Cardiovascular + Renal Flashcards
(95 cards)
1
Q
Clopidogrel
A
P2Y12 inhibitor. Metabolised by CYP2C19 which is highly polymorphic.
2
Q
Ticagrelor
A
P2Y12 inhibitor.
3
Q
Prasugrel
A
P2Y12 inhibitor.
4
Q
Eptifibatide
A
Cyclic heptapeptide gpIIb/IIIa inhibitor.
5
Q
Tirofiban
A
Non-peptide gpIIb/IIIa inhibitor.
6
Q
Abciximab
A
Monoclonal antibody against gpIIb/IIIa.also binds to the vitronectin receptor on platelets. Vitronectin is involved
in cell adhesion and haemostasis.
7
Q
Heparin
A
Binds and activates ATIII which cleaves factors Xa, IXa and thrombin (IIa). Hence heparin compounds are INDIRECT inhibitors.
To inhibit thrombin, it is necessary for heparin to bind to the enzyme as well as to antithrombin III. To inhibit factor Xa, it’s necessary only for heparin to bind to ATIII.
HIT: Caused by IgM or IgG antibodies forming an immune complex with heparin (which acts as a hapten) bound to a platelet-derived chemokine, platelet factor 4. Immune complexes formed will cross-link FcγIIa receptor on platelets. This activates platelets and cause thrombosis. This lowers the number of free platelets circulating, causing thrombocytopenia.
8
Q
Fondaparinux
A
Similar structure and properties to LMWH so is an indirect factor Xa inhibitor.
9
Q
Dalteparin
A
LMWHs are much smaller than unfractionated heparin, thus LMWHs can increase the action of antithrombin III on factor Xa but NOT its action on thrombin. So it’s an indirect factor Xa inhibitor.
10
Q
Danaparoid
A
LMWH so an indirect factor Xa inhibitor. Also a direct inhibitor of factor IX’s activation by thrombin.
11
Q
Bivalirudin
A
Hirudin analogue so a direct thrombin inhibitor.
DTI: ‘BAD’
12
Q
Dabigatran
A
Direct thrombin inhibitor.
13
Q
Rivaroxaban, apixaban, edoxaban
A
Direct factor Xa inhibitor.
14
Q
Argatroban
A
Direct thrombin inhibitor.
15
Q
Tranexamic acid
A
Stabilises formation of new clots by inhibiting plasminogen to plasmin conversion, but by itself is quite useless.
16
Q
Streptokinase
A
Activates plasminogen by acting as a kinase. It’s extracted from cultures of beta haemolytic streptococci.
Streptokinase can cause immune reactions because it’s streptococci by origin.
Note that PLASMIN cleaves fibrin and also breaks down factors 2,5,7.
17
Q
Alteplase, Duteplase
A
Respectively, single- and double-chain recombinant tPA. are more active on fibrin-bound plasminogen than on plasma plasminogen, and are therefore ‘clot selective’.
18
Q
Warfarin
A
Inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1). Inhibits the reduction of vitamin K epoxide to its active hydroquinone form, hence interferes with the carboxylation of glutamate to Gla residues in factors 2, 7, 9, 10. Issues:
(1) Proteins C, S, Z are also vitamin K dependent. Protein C cleaves factors V and VIII. Proteins C and S have a shorter elimination half-life than that of clotting factors, so initially warfarin is pro-coagulant. Need a bridging anti-coagulant like heparin.
(2) VKORC1 gene is polymorphic. CYP2C9, the enzyme that breaks down warfarin, is also polymorphic. Need pharmacogenetic testing to determine the dosage of warfarin.
(3) Interacts with many commonly used drugs and other
chemicals in food and drinks.
(4) Bound to albumin, complicating its pharmacokinetics.
19
Q
Voltage gated Na+ channels
A
Once they open, they stay open only transiently before closing. Remain in this closed state until shortly AFTER the membrane returns to its resting potential.
α, ß1 and ß2 subunits. Expression of the alpha subunit alone will produce a functional channel, other subunits modulate its behaviour.
Alpha subunit has a phosphorylation site and all 3 subunits have glycosylation sites.
α subunit has 4 domains, each of which has 6 transmembrane domains (total 24). For each domain:
(1) S4 segment is voltage sensor and is positively charged.
(2) Region between S5 and S6 forms entrance to the pore. S6 produces selectivity.
All 4 domains combine to form one pore through which Na+ enters.
Inactivation produced by:
(1) Cytoplasmic loop between domains 3 and 4. Note that all loops between domains are cytoplasmic. Since there’s an even number of subunits, N terminus and C terminus of alpha subunit must be cytoplasmic.
(2) S6 segment in domain 4.
(3) S5-S6 loop in domain 4.
AAs on cytoplasmic end of the S6 segment of domain 4
confers local anaesthetic sensitivity on voltage‐gated Na+ channels.
20
Q
Voltage gated Ca2+ channels
A
α1, α2, β, γ and δ subunits. α1 subunit enough to make a functional channel and similar to α subunit of Nav channels.
α2 and δ subunits are linked by a disulphide bridge and are products of the same gene.
α2δ + β subunits enhance channel trafficking, regulate channel expression (gabapentin targets this), influence the behaviour of the α1 subunit.
21
Q
L-type Ca2+ channels
A
Large 30mV depolarisation to open. Open for a long time, inactivates slowly. Large single channel conductance.
Found in ALL excitable cells. Also controls hormone release from endocrine cells.
Mode 1: Channel openings occur in bursts separated by long closed intervals.
Mode 0: Channel does not open at all.
Mode 2: Very long openings separated by short closed intervals.
Agonists favour mode 2, antagonists favour mode 0.
22
Q
T-type Ca2+ channels
A
Small (10-20mV) to open. Open transiently, low single channel conductance.
NOT sensitive to dihydropyridines. Can be blocked by divalent cations like Ni2+, but these block any type of Ca2+ channels.
