Cardiovascular and Renal Flashcards
Lidocaine
Local anaesthetic
Class IB antidysrhythmic
Act on intracellular surface of VGSC, at the C terminus (cytoplasmic end of domain IV segment 6)
Binds to open state of VGSC.
Stabilise channels in their inactivated state and make it harder for the channel to reactivate.
Also used as antidysrhythmics to modify the form of the cardiac action potential. Decrease AP duration with very fast association and dissociation. Point is to keep ischaemic tissue in its ischaemic state so that there are no re-entrant dysrhythmias.
Similar drugs can be used as anti-epileptics
Dihydropyridines e.g. nifedipine, amilodipine
L-type calcium channel blocker
2 binding sites, intracellular
1. On S6 and part of S5-S6 loop domain III
2. Closely related to phenylalkylamine binding site on S5-6 loop in domain IV
Bind to inactivated channels but don’t show use dependence
T-type channels are resistant
Works preferentially on vascular smooth muscle as higher proportion of channels in inactivated state (RP -50mV)
Phenylalkylamines e.g. verapamil
L-type calcium channel blocker
Work on regions that form the pore (S5/6) - binding site is 42 amino acid region that makes up segment 6 and part of the S5-6 loop.
Acts extracellularly
Also class IV antidysrhythmic - reduce Ca2+ entry, slow conduction + prolong refractory period in nodes. Reduced Ca2+ entry can compromise excitation-contraction coupling so limited uses.
Benzothiazepines e.g. diltiazem
L-type calcium channel blocker
Unsure of binding site, modify binding sites of other 2 drugs (dihydropyridines and phenylalkylamines, esp DHPR)
Acts extracellularly
Also class IV antidysrhythmic - reduce Ca2+ entry, slow conduction + prolong refractory period in nodes. Reduced Ca2+ entry can compromise excitation-contraction coupling so limited uses.
Ni2+
Blocks both L and T-type Ca2+ channels
Sulfonylureas
Act on K+-ATP channels to stimulate insulin secretion in Type 2 diabetes mellitus
Long QT syndrome can result from mutations in?
IKs current so KCNE1 and KvLQT2 channels
IKr current so Kv11.1 channel
Cardiac VGSC can produce LQT3
Causes abrupt loss of consciousness or sudden death from ventricular arrhythmia
Treat with beta1 antagonists prophylactically? in most cases
Can cause SADS sudden adult death syndrome when the heart suddenly goes into ventricular fibrillation
Propranolol
Non specific beta antagonist
Atenolol
beta1 specific antagonist
counteracting:
beta1–>Gs–>increase cAMP–> cAMP dep PKA –> phos L-type Ca2+ channel –> enhances calcium entry into cells in bulk of myocardium and also modulates pacemaker current (faster so inc HR)
Cholera toxin
Mimics beta1 stimulation: it stimulates the G-protein
Forskolin
Mimics beta1 stimulation: stimulates adenylyl cyclase
Effects of catecholamines on heart:
1+2. Increased ICa-L and ICa-T via CAMP. beta1–>Gs–>increase cAMP–> cAMP dep PKA –> phos L-type Ca2+ channel –> enhances calcium entry into cells in bulk of myocardium (inotropic +) and also modulates pacemaker current (faster so inc HR chronotropic+)
- Sensitise ryanodine receptors (extra Ca2+ entry) so increased release intracellular Ca2+ stores (inotropic +)
- PKA phosphorylates SERCA2 and phospholamban (inotropic???+)
- If activation potential shifted more positive levels so pacemaker produces more frequent AP (chronotropic+) - I think it means whole thing is shifted up
- Enhances delayed-rectifier K+ channels –> shortened AP duration (chronotropic+)
Effects of ACh on heart:
via M2, Gi/o
- Reduces nodal Ca2+ currents (chronotropic -), not inotropic as M2 in nodal tissue only
- Shifts potential at which If is activated to more negative levels so pacemaker produces more widely spaced AP (chronotropic -)
- Activates IK-ACh, hyp cell –> harder to elicit AP (chronotropic -)
Quinidine and procainamide
Class IA antidysrhythmic Increase AP duration with intermediate rate of association/dissociation Block VGSC (not in nodal tissue)
Flecainide
Class IC antidysrhythmic
No effect on AP duration but very slow association and dissociation.
