Cardiovascular and Renal

Question 1

Lidocaine

Answer 1

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

Question 2

Dihydropyridines e.g. nifedipine, amilodipine

Answer 2

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)

Question 3

Phenylalkylamines e.g. verapamil

Answer 3

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.

Question 4

Benzothiazepines e.g. diltiazem

Answer 4

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.

Question 5

Ni2+

Answer 5

Blocks both L and T-type Ca2+ channels

Question 6

Sulfonylureas

Answer 6

Act on K+-ATP channels to stimulate insulin secretion in Type 2 diabetes mellitus

Question 7

Long QT syndrome can result from mutations in?

Answer 7

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

Question 8

Propranolol

Answer 8

Non specific beta antagonist

Question 9

Atenolol

Answer 9

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)

Question 10

Cholera toxin

Answer 10

Mimics beta1 stimulation: it stimulates the G-protein

Question 11

Forskolin

Answer 11

Mimics beta1 stimulation: stimulates adenylyl cyclase

Question 12

Effects of catecholamines on heart:

Answer 12

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+)

3. Sensitise ryanodine receptors (extra Ca2+ entry) so increased release intracellular Ca2+ stores (inotropic +)
4. PKA phosphorylates SERCA2 and phospholamban (inotropic???+)
5. If activation potential shifted more positive levels so pacemaker produces more frequent AP (chronotropic+) - I think it means whole thing is shifted up
6. Enhances delayed-rectifier K+ channels –> shortened AP duration (chronotropic+)

Question 13

Effects of ACh on heart:

Answer 13

via M2, Gi/o

1. Reduces nodal Ca2+ currents (chronotropic -), not inotropic as M2 in nodal tissue only
2. Shifts potential at which If is activated to more negative levels so pacemaker produces more widely spaced AP (chronotropic -)
3. Activates IK-ACh, hyp cell –> harder to elicit AP (chronotropic -)

Question 14

Quinidine and procainamide

Answer 14

Class IA antidysrhythmic 
Increase AP duration with intermediate rate of association/dissociation
Block VGSC (not in nodal tissue)

Question 15

Flecainide

Answer 15

Class IC antidysrhythmic

No effect on AP duration but very slow association and dissociation.

Question 16

Propanolol, atenolol

Answer 16

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

Question 17

Amiodarone

Answer 17

Class III antidysrhythmic
Prolong AP and thus also the refractory period.
Under different conditions can block both inward Na+ and outward K+ currents.

Question 18

Digoxin, ouabain

Answer 18

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

Question 19

Dobutamine

Answer 19

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.

Question 20

Bisoprolol, carvedilol

Answer 20

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

Question 21

Phentolamine

Answer 21

Alpha-adrenoceptor antagonist

Question 22

Phenothiazines

Answer 22

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).

Question 23

Type II PDE inhibitor

Answer 23

c-GMP stimulated

Question 24

Milrinone

Answer 24

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).

Question 25

Rolipram

Answer 25

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).

Question 26

Dipyridamole, sildenafil

Answer 26

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).

Question 27

Pimobendan, levosimendan

Answer 27

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.

Question 28

Angiotensin converting enzyme (ACE) inhibitors

Answer 28

Used to treat heart failure

Question 29

Phospholamban / SERCA2

Answer 29

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.