23
Q
Phenylalkylamines
A
Verapamil, D600
Binds S6 in domain 4 and S5-S6 loop in domain 4.
24
Q
Dihydropyridines
A
Nifedipine, Amlodipine antagonist. Bay K 8644 agonist.
Binds S6 on domain 3, and S5‐S6 loop in domain 3.
Highly lipid-soluble and gain access to the channel through the lipid phase of the membrane.
DHP binding is reduced by verapamil but enhanced by diltiazem. (Vitrual Reality is DEad)
Block produced by DHP shows less use-dependence and is shorter than that produced by the verapamil or diltiazem.
Selective for vascular L-type Ca2+ channels. Other types are for cardiac L-type Ca2+ channels. Because VSMCs resting potential is -60mV so more channels remain INactivated than in cardiac muscle (resting potential -90mV) and dihydropyridines bind to the inactivated form of the channel.
25
Benzothiazepines
Diltiazem
| Block from the outside don't know where.
26
K+ channels
At resting potential, K+ channels have a high conductance, but low driving force, and small current conducted. K+ channels are responsible for stabilisation of the resting potential in the atria and
ventricles (NOT pacemaker areas).
Kv protein contains 6 transmembrane domains, same as a domain in Na+ channels. Four Kv proteins combine to give a functional K+ channel. Na+ channels arose
from the K+ channel gene through gene duplication.
Some channels show rapid inactivation, some have slow inactivation, some have NO inactivation. Activation is not always rapid as well.
N-type inactivation/Ball and chain inactivation: N-terminus occludes the pore.
C-type inactivation: SLOWER, due to movement of residues near the extracellular surface of the pore.
27
I(K1) current
I(K1) most important for maintenance of the resting potential. Another role is to prevent excessive loss of K+ during the long plateau phase.
Inwardly rectifying K+ channels are NOT voltage-gated.
Made of 4 Kir proteins. Each Kir protein only has TWO transmembrane segments (not 6).
Occluded at depolarised potentials. Occlusion mediated by Mg2+ and spermine.
Some K+ channels show BOTH voltage gating and inward rectification.
Inwardly rectifying K+ channels are found in liver and kidney as well as excitable tissues. Purpose there unknown.
28
I(K-ACh)/HGIRK1
Beta-gamma subunit of Gi opens it to hyperpolarise cardiac cells.
Made of Kir3.1, 3.2, 3.4, 3.5 (NO 3.3).
29
I(K-ATP)
K-ATP channels are octameric containing a core of 4 Kir6.2 proteins, which form the pore of the ion channel, and surrounding this are 4 SUR1 subunits.
Close in the presence of high levels of intracellular ATP, which bind Kir6.2 subunits, and open when ATP levels fall, depolarising and hyper polarising the cells respectively.
Present in pancreatic beta cell, VSMCs, mitochondria - mediates preconditioning.
30
I(To1) + I(To2)
Produced by voltage-gated K+ channels. Activate rapidly in Phase 0 and then inactivate rapidly. Causes phase 1 of cardiac AP.
31
I(Ks)
I(Ks) has 'delayed rectifier' properties. I(Ks) made from TWO different types of K+ channels.
Activates with a delay after depolarisation, and show little or no inactivation.
Contribute outward current during the plateau and thus control the timing of repolarisation.
Mutations cause Long QT syndrome.
32
I(Kr)
Has 'delayed rectifier' properties. Product of the gene hERG, encoding the Kv11.1.
Everything else same with I(Ks).
33
I(Kur)
Kv1.5. Another delayed rectifier.
34
I(Kp)
A plateau K+ current that shows no inward rectification or voltage sensitivity. Twin-pored channels of the TWIK family.
35
I(Cl)
CFTR channel, which is expressed in abundance in the heart. Note that people with cystic fibrosis don't usually have disordered cardiac function.
36
Long QT syndrome
mutation in the cytoplasmic loop connecting domains 3 and 4 of the Nav channel produces LQT3.
Long QT syndrome leads to ventricular fibrillation then cause SADS. SADS also caused by cardiomyopathy.
37
Pacemaker cells and I(f)
Pacemaker cells have If and NO NaV current. L and T-type Ca2+ channels generate phase 0. There is no phase 1 or 2.
HCN channels produce I(f). Has the same S1-S6 structure of Kv channels, activated directly by cAMP.
HCN1 is present in heart + brain.
HCN2 expressed throughout the heart. HCN4 expressed in pacemaker regions and Purkinje fibres.
HCN2 and HCN4 are most abundantly expressed in the heart.
38
Potassium channels: Number of transmembrane segments
6: Ikr, Iks, Ito1, Ito2, Ikur - Form TETRAMERS
4: TWIK - Form DIMERS
2: Ik1, IK-ACh, IK-ATP - Form TETRAMERS
39
Adrenergic neurotransmission in heart
```
ß1 adrenergic receptors on nodal cells and ventricular cells.
Increased I(Ca-L) and I(Ca-T). Time-course of effect on Ca2+ currents by ß1 agonists or cAMP on HCN channels is SLOW: Latent period of 5 seconds, 30 seconds for current to reach maximum. Reversal of effect is also SLOW.
```
Forskolin stimulates adenylate cyclase.
(1) PKA phosphorylates and increases Cav channel activity. Increased Ca2+ inflow during plateau phase, which will SENSITISE ryanodine receptors, so more Ca2+ release from intracellular stores. Positive ionotropic effect.
(2) PKA phosphorylates SERCA2 and phospholamban.
(3) cAMP shifts the potential at which If is activated is shifted to less negative levels. Positive chronotropic effect.
(4) PKA phosphorylates various delayed rectifier channels. Positive lusitropy leads to positive chronotropy.
40
Muscarinic neurotransmission in heart
M2 receptors are mainly confined to the nodes.
