK antagonist, prevent throbs from forming
Stop recycling of VitK via epoxide reductase -> can’t form prothrombin, factors VII, IX and X
CYP2C9/1A2/3A4 - lots of interactions, haemorrhage, GI tract loss, bruising, skin necrosis
1-8h peak, can’t measure blood levels have to use international normalised ratio
Dabigatran
novel oral anticoagulant
Haparin
Bind antithrombin III to inactivate thrombin as well as mediate factor Xa (creates thrombin)
Enoxaparin (safer_
Subcutaneous administration, half life 406h, cleared by urine
Use to treat deep vein thrombosis