Propanolol, atenolol
Class II antidysrhythmics
Sympathetic antagonists/beta blockers. During myocardial infarction there is increased sympathetic stimulation. Counteracts this.
Treat ectopic pacemaker (SAN damage or increase in excitability in any part of the conducting system).
Used for ventricular and re-entrant dysrhythmias that don’t respond to class I
Amiodarone
Class III antidysrhythmic
Prolong AP and thus also the refractory period.
Under different conditions can block both inward Na+ and outward K+ currents.
Digoxin, ouabain
Cardiac glycosides
Antidysrhythmic
Treat heart failure (limited use)
Inhibit the Na+/K+ pump which produces the Na+ electrogenic gradient that powers the Na:Ca exchanger (3:1). Digoxin increases [Na+]I by 1-1.5mM. Sufficient to raise intracellular Ca2+ (that enters during the cardiac AP) by a significant amount - related by [Na+]in^3. Inotropic + WITHOUT increase in oxygen demand.
Hard to use as
1. minimum toxic dose v close to minimum therapeutic dose
2. v long half life so hard to dose
Also act as antidysrhythmic - increase vagal activity through CNS action, inhibit AVN, affect atral refractory period
Dobutamine
Beta1 agonist as ‘cardiotonic agent’
Positive inotropic effect similar to sympathetic stimulation
However:
1. Increases cardiac oxygen demand
2. Increase HR so may precipitate or potentiate hypertension if already present
Dobutamine: inotropic effect > chronotropic effect. May be used acutely in shock, to improve CO after open heart surgery, or in heart failure in the absence of hypertension.
Bisoprolol, carvedilol
3rd gen Beta blockers
To counteract homeostatic response (SNS activation) to heart failure, which long term chronically and progressively diminishes cardiac function and worsens heart failure.
Change in ratios of beta1:beta2:alpha1 from 70:20:10 to 50:25:25 –> diminished proportion beta1 –> adrenergic output increases. Long term stim adrenoceptors can enhance apoptosis in cardiomyocytes
Phentolamine
Alpha-adrenoceptor antagonist
Phenothiazines
PDE type I
Ca2+/calmodulin dependent
Used for schizophrenia
Inodilators (inotropic vasodilators)/Phosphodiesterase inhibitors
Inhibits the enzyme that catalyses cAMP breakdown so raises [cAMP]I so mimics beta-receptor stim. (thus inodilators can lead to dysrhythmias).
Type II PDE inhibitor
c-GMP stimulated
Milrinone
Type III PDE inhibitor
c-GMP inhibited
Type most often used in heart failure. Limited due to dysrhythmia problem. Use confined to short-term treatment of severe heart failure unresponsive to more conventional therapy.
In smooth muscle cells PDE III inhibition –> increased cAMP –> vasodilation –> reduces afterload on heart –> therapeutically beneficial.
Inodilators (inotropic vasodilators)/Phosphodiesterase inhibitors
Inhibits the enzyme that catalyses cAMP breakdown so raises [cAMP]I so mimics beta-receptor stim. (thus inodilators can lead to dysrhythmias).
Rolipram
Type IV PDE inhibitor
cAMP-specific
Inodilators (inotropic vasodilators)/Phosphodiesterase inhibitors
Inhibits the enzyme that catalyses cAMP breakdown so raises [cAMP]I so mimics beta-receptor stim. (thus inodilators can lead to dysrhythmias).
Dipyridamole, sildenafil
Type V PDE inhibitor
cGMP specific
Inodilators (inotropic vasodilators)/Phosphodiesterase inhibitors
Inhibits the enzyme that catalyses cAMP breakdown so raises [cAMP]I so mimics beta-receptor stim. (thus inodilators can lead to dysrhythmias).
Pimobendan, levosimendan
Inodilator
Treats canine dilated cardiomyopathy and in advanced canine mitral valve regurgictation.
Calcium sensitiser: sensitise and increase Ca2+ binding efficiency (to troponin) without a requirement for more energy consumption. Also peripheral vasodil by inhibiting PDE III (decrease afterload).
Levosimendan only human, used in hospitals (but not licensed in UK) for heart failure.