So decrease in I(Ca-L) and I(Ca-T) cause reduced chronotropy, NOT inotropy.
Potential at which If is activated is shifted to more negative levels. Negative chronotropy.
ACh increases I(K-ACh), which hyperpolarises the cell, making it more difficult to elicit action potentials
41
Lidocaine/Procaine/Quinidine
Aδ and C fibres most susceptible to LA.
LAs shift the inactivation curve is shifted to hyperpolarized potentials. Inactivation curve is a graph of I(Na) vs pre-pulse membrane potential. So at any given membrane potential, a greater proportion of the channels is inactivated.
Reason: LAs bind preferentially to the inactivated state of the channel and stabilizes this state.
Lidocaine/procaine are weak BASEs of pKa 8-9 (B + H+ -> BH+). Blocks the channel best in its charged form, but it has to enter the cell in its uncharged form to its site of block. So if added outside cell, needs high pH, if added inside cell, needs low pH.
Use-dependence: Block is FASTER in onset and offset if the channels are opening frequently. Lidocaine is a fast-in, fast-out’ LA, showing use-dependence only at high rates of stimulation. Used in ventricular arrhythmia. Quinidine is a ‘slow-in, slow-out’ LA. Used in SVT.
Voltage-dependence: For a given pulse size, the initial rate of block is increased by giving a hyperpolarising pre-pulse, because the more negative the pre-pulse, the more channels will be in the activatable form, and hence block is FASTER. The more depolarising the test pulse, the faster the block, because positive test pulse increases the potential driving the LA into the channel.
42
QX314
Quaternary LA that's always charged. Ineffective when added to the outside of axon, but is a potent LA when perfused inside.
43
Benzocaine
Uncharged. No use-dependence or voltage-dependence. The block is faster in onset and offset than for procaine at pH 6 (maybe because procaine is charged at that point so bad at entering cells).
Other LAs block from inside the cell to get INSIDE the channel - hydrophilic pathway. Benzocaine uses a hydrophobic pathway within the membrane for uncharged LAs.
44
Tetrodotoxin and Saxitoxin
Has guanidinium groups, block Na+ channels from the outside. They do not show use-dependence or voltage-dependence.
45
Desensitisation of the β2-adrenoceptor
(1) Uncoupling of the receptor from its G-protein. Takes seconds to minutes.
(2) Sequestration of receptors by endocytosis. Receptors either recycled or destroyed. Takes minutes.
(3) Down-regulation is reduced number of receptors available to be shuttled to and from the plasma membrane. Due to reduced receptor synthesis by an effect of PKA on mRNA stability. Takes minutes to hours.
46
Uncoupling: Heterologous desensitisation
PKA phosphorylates the receptor at 3rd cytoplasmic loop and beginning part of C-terminal cytoplasmic domain (since GPCRs have 7 transmembrane segments, N-terminal is extracellular).
This uncouples the receptor from the α-subunit of Gs.
PKA can also phosphorylate other GPCRs, so other receptors can be desensitised without having first been stimulated by ligand binding.
Heterologous desensitisation takes place with LOWER concentrations of ligand, since there's amplification to make PKA.
47
Uncoupling: Homologous desensitisation
β-adrenoceptor kinase (βARK) phosphorylates sites at the end of the C-terminal domain.
Phosphorylation increases the affinity of the β2-receptor for another protein called β-arrestin.
Binding of β-arrestin uncouples receptor from α-subunit of Gs.
βARK only works on agonist-occupied receptors.
Homologous desensitisation takes place with HIGHER concentrations of ligand
48
Dysrhythmias pathophysiology
Discharge rates from SAN: 70 per min
AVN, Bundle of His and Purkinje fibres are 60, 50 and 40 min-1 respectively.
Cardiac muscle is a functional syncytium and can conduct in any direction. The 3D branching
arrangement of conducting fibres means that APs that have travelled via different pathways, collide at common points. By doing this they extinguish each
other. Correct pattern of extinction important for normal function.
How this well organised heartbeat becomes disrupted:
(1) Myocardium is damaged, SLOWing the velocity of conduction, making the impulse arrive late. Late arriving
impulse can excite tissue that would have been refractory if the impulse had arrived at the correct time. (2) Late arriving impulse also alters the extinction pattern.
(3) Ectopic foci due to SAN not working properly or excessive catecholamine stimulation.
49
Reasons for dysrhythmias
(1) Ischaemic heart disease causing angina pectoris. Ischaemic myocardium cannot operate efficiently, although it's still capable of conduction.
(2) Myocardial infarction - necrosis of tissue due to ischaemia. Cardiac tissue replaced by connective tissue which is non-conductive.
(3) Wolff-Parkinson-White syndrome - Have extra bundle of Kent. This accessory pathway does not share the rate-slowing properties of the AV node. WPW causes atrio-ventricular re-entrant tachycardia.
(4) LQT Syndrome
50
Class I
Block Nav channels. Decreases peak height of AP and slope of phase 0 in the order CAB.
Increases AP duration in the order ACB (C does nothing, B decreases).
51
Class Ia
Quinidine, procainamide
Higher affinity for the open state than for the inactivated state. Therefore AP duration has no effect on drug action. Show use-dependence at normal resting potentials.
Prolongs repolarisation and hence AP duration and is thus pro-dysrhythmic.
Have anticholinergic action, especially at the nodes. So when using class Ia drugs, need concomitant treatment with a beta-blocker or calcium-channel blocker to slow AVN conduction.
52
Class Ib
Lidocaine
Higher affinity for the inactivated state and thus show use dependence at depolarised resting potentials/diastolic potentials, which occurs during ischaemia (Na/K pump doesn't work which depolarises cell slightly).
Usually 'fast-in-fast-out' drugs. So used for places with high rates of firing. Used to suppress tachyarrhythmias caused by re-entry mechanisms.
Affinity for inactivated state also means it's affected AP duration. Hence they're used in parts of the heart where AP is longest.