Question 30

Plasmin

Answer 30

``` 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 ```

Question 31

Streptokinase

Answer 31

47kDa protein formed by haemolytic streptococci. | Binds to plasminogen activator and causes generation of plasmin --> degradation of fibrin in clots

Question 32

Anistreplase

Answer 32

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

Question 33

Alteplase

Answer 33

Single chain recombinant human tissue plasminogen activator | Has greater activity on plasminogen bound to fibrin in clots, so localising their action

Question 34

Duteplase

Answer 34

Double chain recombinant human tissue plasminogen activator | Has greater activity on plasminogen bound to fibrin in clots, so localising their action

Question 35

Asprin

Answer 35

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

Question 36

Clopidogrel

Answer 36

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

Question 37

Eptifibatide

Answer 37

Cyclic heptapeptide inhibitor of glycoprotein IIb/IIIa receptor (thromboxane binds to this allow fibrinogen bridging between platelets and between platelets and foreign surfaces)

Question 38

Tirofaban

Answer 38

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

Question 39

Abciximab

Answer 39

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

Question 40

Heparin

Answer 40

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

Question 41

Warfarin

Answer 41

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.

Question 42

Dabigatran

Answer 42

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)

Question 43

Rivaroxaban

Answer 43

The first factor Xa inhibitor to be introduced

Question 44

Aminocaproic acid

Answer 44

Chemically similar to lysine Competitively inhibits plasminogen activation Stops excessive clot lysis opposite way to all the others

Question 45

Transexamic acid

Answer 45

Analogue of aminocaproic acid Competitively inhibits plasminogen activation Stops excessive clot lysis opposite way to all the others

Question 46

GFR

Answer 46

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

Question 47

Juxtaglomerular apparatus, macula densa

Answer 47

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

Question 48

Diuretics

Answer 48

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.

Question 49

Furosemide, bumetanide

Answer 49

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

Question 50

Probenecid

Answer 50

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)

Question 51

Hydrochlorothiazide, bendroflumethiazide

Answer 51

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

Question 52

Diazoxide

Answer 52

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.

Question 53

Amiloride, Triamterene

Answer 53

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)

Question 54

Spironolactone

Answer 54

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)

Question 55

Canrenone/its salt potassium canrenoate

Answer 55

K+ sparing diuretic

Question 56

Acetazolamide

Answer 56

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

Question 57

Mannitol

Answer 57

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.

Question 58

Botensan

Answer 58

Blocks endothelin1 effects so decreases blood pressure

Question 59

Captopril

Answer 59

ACE inhibitor | Antagonises renin-angiotensin system, so reduces sodium and water retention, reduces BP

Question 60

Enalapril

Answer 60

ACE inhibitor Antagonises renin-angiotensin system, so reduces sodium and water retention, reduces BP Inactive, converted in liver to active metabolite enalaprilat

Question 61

Saralasin

Answer 61

AngII partial agonist | Peptide so not suitable for oral administration, not competitive with other antihypertensives

Question 62

Losartan

Answer 62

Angiotensin receptor blockers (ARBs), non-peptide ang II antagonists Act on AT1 receptors (for angiotensin II)

Question 63

What are the different angiotensin II receptors and what are their roles?

Answer 63

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

Question 64

Aliskiren

Answer 64

Renin inhibitor

Question 65

Brain aminopeptidase-A

Answer 65

Converts AngII to AngIII in the brain

Question 66

Aminopeptidase-N

Answer 66

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.

Question 67

Bradykinin, kallikrein

Answer 67

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.

Question 68

Reserpine

Answer 68

Blocks VMAT | Can be used to dope racehorses

Question 69

INa

Answer 69

VGSC | Responsible for phase 0

Question 70

ICa-L

Answer 70

L-type calcium channels | main current during plateau

Question 71

ICa-T

Answer 71

T type calcium channels | In nodal and connective tissue

Question 72

I Na-Ca

Answer 72

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

Question 73

I TO1 and I TO2

Answer 73

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

Question 74

IKs

Answer 74

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

Question 75

IKr

Answer 75

Another delayed rectifier hERG gene product - Kv11.1 Mutations result in long QT

Question 76

I Kur

Answer 76

Third delayed rectifier | Kv1.5

Question 77

I Kp/I Cl

Answer 77

``` 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. ```

Question 78

IK1

Answer 78

Inward-rectifier stabilising the resting potential and preventing K+ loss. IK-ACh and IK-ATP too

Question 79

If

Answer 79

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)

Question 80

Pindolol

Answer 80

mild partial beta agonist - little change in cardiac output. | no effect on plasma renin

Question 81

Prazosin

Answer 81

Alpha1 adrenoceptor antagonist.

Question 82

Doxazosin

Answer 82

Alpha1 adrenoceptor antagonist dilates resistance and capacitance vessels Lack of marked tachycardia, probably due to lack of block of presynaptic alpha2 receptors

Question 83

Phentolamine

Answer 83

Non-selective alpha blockade | vasodilation leads to marked reflex tachycardia

Question 84

Labetalol

Answer 84

alpha1, beta1 and beta2 antagonist, more so beta than alpha

Question 85

Amilodipine

Answer 85

Dihydropyridine L-type calcium channel blocker | used to treat hypertension in the long term

Question 86

Minoxindil

Answer 86

K+ channel opener used in severe refractory hypertension along with a beta blocker and a diuretic Used as a topical hair loss treatment

Question 87

Glibenclamide

Answer 87

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

Question 88

Clonidine

Answer 88

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

Question 89

Guanfacine

Answer 89

Centrally acting alpha2/I1 agonist | Low efficacy as antihypertensive

Question 90

Moxonidine

Answer 90

Imidazoline drug mimics catecholamines. | centrally acting hypertensive.

Question 91

Alpha-methyldopa

Answer 91

False transmitter Alpha-methylnoradrenaline formed more potent on alpha2 less on alpha1 than NA

Question 92

Sodium nitroprusside

Answer 92

Metabolised to NO - so direct acting vasodilator in treatment of hypertension. In solution also hydrolyses to cyanide

Question 93

Hydralazine

Answer 93

Directly acting arteriolar vasodilator, mechanism unknown

Question 94

Simvastatin

Answer 94

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

Question 95

Evolocumab, Alirocumab

Answer 95

MAb against PCSK9, so enhance internalisation and recycling of LDL-R (and so LDL uptake)

Question 96

Bezafibrate, clofibrate

Answer 96

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

Question 97

Pioglitazone

Answer 97

PPARgamma agonist, induces LXRalpha transcription and so ABCA1 expression --> reverse cholesterol transport increased

Question 98

Colestyramine

Answer 98

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.