Angiotensin converting enzyme (ACE) inhibitors
Used to treat heart failure
Phospholamban / SERCA2
Endogenous muscle-specific SERCA2 inhibitor, regulates uptake of Ca2+ into the ER.
Under influence of SNS –> beta-receptor activation –> PKA phos –> ryanodine/SERCA/phospholamban phos –> calcium transients with higher amplitudes and faster reuptake Ca2+ into ER
Reduced Ca2+ transient amplitude and slowed rates of SR reuptake have bene observed in cardiac muscle cells from failing human hearts as well as altered expression and phosphorylation status of the SR components directly regulating the transient –> manipulating these regulators may recover cardiac contractility
Could also directly do SERCA2 gene therapy.
Plasmin
Serine protease (Arg-Lys bonds) which degrades fibrin in clots and breaks down clotting factors II, V, VII Most anti-clotting drugs catalyse its production from plasminogen
Streptokinase
47kDa protein formed by haemolytic streptococci.
Binds to plasminogen activator and causes generation of plasmin –> degradation of fibrin in clots
Anistreplase
Combination of plasminogen and anisoylated streptokinase
Streptokinase inactive until the anisoyl group is removed in the blood. Slow - t1/2 2 hours to give more prolonged activity (4-6h) than streptokinase alone
Alteplase
Single chain recombinant human tissue plasminogen activator
Has greater activity on plasminogen bound to fibrin in clots, so localising their action
Duteplase
Double chain recombinant human tissue plasminogen activator
Has greater activity on plasminogen bound to fibrin in clots, so localising their action
Asprin
Used alongside other therapies to prevent further thrombosis
Inhibits the cox enzymes which convert activated arachidonic acid to thromboxane
Combine with clopidogrel to improve morbidity and mortality for patients over a wide range of heart disease
Clopidogrel
Inhibits platelet aggregation by inhibiting the binding of ADP to its receptor on platelets
Used alongside asprin to improve morbidity and mortality for patients over a wide range of heart disease
Eptifibatide
Cyclic heptapeptide inhibitor of glycoprotein IIb/IIIa receptor (thromboxane binds to this allow fibrinogen bridging between platelets and between platelets and foreign surfaces)
Tirofaban
Non-peptide inhibitor of glycoprotein IIb/IIIa receptor (thromboxane binds to this allow fibrinogen bridging between platelets and between platelets and foreign surfaces)
Can be used like heparin
Used for prevention of MI in patients with unstable angina or in patients who have recently surffered certain types of MI
Abciximab
Monoclonal Ab against glycoprotein IIb/IIIa receptor (thromboxane binds to this allow fibrinogen bridging between platelets and between platelets and foreign surfaces)
Also binds to the vitronectin receptor on platelets (involved in cell adhesion and haemostasis), endothelial cells and vascular smooth muscle cells
Used with coronary angioplasty for coronary artery thrombosis
Heparin
Naturally occurring anticoagulant produced by basophils and mast cells
Binds to enzyme inhibitor antithrombin III, causes a conformational change which results in exposure of its active site
Activated AT-III then inactivates thrombin and other proteases involved in blood clotting (exp factor Xa).
Like tirofiban, can be used for unstable angina and after MI, but can also be used for DVT and as a prophylactic to prevent clots forming during and as a result of surgery.
Injection
Warfarin
Inhibits clotting, can be given orally.
Inhibits synthesis of clotting factors II, VII, IX and X as well as the regulatory factors protein C, S and Z.
Used by people who have an increased tendency for thrombosis and can be used as prophylaxis for individuals who have already formed a blood clot which required earlier treatment.
Also used (unlike heparin) to prevent clot formation on prosthetic heart valves.
Interacts with many commonly used drugs.