Decreases repolarisation length hence AP duration.
53
Class Ic
Flecainide
Associate and dissociate slowly so great at suppressing ectopic beats. But since they're so slow they suppress almost everything else as well, making them pro-dysrhythmic. Class Ic drugs are only used prophylactically against paroxysmal atrial fibrillation.
No effect on repolarisation length or AP duration.
54
Class II
ß1-antagonists - bisoprolol, atenolol, nebivolol. 'BAN'
Nebivolol - one of its metabolites is a ß3 agonist --> NO production and vasodilation
Used in dysrhythmias where the tissue abnormality leads to increased excitability. E.g. in ischaemic myocardium, tissue becomes sensitised to catecholamines. Catecholamines can produce enough inward current in ischaemic tissue to create an ectopic foci.
Cardiac glycosides and volatile anaesthetics can also sensitise myocardium to catecholamines.
D and L-propranolol have Class I actions (only L-propranolol is a ß-blockers) and sotalol has Class III actions.
Hypertension and angina:
Decrease blood pressure, and hence cardiac afterload. Decrease BP in 4 ways:
(1) Decreased CO
(2) Long-term use of beta blockers causes a fall in peripheral vascular resistance. Mechanism unknown.
(3) Decreased renin release
(4) Decreased sympathetic output from CNS and baroreceptors. Not that important has hydrophilic ß-blockers, like atenolol penetrate the CNS much less but decrease BP just as effectively as penetrant antagonists.
Unlike α1 antagonists, beta blockers don't induce postural hypotension, because the α adrenoceptors remain unaffected.
Note that in heart failure (which frequently occurs with angina), it's necessary to maintain adequate sympathetic stimulation to produce an adequate CO.
Beta-blockers also used in hyperthyroidism, and glaucoma.
55
Why non-selective beta blockers are not good
(1) They mask the tachycardia that serves as a warning sign for insulin-induced hypoglycaemia in diabetic patients.
(2) Blockade of β2-adrenoceptors leads to decreased glycogenolysis in liver, exacerbating hypoglycaemia after insulin injection.
(3) Coronary blood vessels have ß2 and α1 receptors. Normally the α1 response is overwhelmed by the ß2 response, but nonspecific ß-antagonists inhibit this, and unmask the α1-mediated constriction.
(4) Decreased bronchodilation.
56
Class III
Amiodarone
Substantially prolong the cardiac AP by inhibiting the K+ currents that result in repolarisation. Hence pro-dysrhythmic and can cause LQT syndrome and torsades de pointes syndrome.
```
Amiodarone also inhibits inward Na and Ca currents. Inhibition is greater in tissues with higher rate of AP firing and with depolarised resting potentials (like class Ib).
Thus AP duration is shortened if the inhibitory action of amiodarone on the inward current is greater than on the outward current, and vice versa.
```
57
Class IV
Cav blockers selective for myocardium - phenylalkylamines.
important that excessive Class IV drugs
are not given because this can inhibit excitation-contraction coupling too much.
So not used not when used when cardiac function is severely compromised (e.g. cardiogenic shock, severe MI).
Non-phenylalkylamines are vascular selective. They also have a role in the heart - perform myocardial salvage by decreasing Ca2+ loading of ischaemic tissue (which leads to excitotoxicity and cell death), since ischaemic tissue have DECREASED Na/K pump numbers (P.28 notes) which makes calcium loading easier due to less efficient NCX.
Vasodilator effect also decreases myocardium O2 demand by reducing afterload.
58
Adenosine
Atypical neurotransmitter - NOT stored in vesicles, nor released in a Ca2+ dependent manner. Made from ATP hydrolysis by ecto-nucleotidases. Uptake into cells by nucleoside transporter (NsT), which is blocked by dipyridamole. Adenosine broken down by adenosine deaminase to inosine.
(1) Acts on A1 receptors in the AV node. Gi coupled. βγ subunit opens HGIRK1 which hyperpolarises AVN. Used for supraventricular tachycardia. Short half-life so safer than other alternatives.
(2) Ischaemic preconditioning - Opens mitK(ATP) channels, decreasing activity of F1F0-ATPase, increases ATP levels in the cell, decreases opening of MPTP.
(3) Relaxation of vascular smooth muscle by acting through A(2A) and A(2B) receptors, Gs coupled. A(2A) agonist regadenoson dilates coronary vessels. Used in adults who can't exercise for a stress test.
(4) Presynaptic A1 receptors decrease excitatory transmitter release. Methylxanthines - A1 antagonist and non-selective PDE inhibitors makes us more awake.
(5) Anti-inflammatory effects. So methotrexate increases extracellular adenosine - mechanism unclear.
59
Cardiac glycosides
Digoxin, ouabain (too powerful to be used clinically)
Increase vagal activity through an action in the CNS. Slows AVN conduction - decreased dromotropy.
Inhibits Na/K-ATPase, increasing intracellular sodium. Decreases driving force for Ca2+ exit (learn equation P.28), more Ca2+ in cell, increased inotropy.
Lower plasma K+ potentiates action of cardiac
glycosides, which compete with K+ for binding to the Na+/K+-pump.
60
Heart failure
Definition: A heart that produces a CO that is inadequate to meet the metabolic demands of the body.
Caused by many things: Cardiomyopathy, abnormal valves, hypertension, past MI, dysrhythmia, coronary artery disease, diabetes, congenital heart defects, hyperthyroidism.
New York Heart Association 4 stages:
(1) Minimal dyspnoea (laboured breathing)
(2) Dyspnoea when walking on flat surface
(3) Dyspnoea when getting in/out of bed
(4) Dyspnoea when lying in bed
Defining feature, especially chronic heart failure, is raised catecholamine output:
(1) Body fails to distinguish from low ABP due to heart failure and low ABP due to haemorrhage. Maybe natural selection favoured mechanisms that would benefit young hunters who are often at risk of haemorrhage, and that elderly people at risk of heart failure are past their reproductive prime.