Question 99

Ezetimibe

Answer 99

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.

Question 100

Nicotinic acid

Answer 100

• Inhibits liver triglyceride production and VLDL secretion when used in very large doses. Increases levels of tissue plasminogen activator.

Question 101

Fish oil

Answer 101

Reduces hypertriglyceridaemia

Question 102

Glyceryl trinitrate

Answer 102

Nitrovasodilator Used to treat angina Taken sublingually as poorly absorbed in the stomach

Question 103

Isosorbide dinitrate

Answer 103

Has to be metabolised to active isosorbide mononitrate in the liver nitrovasodilator used in treatment of angina

Question 104

Amyl nitrite

Answer 104

Nitrovasodilator | Used in acute attacks of angina

Question 105

Dipyridamole

Answer 105

Vasodilator Also dilates arterioles in well oxygenated conditions gives rise to coronary steal

Question 106

Ivabradine

Answer 106

Blocks funny current, slows heart rate, more time in diastole for blood to flow into the myocardium Treatment of angina

Question 107

Ranolazine

Answer 107

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

Question 108

Nicorandil

Answer 108

Ischaemic preconditioning 1. mitoK ATP channel opening drug, preserve ATP levels during ischaemia, better ionic homeostasis, inhibits MPTP 2. NO donor 3. Opens plasma membrane K ATP channels, so improves perfusion

Question 109

Sirolimus

Answer 109

Macrolide antibiotic used to coat stents to prevent neointimal proliferation

Question 110

Adenosine

Answer 110

Adenosine --> A1 in AVN --> Gi  reduced cAMP --> activate I K-ACh --> hyperpolarisation of pacemaker and conductive tissue Use for certain superventricular tachycardias

Question 111

How do we treat heart failure?

Answer 111

1. Cardiac glycosides digoxin 2. Beta1 agonist dobutamine 3. Beta blockers bisoprolol, carvedilol 4. Inodilators/ PDE inhibitors - milrinone 5. ACE inhibitors 6. Potential future - SERCA2/phospholamban targeting

Question 112

How do we affect the formation and degradation of blood clots?

Answer 112

P1. Degrade them = streptokinase/anistreplase/alteplase/duteplase P2. Prevent formation = asprin/clopidogrel/eptifibatide/heparin/warfarin/dabigatran/rivaroxaban P3. Prevent lysis = aminocaproic/tranexamic acid

Question 113

What are the classes of diuretic drugs?

Answer 113

1. Loop diuretics furosemide, bumetanide 2. Thiazide diuretics bendrofluoromethiazide, hydrochlorothiazide 3. potassium-sparing diuretics amiloride, triamterene, spironolactone 4. CA inhibitors acetazolamide 5. osmotic diuretics mannitol

Question 114

Discuss the agents that act on the renin-angiotensin-aldosterone system

Answer 114

P1: ACE inhibitors captopril, enalapril P2: Ang II antagonists/partial agonists saralasan, losartan P3: Ca2+ channe antagonists nifedipine, amilodipine

Question 115

Write an essay on the mechanism of action of antihypertensives

Answer 115

1. Diuretics - thiazides, bendroflumethiazide, hydrochlorothiazide 2. ACE inhibitors captopril, enalapril 3. Beta blockers atenolol, bisoprolol 4. Alpha1 antagonists prazosin 5. Calcium channel antagonists amilodipine, nifedipine 6. K+ channel openers minoxindil 7. Alpha2/I1 agonists - clonidine guanfacine 8. Sympatholytics guanethidine, reserpine 9. Ganglion blockers hexamethonium, trimethaphan 10. directly acting vasodilators sodium nitroprusside, hydralazine

Question 116

Drugs used to arrest atherosclerosis?

Answer 116

1. Statins simvastatin 2. PCSK9 inhibitors evolocumab, alirocumab 3. fibrates bezafibrate, clofibrate 4. interfere with enterohepatic circulation colestyramine, ezetimibe 5. nicotinic acid 6. fish oil

Question 117

Drugs used to treat angina?

Answer 117

1. Nitrovasodilators glyceryl trinitrate, isosorbide dinitrate, amyl nitrite 2. beta blockers atenolol 3. calcium channel blockers nifedipine 4. If blocker ivabradine 5. Inhibit late Na+ current ranolazine 6. ischaemic preconditioning nicorandil 7. coronary angioplasty

Question 118

Antidysrhythmics?

Answer 118

``` 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 ```

Question 119

What are the uses of beta blockers?

Answer 119

1. Heart failure (bisoprolol, carvedilol) 2. Hypertension 3. Angina

Question 120

What are the uses of calcium channel blockers?

Answer 120

1. Mild diuretic 2. Antihypertenisve nifedipine 3. Angina nifedipine 4. Antidysrhythmic verapamil