Dabigatran
Used in patients with atrial fibrillation and one additional risk factor for stroke (meant to be 40% better at reducing risk compared to warfarin)
Thrombin inhibitor
Also used prophylactically in the short term to prevent thromboembolism in individuals who have had recent knee or hip replacement surgery (e.g. clots can develop after surgery and be carried to the lungs)
Rivaroxaban
The first factor Xa inhibitor to be introduced
Aminocaproic acid
Chemically similar to lysine
Competitively inhibits plasminogen activation
Stops excessive clot lysis
opposite way to all the others
Transexamic acid
Analogue of aminocaproic acid
Competitively inhibits plasminogen activation
Stops excessive clot lysis
opposite way to all the others
GFR
Glomerular filtration rate
Measured by inulin clearance
Too low –> excessive reabsorption of solute and concentration of toxic solutes in a low volume of urine
Too high –> Inadequate reabsorption
Juxtaglomerular apparatus, macula densa
JGA: Between early distal tubule and glomerular afferent and efferent arterioles. Cells around afferent arteriole secrete renin(when want to degrease Na+/H2O secretion)–> Ang II
Macula densa: bit that detects levels of Na+ and Cl- in the filtrate and secretes local hormones to autoregulate GFR
Diuretics
Produce a large increase in the excretion of both solutes and water so reduce volume of body’s ECF compartment (unlike when you drink a lot of water).
Alleviates oedema, reduces blood volume so used in treatment of heart failure and hypertension. Also used to maintain kidney function in renal diseases.
Furosemide, bumetanide
Loop diuretics
Act on loop of Henle
‘High ceiling’ diuretics as can cause a v high rate of diuresis up to 4l/day. At peak can cause 15-25% of the filtrate to be excreted.
Sulphonamides
Block NKCC cotransport in the apical/luminal membrane of thickAL cells so lose osmotic gradient in medulla. Lose ability to produce concentrated urine as no osmotic gradient, loses ability to produce v dilute urine as filtrate has increased concentration of Na+.
Actively secreted into the proximal tubule, giving a conc in the thickAL 10-30x that in the plasma.
Also produce a very weak inhibition of carbonic anhydrase.
On repeated administration effect reduced as the decreased ECFV leads to enhanced reabsorption into the tubules.
Used in acute heart failure
Furosemide acts in 10 mins IV (1-1.5h oral). This precedes the diuresis - as furosemide also causes venodilation and so reduces atrial filling pressure. VENOdilation also increases effect by increasing renal blood flow without a change in GFR (reduces fraction of the blood flow that is filtered at the glomerulus).
Problems: main hypokalaemia, metabolic alkalosis, Ca2+ and Mg2+ loss, uric acid secretion decreased
Probenecid
Treats gout: when excess production of purines leads to deposition of sodium urate crystals in the synovial tissues of joints.
Competes for the same carrier as uric acid in the proximal tubule, and thereby inhibits uric acid reabsorption (also the same carrier as loop diuretics eg furosemide)
Hydrochlorothiazide, bendroflumethiazide
Thiazide diuretics
Can produce some inhibition of carbonic anhydrase (not that important)
Partly inhibit formation of a dilute urine, but not a concentrated urine
Act on cortical segment of the thickAL or distal tubule
Act in early DT by blocking Na+-Cl- cotransport (probably by binding at the Cl- site)
VASOdilatory - when given for hypertension they initially reduce BP by diuretic action, but later have a direct action on blood vessels (reduce afterload?)
Increase blood glucose levels
Can result in loss of 10-15% of the filtered load
Problems:
1. Hypokalaemia
2. Metabolic alkalosis
3. Increase Mg2+ excretion but decrease that of Ca2+
4. Uric acid excretion decreased
Diazoxide
Non-diuretic thiazide which has a vasodilator action
Acts by opening ATP-sensitive K+ channels.
Used as an antihypertensive in hypertensive emergency,
Opening KATP channels in beta cells produces hyperpolarisation and inhibition of insulin release leading to a rise in blood glucose.
Amiloride, Triamterene
Potassium-sparing diuretic, weak diuretic effect
Prevent Na+ reabsorption by blocking apical Na+ channels. K+ loss decreased.
Amiloride blocks Na+ transport only when applied on the apical side.