(2) Low ABP decreases afferent renal arteriole flow leading to increased renin release via afferent arteriole baroreceptor.
(3) In normal heart, ratio of ß1, ß2, α1 receptor is 70:20:10, but in chronic heart failure the ratio changes to 50:25:25%. In an attempt to maintain CO, in the conditions of a diminished proportion of ß1 receptors, catecholamine output increases.
61
Why increased catecholamine is bad
(1) Increased O2 demand.
(2) Increased afterload via vasoconstriction.
(3) Abnormal cardiac tissue remodelling, cardiac hypertrophy
(4) Increased apoptosis of cardiac myocytes.
(5) Desensitisation of the ß adrenoceptors.
(6) Increase TPR and MSFP. Normally, TPR does not decrease CO, but this requires an increase in cardiac work, which a failing heart can't manage. So TPR rise decreases CO.
Also, CO normally increases with MSFP due to Starling's law. In a failing heart, increase in MSFP won't increase CO, but will instead increase atrial filling pressure, causing oedema and increasing preload.
Right side: Peripheral oedema + ascites (fluid forced out of liver into abdomen).
Left site: Pulmonary oedema compromises the ability of the lungs to oxygenate blood, which exacerbates heart failure, and can cause cardiogenic shock.
Hence in heart failure: Atrial pressure is too high, arterial pressure is too low, and venous pressure is too high.
62
Treatment for heart failure
Acute (used after open heart surgery, cardiogenic shock) heart failure:
(1) Cardiac glycosides
(2) ß1 agonists, but this increases O2 demand, increase HR which could cause/precipitate dysrhythmias, cause/potentiate hypertension. For dobutamine, its positive inotropic effect is greater than its chronotropic effect.
(3) Inodilators/PDE inhibitors, especially milrinone. Issue with acting like a beta-adrenoceptor simulator. Good point is increased cAMP dilates vascular smooth muscle cells, decreasing afterload.
Chronic heart failure:
(1) ß1 antagonists. Bisoprolol and carvedilol (alpha 1, non-selective beta antagonist) are used in the UK. Danger of compromising heart function too much so must be used with caution.
(2) Levosimendan and pimobendan (used in animals) are calcium sensitisers. They increase Ca2+ binding efficiency to troponin, without a requirement for more O2 consumption. They both also inhibit PDE 3.
(3) ACE inhibitors/ARBs.
63
SERCA2
PKA phosphorylates SERCA2, phospholamban, and ryanodine receptors. Causes intracellular Ca2+ transients with higher amplitude and faster
re-uptake into the SR Ca2+ store (increased lusitropy). Phospholamban phosphorylation dissociates it from SERCA2.
In failing heart cells, reduced intracellular Ca2+ transient amplitudes and slowed rates of SR Ca2+ re-uptake have been observed.
Phospholamban:
Knock out phospholamban gene in mice, or viral delivery of antisense phospholamban causes better calcium handling and contraction, however it causes dilated cardiomyopathy.
SERCA2:
Transfect failing rat heart cells with SERCA2 gene causes increased inotropy and lusitropy. Also, rats’ ECGs showed a reversal of dysrhythmia when an attempt was made to stimulate dysrhythmia using catecholamines. Now need human trials, but there's issue with immune response against viral vectors used to carry SERCA2 gene.
64
Fall in GFR
Decreased NaCl to macula densa which lines wall of DCT. Induces cAMP increase in granular cells (a.k.a juxtaloglomerular cells), which are specialised smooth muscle cells lining the afferent arteriole, to secrete renin. Also, PGI2 is released which dilates afferent arteriole.
65
Rise in GFR
Increased NaCl to macula densa. Adenosine released, binds A1 receptor at granular cells, decreased cAMP, decreases renin release, decrease efferent arteriole constriction.
66
RAA system
Renin cleaves peptide bond near C terminus of angiotensinogen, releasing ANG I.
ACE, abundant in lungs, cleaves peptide bond at C terminus to make ANG II. ANG II increases aldosterone production, vasoconstricts, increases Na+ reabsorption, stimulates thirst and Na+ intake.
ANG II is converted to ANG III by brain aminopeptidase-A by cleavage at N-terminal. ANG III has same affinity for AT1 and AT2 receptors as ANG II. Anti-aminopeptidase-A can be used to treat hypertension.
ANG III is converted to ANG IV by aminopeptidase-N by cleavage at N-terminal. ANG IV acts on AT4 receptors which is involved in memory enhancement for Alzheimer's.
Low ECV stimulates renin in 3 ways:
(1) Low BP stimulates baroreceptors which increases sympathetic stimulation to JG cells.
(2) Decreased NaCl at macula densa.
(3) Decreased perfusion to afferent arteriole baroreceptor.
Renin release decreased in 3 ways:
(1) Atrial Natriuretic Peptide (ANP) inhibits renin release via cGMP activity.
(2) ANG II causes feedback inhibition on renin secretion via IP3.
(3) Adenosine, via its A1 receptor, decreases cAMP in JG cells.
67
Diuretics
When you drink a lot of water, ADH secretion inhibited, collecting duct becomes impermeable to water, urine is composed mainly of water; solute excretion is NOT increased.
With diuretics, BOTH solute AND water excretion is increased. This leads to reduction in ECV volume hence can treat hypertension, heart failure.
68
Loop diuretics
Furosemide, Bumetanide
Loop diuretics are actively secreted into the PCT.
(1) Inhibits NKCC2 in TAL by binding to the Cl- binding site. Very powerful: can cause 15-25% of filtrate to be excreted.
On repeated administration, effect is reduced because decrease in ECV leads to enhanced reabsorption in
tubules.