Interfere with Na+ entering through an apical channel (Na+/K+pump powered) in the late distal tubule(this normally produces the potential gradient across the apical membrane for K+, and H+, loss)
Spironolactone
Potassium-sparing diuretic
Competitive antagonist to action of aldosterone so only effective when distal tubule is under the influence of aldosterone
(aldosterone migrates across cell membrane into the cell and there combines with cytoplasmic steroid receptor –> nucleus –> synthesis of Na+ channels and Na+/K+ ATPase –> increase in channel number), so spironolactone blocks the synthesis - slow action
Some spironolactone metabolised to canrenone in the liver - some but not all of the effect of spironolactone is due to this
Can be used along with loop and thiazide diuretics to counteract hypokalaemia
Interfere with Na+ entering through an apical channel (Na+/K+pump powered) in the late distal tubule (this normally produces the potential gradient across the apical membrane for K+, and H+, loss)
Canrenone/its salt potassium canrenoate
K+ sparing diuretic
Acetazolamide
Carbonic anhydrase inhibitors
Decrease the available H+ available to move into the lumen exchanged for Na+. More H2O stays in lumen, pulls K+ in, increasing K+ loss.
Now to all intents and purposes obsolete
Inhibit NaHCO3 reabsorption in the proximal (80% of reab) and distal tubules
CA is only intracellular in early distal tubule cells (intra end extra elsewhere)
Weak diuretics. Main use now is glaucoma (suppression of HCO3- secretion, which is normally part of the process of formation of aqueous humour in the eye).
Self limiting as excess HCO3- loss results in metabolic acidosis
Can be used to help acclimitisation to high altitudes and can guard against mountain sickeness and help alleviate sleep apnoea at high altitudes
Mannitol
Osmotic diuretic
Small molecular weight substances filtered at the glomerulus but not reabsorbed at all.
Retain their osmotic equivalent of water and so increase urine volume
Decrease Na+ reabsorption in the PT as concentration is lowered.
Useful where urine flow is reduced as a decreased GFR leads to excessive reabsorption of salt and water (osmotic diuretics maintain urine flow)
Rapidly reduces intracranial and intraocular pressure so useful in cerebral oedema. Doesn’t cross BBB.
Botensan
Blocks endothelin1 effects so decreases blood pressure
Captopril
ACE inhibitor
Antagonises renin-angiotensin system, so reduces sodium and water retention, reduces BP
Enalapril
ACE inhibitor
Antagonises renin-angiotensin system, so reduces sodium and water retention, reduces BP
Inactive, converted in liver to active metabolite enalaprilat
Saralasin
AngII partial agonist
Peptide so not suitable for oral administration, not competitive with other antihypertensives
Losartan
Angiotensin receptor blockers (ARBs), non-peptide ang II antagonists
Act on AT1 receptors (for angiotensin II)
What are the different angiotensin II receptors and what are their roles?
AT1 - blocked by losartan - mediates vasoconstriction and aldosterone secretion
AT2 - causes vasodilation by generation of nitric oxide with a subsequent increase in cGMP and binding of angII to AT2 inhibits, in certain cells, proliferation, mediates differentiation in neural tissue, and can induce apoptosis
Aliskiren
Renin inhibitor
Brain aminopeptidase-A
Converts AngII to AngIII in the brain
Aminopeptidase-N
converts AngIII to AngIV
AngIV may act via AT4 receptor: a transmembrane enzyme insulin-regulated membrane aminopeptidase (IRAP). Activation may be used for memory enhancement, particularly in Alzheimer’s disease.
Bradykinin, kallikrein
Short peptide released from various cells
Potent natriuretic
Renal vasodilator
Degraded by ACE
Many peptides in prox tubule (insensitive to ACE inhibitors) which metabolise bradykinin
EDT kininogen and kallikrein (breaks down kininogen to bradykinin)
Collecting duct kininogen and bradykinin B2 receptors
If very high Na+ reaches the distal tubule, kallikrein released, bradykinin formed from kininogen and Na+ reabsorption inhibited.
Reserpine
Blocks VMAT
Can be used to dope racehorses
INa
VGSC
Responsible for phase 0
ICa-L
L-type calcium channels
main current during plateau
ICa-T
T type calcium channels
In nodal and connective tissue
I Na-Ca
Result of electrogenic activity of Na/Ca exchanger
removes Ca2+ which has entered during the plateau phase
Affected indirectly by cardiac glycosides to treat heart failure
I TO1 and I TO2
VGKC of unusual nature
Activate rapidly in Phase 0 and then inactivate rapidly
gives name - I transient outward
responsible for small notch that constitutes phase 1
IKs
Delayed rectifier
Activates with a delay after dep, shows little or no inactivation
contribute to outward current during the plateau, so control the timing of repolarisation
blocking these prolongs the AP duration
Result of KCNNE1 and KvLQT2, mutations result in Long QT syndrome
IKr
Another delayed rectifier
hERG gene product - Kv11.1
Mutations result in long QT
I Kur
Third delayed rectifier
Kv1.5
I Kp/I Cl
IKp = plateau K+ current that shows no particular rectification or voltage-sensitivity. TWIK family (twin-pored K+ channel involved in the resting potential of many kinds of cells). ICl = chloride current. contribute little to membrane or action potentials. Prob CFTR, but disorder doesn't really affect the heart.
IK1
Inward-rectifier stabilising the resting potential and preventing K+ loss. IK-ACh and IK-ATP too
If
Pacemaker current
HCN channels
Almost as permeable to Na+ as K+, so on hyperpolarisation, Na+ begins to enter, leading to slow depolarisation.
Activated directly by cAMP (not via PKA)
Pindolol
mild partial beta agonist - little change in cardiac output.
no effect on plasma renin
Prazosin
Alpha1 adrenoceptor antagonist.
Doxazosin
Alpha1 adrenoceptor antagonist
dilates resistance and capacitance vessels
Lack of marked tachycardia, probably due to lack of block of presynaptic alpha2 receptors
Phentolamine
Non-selective alpha blockade
vasodilation leads to marked reflex tachycardia
Labetalol
alpha1, beta1 and beta2 antagonist, more so beta than alpha
Amilodipine
Dihydropyridine L-type calcium channel blocker
used to treat hypertension in the long term
Minoxindil
K+ channel opener used in severe refractory hypertension along with a beta blocker and a diuretic
Used as a topical hair loss treatment
Glibenclamide
Sulfonylurea that antagonises KCOs via a separate receptor that modulates the K-ATP channel, not the channel itself.
Used as an anti-diabetic, so that more insulin secreted
Clonidine
Centrally acting alpha2/I1 agonist.
Decreases BP when microinjected into ventrolateral medulla - area rich in alpha2R, but might actually be mediated by imidazoline I1 receptor
Guanfacine
Centrally acting alpha2/I1 agonist
Low efficacy as antihypertensive
Moxonidine
Imidazoline drug mimics catecholamines.
centrally acting hypertensive.
Alpha-methyldopa
False transmitter
Alpha-methylnoradrenaline formed
more potent on alpha2 less on alpha1 than NA
Sodium nitroprusside
Metabolised to NO - so direct acting vasodilator in treatment of hypertension. In solution also hydrolyses to cyanide
Hydralazine
Directly acting arteriolar vasodilator, mechanism unknown
Simvastatin
Statin
Inhibits HMG-CoA reductase, rate limiting step in cholesterol synthesis pathway
Means liver has to upreg LDL R so that more LDL is taken up for the enterohepatic circulation
Evolocumab, Alirocumab
MAb against PCSK9, so enhance internalisation and recycling of LDL-R (and so LDL uptake)
Bezafibrate, clofibrate
Fibrate, lowers VLDL and LDL to a lesser extent. Stim lipoprotein lipase, releasing triglycerides from VLDL and chylomicrons, so that they can be taken by fat or muscle and metabolised. Also work by stimulating PPARs –> induces LXRalpha transcription and so ABCA1 expression –> reverse cholesterol transport increase
Pioglitazone
PPARgamma agonist, induces LXRalpha transcription and so ABCA1 expression –> reverse cholesterol transport increased
Colestyramine
Anion exchange resin. Forms insoluble complexes with bile acids in the intestines which then cannot be reuptaken and are then excreted into the faeces. Causes an increase in cholesterol metabolism to synthesise bile acids in the liver.
Ezetimibe
Inhibits intestinal absorption of cholesterol. Can be used with a statin or alone. Binds to brush border – target NPC1L1 Niemann-Pick C1-Like 1. Protein mediates sterol transport across the brush border of intestinal epithelial cells, also present in liver where it helps in reabsorption of cholesterol from bile. The drug circulates enterohepatically.
Nicotinic acid
• Inhibits liver triglyceride production and VLDL secretion when used in very large doses. Increases levels of tissue plasminogen activator.