(2) Has a VENOdilator effect which precedes the onset of diuresis, by opening K(ATP) channels, decreasing preload. It can also decrease insulin secretion and increase blood glucose levels.
Venodilator effect increases the effect of diuretic on the nephron by increasing renal blood flow without a
change in GFR.
(3) Very weak inhibition of carbonic anhydrase.
Hypokalaemia: Increased Na delivery to DCT, increasing ENaC activity, which increases driving force for K+ excretion.
Metabolic alkalosis: Increased ENaC activity also increases driving force for H+ loss.
Ca2+ and Mg2+ loss are increased.
Uric acid excretion is decreased. This can result in gout, treated with probenecid, which prevents uric acid reabsorption.
Bartter syndrome, due to NKCC2 mutation, is like taking loop diuretic.
69
Thiazide diuretics
Bendroflumethiazide, Hydrochlorothiazide
Block the NCC co-transporter in early DCT by binding to the Cl- site. Everything else same as loop diuretics.
Exception: Increase Mg2+ excretion, but decrease that of Ca2+. 'TDC'
Thiazides are also used to treat nephrogenic diabetes insipidus. They partly inhibit the formation of a dilute urine, but don't inhibit formation of a concentrated urine.
Diazoxide is also a thiazide but has very little diuretic action. It's main action is a vasodilator.
Gitelman syndrome, due to NCC mutation, is like taking thiazide diuretics.
70
Potassium sparing diuretics
Amiloride + Triamterene block ENaC channels. Weak diuretic effect but prevents K+ loss.
Aldosterone works by increasing apical ENaC and basolateral Na/K pump density by upregulating SGK which phosphorylates and inhibits Nedd4-2, reducing ENaC degradation. This can be demonstrated in frog skin by an aldosterone-induced increase in 14C-amiloride binding, since amiloride binds ENaC.
Spirinolactone competes with aldosterone for its cytoplasmic steroid receptor.
Spirinolactone is metabolised to canrenone in the liver, and potassium canrenoate can also work as a K+ sparing diuretic.
Thus effect of spironolactone is only significant when distal tubule cells are under the influence of aldosterone. Because the mechanism depends on the turnover of ENaC channels, the rate of onset of diuresis produced by spironolactone is SLOW.
71
Carbonic anhydrase inhibitors
For HCO3- reabsorption, net effect of reabsorption 'cycle' (draw in exam) is reabsorption of NaHCO3. Acetazolamide inhibits enzyme but need to inhibit over 99% of enzymes to have an effect.
Acetazolamide, though the first diuretic to be introduced, is now obsolete. Main therapeutic use now is in glaucoma and altitude sickness treatment.
Carbonic anhydrase is localised both to the brush border (apical membrane) and intracellularly in the proximal tubule, but is only intracellular in EARLY distal tubule cells.
Can cause hypokalaemia, since by inhibiting carbonic anhydrase, H+ exit into lumen is decreased, and more K+ will hence be lost.
Actions of carbonic anhydrase inhibitors are self-limiting because excess HCO3- loss results in metabolic acidosis.
72
Osmotic diuretics
Mannitol is not reabsorbed, so retain its osmotic equivalent of water and so increase urine volume. Decrease luminal Na+ concentration thus decreasing Na+ reabsorption also.
Used when GFR is very low, which causes lots of Na+ and water reabsorption in PCT. This 'dries up' DCT, and cause irreversible damage.
Doesn't cross BBB, but is used to reduce intracranial pressure during cerebral oedema as it sucks water out of the head.
73
ACE Inhibitors and ARBs
ACE Inhibitors: Ramipril, lisinopril, perindopril --> perindoprilat.
They work by not only inhibiting ANG II's effects, but also by inhibiting bradykinin breakdown. B1 receptor activation causes PGI2 production. B2 receptor causes NO production. They both mediate vasodilation. So ACE inhibitors prevent vasoconstriction and increase vasodilation.
Saralasin is a AT1 receptor partial agonist. But it's a peptide so can't be taken orally.
Losartan is a non-peptide AT1 antagonist.
AT2 receptors causes vasodilatation by generating NO, apoptosis, neural tissue differentaition. Very different.
Aim of these drugs in heart failure patients is to reduce vascular resistance, NOT BP, since those with heart failure have low BP already.
ACE inhibitors are almost always combined with diuretics. The reduction in aldosterone should help to avoid hypokalaemia caused by diuretics.
Side effects: Dry cough due to bradykinin accumulation, hypotension, renal failure.
74
Renal kallikrein system
If very high Na+ reaches the distal tubule, kallikrein is released, bradykinin is formed, which inhibits Na+ reabsorption. Minimal role under normal physiological conditions.
Role in hypertension unknown.
75
ANP
(1) Reduces renin release. Acts via membrane bound GC-A receptor to increase cGMP.
(2) Increases GFR and inhibits Na+ reabsorption in collecting duct.
(3) Vasodilator
(4) Reduces NA release.
Role in hypertension unknown, however mice lacking the GC-A gene are hypertensive (which is NOT made worse by a high salt diet).
76
Hypertension
Most are 'essential hypertension', with no obvious cause. But specific ones include phaeochromocytoma (tumour of chromaffin cells in adrenal medulla) - detected by increased VMA in urine, renal artery stenosis, Conn's syndrome (primary hyperaldosteronism), Liddle's syndrome.
Defined as a BP of 140/90 or higher. But poor way of defining because of physiological responses of stress in exercise, exams, white coat effect, etc. Nocturnal BP correlates better with any pathologic state. Also different people have different targets. Diabetics' target is 130/80.
77
Liddle's syndrome
Mutations in the β and γ subunits of the ENaC trimer prevents the binding of Nedd4-2, so there’s still increased density of ENaC in the absence of aldosterone. Hypertension.
Thus Liddle's syndrome and Conn's syndrome looks very similar, but the former has low aldosterone levels but latter has high aldosterone levels.
Liddle's syndrome = Pseudo-hyperaldosteronism.
78
Mechanisms of essential hypertension
(1) Sympathetic overactivity causes raised CO, which elevates BP in very early hypertension. The subsequent rise in peripheral vascular resistance prevents the raised BP from being transmitted to the capillary bed where it would affect cell homeostasis.
(2) ANS responsible for maintaining normal BP. No evidence to suggest ANS has a role in causing essential hypertension. But drugs inhibiting ANS do lower BP.
(3) Endothelium produces NO and endothelin. Endothelin produce a salt-sensitive rise in blood pressure and activate local RAA systems. Endothelial dysfunction causes decreased NO production. Endothelial dysfunction is irreversible, because drugs can only restore NO production but NOT endothelium-dependent relaxation.
(4) Bradykinin + ANP (see above).
(5) Local RAA system: Control blood pressure by regulating regional blood flow.
(6) Gene mutations. Mutated gene products that have been identified to definitively cause hypertension ALL act in the kidney. Evidence: Renal transplant recipients are more likely to develop hypertension if the donors’ relatives are hypertensive.
79
Anti-hypertensive drugs
(1) ACE inhibitor + diuretics - 1st line treatment.
(2) Over 55s + Afro-Carribean: Swap ACE inhibitor for calcium-channel antagonist (since renin levels in those people are low).
(3) Alpha-1 antagonists - Dilates resistance AND capacitance vessels. Also blocks CENTRAL alpha-1 receptors to reduce sympathetic discharge from baroreceptors (reduce renin release). Also inhibits prostate hypertrophy.
Side effects: No tachycardia, but have postural hypotension and urinary incontinence.
(4) Ca2+ channel antagonists - Also have a mild DIURETIC effect, which is independent of any RPF or GFR change, since it inhibits ANG II stimulated aldosterone release. Reduce sympathetic discharge from baroreceptors. Amlodipine most commonly used.
(5) K+ channel openers - Minoxidil main one. Act on K(ATP) channels in vascular smooth muscle cells. Need concomitant use of beta-blocker and diuretic to inhibit reflex tachycardia and increase in blood volume. Minoxidil causes hirsutism so used to treat hair loss.
(6) Alpha-2 agonists. Guanfacine, clonidine, alpha-methyldopa, xylazine. They all have effect on imidazole I1 receptor in the brain, apart from xylazine. Of course alpha-2 agonists also decrease transmitter release peripherally and centrally.
Moxonidine is a specific I1 agonist. I1 receptor acts via GPCR, and increase DAG + arachidonic acid. Moxonidine has fewer side effects than alpha-2 agonists, and withdrawal leads to less rebound hypertension.
(7) Anti-aminopeptidase-A (put in ACEI section).
80
Atherosclerosis
Causes ischaemic heart disease, of which angina pectoris is the first sign.
Lipoproteins made of central core of hydrophobic lipid (including triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol and apoprotein. LDL has ApoB, HDL has ApoA.
How to reduce LDL:
Liver needs lots of cholesterol to make bile. Bile = cholesterol + bile salts. Secreted into duodenum, emulsify fats, and reabsorbed to liver (enterohepatic circulation). Pool needs to be topped up by de novo cholesterol synthesis, or cholesterol taken up from the blood. LDL binds LDL receptor on liver and taken up by receptor-mediated endocytosis. So increase LDL absorption.
81
Statin
Atorvastatin, simvastatin
They inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis. Liver has to take up more LDL from the blood, and makes more LDL receptors to do this.
(1) SREBPs are normally anchored in the ER via tight interactions with SREBP cleavage activating protein (SCAP), which is bound to a protein of the INSIG family.
(2) When cholesterol is NOT present (due to action of statins), SCAP no longer can bind INSIG, and SCAP acts as a chaperone protein and transports SREBPs from ER to Golgi. SCAP does so by undergoing a conformation change that exposes a portion of the protein that signals it to be included as cargo in COPII vesicles that move from ER to Golgi. In these vesicles, SCAP drags SREBPs along with it.
(3) At the Golgi, two proteases, site 1 and site 2 protease (S1P and S2P) sequentially cleave the SREBPs. These cleavages must occur in the proper order.
(4) The first cleavage, by S1P, separates SREBP’s two domains, both of which remain membrane bound (each domain still has a membrane-spanning helix).
(5) After the two halves of the SREBP have separated, S2P cleaves within the membrane-spanning helix of the transcription factor/N-terminal domain.
(6) This liberates the transcription factor domain of the SREBP proteins, and allows them to enter the nucleus, bind to SRE of target genes and activate LDL receptor gene transcription.
Pleiotropic effect: Stabilise plaques, inhibits thrombus formation, decreased oxidative stress and inflammation, beneficial effects on immune system, CNS, bone, slow development of Alzheimer's disease.
82
PCSK9
Evolocumab, Alirocumab
LDL binds LDL receptor causing internalisation. If PCSK9 binds LDL receptor in the endosome, it prevents conformational change of the LDL receptor, leading to destruction, instead of recycling, of LDL receptor.
83
Fibrates
Bezafibrate
Stimulates lipoprotein lipase, releasing triglycerides from VLDL and chylomicrons, which can then be stored in fat or metabolised. Activates PPARs to increase HDL levels.
ABCA1 transfers cholesterol from peripheral tissues to ApoA-1, then to a HDL molecule. Cellular cholesterol efflux is the rate-limiting step of HDL formation, as shown by those with Tangier disease, where ABCA1 is non-functional, hence they have low HDL levels. HDL is taken up by liver via scavenger receptor B1.
PPARα and PPARγ induce LXR transcription; LXR normally acts as a metabolic sensor of cholesterol content, and will increase ABCA1 synthesis when cholesterol levels are high in the cell.
Pioglitazone is a PPARγ agonist, and fibrates activate PPARs.