Fish oil
Reduces hypertriglyceridaemia
Glyceryl trinitrate
Nitrovasodilator
Used to treat angina
Taken sublingually as poorly absorbed in the stomach
Isosorbide dinitrate
Has to be metabolised to active isosorbide mononitrate in the liver
nitrovasodilator
used in treatment of angina
Amyl nitrite
Nitrovasodilator
Used in acute attacks of angina
Dipyridamole
Vasodilator
Also dilates arterioles in well oxygenated conditions
gives rise to coronary steal
Ivabradine
Blocks funny current, slows heart rate, more time in diastole for blood to flow into the myocardium
Treatment of angina
Ranolazine
Inhibits the late phase of the sodium current in cardiac myocytes, so reduces Ca2+ overload and diastolic wall stress, leading to improved coronary blood flow
Nicorandil
Ischaemic preconditioning
- mitoK ATP channel opening drug, preserve ATP levels during ischaemia, better ionic homeostasis, inhibits MPTP
- NO donor
- Opens plasma membrane K ATP channels, so improves perfusion
Sirolimus
Macrolide antibiotic used to coat stents to prevent neointimal proliferation
Adenosine
Adenosine –> A1 in AVN –> Gi reduced cAMP –> activate I K-ACh –> hyperpolarisation of pacemaker and conductive tissue
Use for certain superventricular tachycardias
How do we treat heart failure?
- Cardiac glycosides digoxin
- Beta1 agonist dobutamine
- Beta blockers bisoprolol, carvedilol
- Inodilators/ PDE inhibitors - milrinone
- ACE inhibitors
- Potential future - SERCA2/phospholamban targeting
How do we affect the formation and degradation of blood clots?
P1. Degrade them = streptokinase/anistreplase/alteplase/duteplase
P2. Prevent formation =
asprin/clopidogrel/eptifibatide/heparin/warfarin/dabigatran/rivaroxaban
P3. Prevent lysis =
aminocaproic/tranexamic acid
What are the classes of diuretic drugs?
- Loop diuretics furosemide, bumetanide
- Thiazide diuretics bendrofluoromethiazide, hydrochlorothiazide
- potassium-sparing diuretics amiloride, triamterene, spironolactone
- CA inhibitors acetazolamide
- osmotic diuretics mannitol
Discuss the agents that act on the renin-angiotensin-aldosterone system
P1: ACE inhibitors captopril, enalapril
P2: Ang II antagonists/partial agonists saralasan, losartan
P3: Ca2+ channe antagonists nifedipine, amilodipine
Write an essay on the mechanism of action of antihypertensives
- Diuretics - thiazides, bendroflumethiazide, hydrochlorothiazide
- ACE inhibitors captopril, enalapril
- Beta blockers atenolol, bisoprolol
- Alpha1 antagonists prazosin
- Calcium channel antagonists amilodipine, nifedipine
- K+ channel openers minoxindil
- Alpha2/I1 agonists - clonidine guanfacine
- Sympatholytics guanethidine, reserpine
- Ganglion blockers hexamethonium, trimethaphan
- directly acting vasodilators sodium nitroprusside, hydralazine
Drugs used to arrest atherosclerosis?
- Statins simvastatin
- PCSK9 inhibitors evolocumab, alirocumab
- fibrates bezafibrate, clofibrate
- interfere with enterohepatic circulation colestyramine, ezetimibe
- nicotinic acid
- fish oil
Drugs used to treat angina?
- Nitrovasodilators glyceryl trinitrate, isosorbide dinitrate, amyl nitrite
- beta blockers atenolol
- calcium channel blockers nifedipine
- If blocker ivabradine
- Inhibit late Na+ current ranolazine
- ischaemic preconditioning nicorandil
- coronary angioplasty
Antidysrhythmics?
1 bind to VGSC 1A quinidine, procainamide 1B lidocaine 1C flecainamide 2 beta blocker 3 amiodarone 4 calcium channel blocker verapamil 5 adenosine, cardiac glycosides
What are the uses of beta blockers?
- Heart failure (bisoprolol, carvedilol)
- Hypertension
- Angina
What are the uses of calcium channel blockers?
- Mild diuretic
- Antihypertenisve nifedipine
- Angina nifedipine
- Antidysrhythmic verapamil