84
Colestyramine
Anion exchange resin. It prevents re-uptake of bile acids from the intestine, causing liver to make more or take up more cholesterol
85
Ezetimibe
Inhibits Niemann-Pick C1-Like 1 protein.
This protein normally helps absorption of cholesterol from intestine, and absorption of cholesterol from bile in the liver.
Ezetimibe is enterohepatically circulated.
86
Nicotinic acid
Inhibits liver triglyceride production and VLDL secretion, increases levels of t-PA. 'Turn on TV'
87
Fish oil
Contain eicosapentaenoic acid, which makes PGI3 (as effective an anti-thrombotic as PGI2), and TXA3 (much less effective than TXA2).
88
Angina
Caused by ischaemic heart disease, which is usually caused by atherosclerosis.
Initially patient only gets angina during exercise. Sympathetic stimulation predisposes to pain because:
(1) Increases HR, reducing proportion of time spent in diastole and thus time capable of being perfused, thus gets less O2.
(2) Increased inotropy, thus O2 demand.
(3) Decreased cardiac efficiency (more O2 used to perform same amount of work).
In 'normal' people, increase in O2 demand leads to dilatation of coronary arterioles and increased coronary blood flow. In those that get angina during exercise, resting O2 demand is met but only when coronary arteries are fully dilated already, due to atheroma blockage. No room for further dilation during exercise, and myocardium becomes ischaemic, causing angina.
Those with ischaemic heart disease develop collateral blood vessels over time. Hence sudden death due to occlusion of a coronary artery is more likely to be fatal
in a younger patient than in one who has had an extended period to adapt to the ischaemia.
Variant angina is when coronary arteries go into spasm, without the need for them to be blocked by plaques. This is more painful than classical type.
89
Nitrovasodilators
Glyceryl trinitrate, isosorbide mononitrate and amyl nitrite.
Glyceryl trinitrate poorly absorbed in the stomach so it's taken sublingually. Isosorbide dinitrate needs to be converted to isosorbide mononitrate to work.
They work by being converted by NO. activates soluble guanylyl cyclase, increasing formation of cGMP, which activates PKG, causing relaxation.
They produce VENOUS dilation, reducing preload, and hence work done by the heart. They also dilate collateral blood vessels.
Dipyridamole, a vasodilator, dilates ALL vessels, which will divert blood away from ischaemic areas, producing coronary steal.
Nitrovasodilators can precipitate migraine, since the 'vascular hypothesis' proposes that extracerebral vasodilation causes headache.
90
Ivabradine
Reduces If, slows HR, increasing diastolic perfusion time.
People with stable angina often have very high heart rates, so ivabradine is good for these people.
Ivabradine is selective for HCN channel in SAN, and has no effect anywhere else in the heart. Though unpopular, it has limited side effects.
91
Ranolazine
ischemia causes an increased late Na+ current (window current), which prolongs plateau + decreases NCX activity, increases intracellular Ca2+.
This impairs relaxation of cardiac myocytes (a.k.a decreased diastolic function), and this increases ventricular diastolic wall stiffness and end-diastolic pressure.
This exacerbates ischaemia on both limbs of the supply-demand mismatch (decreases pressure gradient in coronary arteries for diastolic flow + increased preload).
Ranolazine inhibits window current.
92
Nicorandil
Ischaemic reperfusion injury is due to opening of the MPTP. Opened during high mitochondrial [Ca2+], oxidative stress, ATP depletion and mitochondrial depolarisation.
Opening causes uncoupling of the respiratory chain, accumulation of SUCCINATE, generation of ROS, mitochondrial dysfunction, apoptosis.
Ischameic preconditioning: Several short periods of ischaemia increase the ability of the heart to withstand longer periods of ischaemia. Mechanism mentioned in adenosine section. Nicorandil also opens mitK(ATP), and is also a NO donor.
93
Percutaneous coronary intervention
PCI initially done by angioplasty/balloon dilatation. But restenosis happened in 30-50% of patients. Mechanism:
(1) Elastic recoil of the vessel and shrinkage of the vessel wall (negative remodelling).
(2) Development of scar tissue that encroached into the lumen (neointimal proliferation).
PCI was then done by stents. Negative remodelling prevented, by caused MORE neointimal proliferation.
Drug-eluting stents prevent neointimal proliferation. They contain drugs like sirolimus and paclitaxel.
94
Drugs
```
Hypertension:
ACEI/ARBS/anti-aminopeptidase A
Diuretics
Beta blockers
Ca2+ channel blockers
K+ openers
alpha-1 antagonist
alpha-2 agonist/imidazole-1 agonist
Organic nitrates/Nitroprusside (but turns into thiocyanate!)/Hydralazine (vasodilator)
ANS system blockers - Ganglionic blockers earliest hypertensive but not used due to lack of selectivity between symp and parasymp ganglia, Reserpine, Guanethidine/bretylium, Tyramine with MAO cause hypertension,
```
Angina: Target Afterload, Preload, HR (diastolic filling of heart)
Organic nitrates
Beta blockers (prevent remodelling of the heart to stop them from going into heart failure) - High up in priority
ACE inhibitors/ARBs - ANG II also remodel the heart and change receptor profile like sympathetic stimulation.
All the other anti-hypertensive to reduce afterload (NOT to dilate coronary vessels as they're fully dilated already)
Ranolazine
Ivabradine
Nicorandil/Adenosine
Prevent consequences of angina: Anti-coagulatory drugs to prevent rupture of the plaque - anti-platelets + anti-clotting. Not too much.
Cholesterol-lowering drugs as well. Not too much.
Diabetic control...
Heart failure (see above)
95
ApoA1-Milano
ApoA1 Milano is a variant of ApoA1 identified in individuals in Italy with very low levels of HDL but almost no cardiovascular disease. Infusion of recombinant ApoA-I Milano– phospholipid complexes causes rapid regression of atherosclerosis in animal models.
