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BMS 109 > CDL2 > Flashcards

CDL2 Flashcards

1
Q

What causes vessel dilation/constriction? Effect?

A

Vasoconstriction: narrowing lumen by contracting the smooth muscle- reducing blood supply and increasing BP.
Vasodilation: widening lumen by relaxation of smooth muscle cells- increase blood supply to tissue, increase O2 to.

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2
Q

use of Vasoconstriction/dilation?

A

to target blood to certain places depending on physiology.

e. g. Exercise/fright- periphery skin vasoconstriction so blood gets to heart and lungs and skeletal muscle, but less to GI tract.
e. g. digestion- more to GI tract
e. g. Thermoregulation- dilate in skin if want to lose heat

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3
Q

which blood vessels regulate blood pressure?

A

Smaller muscular Arteries and arterioles

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4
Q

What are arterioles/venules?

A

Smaller blood vessels that regulate the blood supply to capillaries. Capillaries cqan vastly increase the surface area of blood vessels.

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5
Q

Structure of lumen of arteries?

A

Out in
‘Adventitia’ collagen,, elastin matrix that gives strength and structure.
External elastic layer
‘Tunica media’
Smooth muscle- determines lumen diameter contraction/relaxation
Internal elastin layer- recoil- pulsatile flow
Intima:
Enodthelial layer- cells that contact the blood.

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6
Q

Smooth muscle contraction is controlled by? (vague)

A

(controlled by circulating hormones, Sympathetic nerves or local mediators from endothelium)

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7
Q

How do veins structure vary internally?

A

The big ones have valves

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8
Q

Relationship between the endothelial cells and smooth muscle cells?

A

Close proximity. Endothelial cells are in contact with the blood and circulating cells and hormones. This can be converted into chemicals that the SMC’s can respond to (e.g. NO). Also they have gap junctions between them so Ca can release syncronisedly through the SMCs. Coordinated.

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9
Q

Healthy endothelial cells secrete..

A

Glycocaylx- carbohydrate. Stops circulating blood cells interacting with endothelial cells via adhesion molecules e.g. WBCs and platelets (anticoagulant)

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10
Q

When endothelial cells are activated they shed/ damaged..?

A

Glycocaylx so adhesion molecules (ICAM1, VCAM1) can bind to glycans on leukocytes, monocytes can roll and interact and infiltrate into the blood vessel.
ATHEROSCLEROSIS

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11
Q

What can cause activation of endothelial cells?

A

disturbed blood flow (turbulant)
Injury, infection, inflammation,
Ox-LDL in blood

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12
Q

Molecules in blood for in healthy endothelial cells?

A

High linear blood flow- Increase Ca
ACh, histamine, seratonin, bradykinins to IP3 receptors (vasodilators)- increase Ca
Increase Ca activates eNOS (endothelial nitric oxide synthase).
eNOS converts arginine to Nitric Oxide, which is gas membrane permeable so can act on SMC’s

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13
Q

Healthy endothelial cells impact on SMCs?

A
  1. NO (from endothelial) acts on Guanylyl cyclase to increase cGMP levels. This reduces Ca levels, but also activates PKG which activates myosin phosphatase to inactive myosin =RELAXATION.
  2. Also Gs coupled: b-agonists, Adenosine, Prostaglandins to Gs coupled receptors- Increase CAMP- decrease in Ca levels.
3. K+ channels:
BK channels (large conductance),SK channels (small conductance) b-agonists (via bg G-protein) increase K efflux- hyperpolarisation- decrease in Ca levels.

DECREASE CA no contraction- dilated lumen

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14
Q

molecules in the blood that cause activated endothelial cell etc? What produced in the EC?

A

circulating Il-1, thrombin, endotoxin to receptors increase ET-1 (endothelin-1).
Above and disturbed blood flow also increases ROS, I/VCAM1 (adhesion molecules),IL-18, COX2.

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15
Q

Activated endothelial cells impact on SMCs?

A
  1. ET-1 acts upon ETA/B or Tp, NorA, Histamine act to GPCRs coupled to Gq. PLC- IP3- Ca out of SR.
  2. TRP store operated Ca channels or votlage sensitive- Ca in.

Ca binds to Calmodulin- activates MLCK which phosphorylates inactive myosin into active
CONTRACTION.

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16
Q

Active vs inactive myosin?

A

Smooth muscle cells need to be phosphorylated to activate (unlike skeletal) by MLCK (myosin light chain kinase) and inactivated by Myosin phosphatase

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17
Q

How is Ca normally kept low in smooth muscle cells?

A

Normally in nm concentrations- calcium is pumped out through Ca ATPases and sequestered in the SER/ER.

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18
Q

What enzymes hydrolyse CAMP and cGMP?

A

Phosphodiesterases hydrolyse cGMP or CAMP to breakdown

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19
Q

Nitric oxide is..

A

An endothelial derived relaxing factor.

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20
Q

Where is eNOS located?

A

in caveola where acetylations anchor it to the PM so NO production is near to VSMC’s.

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21
Q

eNOS imparied by?

A

smoking reduces NO bioavailability by interferring with eNOS acetylation.
High sugar diet- hyperglycaemia- reduction in eNOS phosphorylation
HIgh LDL- oxLDL can displace eNOS in calveolar- hypertension

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22
Q

Prostanoids are produced how?

A

in endothelium after Ca or ROS increase.

Ca and ROS activates COX 1/2, which converts arachidonic acid to prostaglandin H2 (or others depending on enzyme)

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23
Q

In smooth muscle cells which prostanoids do what?

A

Prostanoids produced in EC to act on SMCs. PG H2 made then depending on enzymes different from.

PGI2 to IP- Gs-AC-CAMP- RELAX

Thromboxane A2-Thromboxane (TP) R- PLC, IP3-Ca CONTRACTION

PGE2 to EP.R(1-4) depends on cellular levels of Gs or Gi as Gi inhibits AC so inhibits CAMP so causes CONTRACTION, whereas Gs activates AC, increasing CAMP so RELAX.

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24
Q

Endothelin precursor?

A

ET-1 precursor is big endothelin (upregulated by pathogenic/ inflammatory signals)

ECE/Endothelin converting enzyme cleaves big endothelin to endothelin (ET-1)

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25
Q

Big endothelin upregulated production by what factors?

A

IL-1, Thrombin, Glucose, OxLDL, Insulin, Angiotensin II, Cortisol, Adrenaline, Hypoxia

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26
Q

Endothelin feedback loop?

A

Negative feedback mechanism: ET-1 acts back on EC via ETB receptors to block ECE activity, and to increase NO as shown, to oppose contraction of VSCMs. Endothelium only expresses ETB receptors (not A). This is of interest therapeutically as we may wish to specifically block ETA receptors and not ETB receptors to preferentially downregulate production of ET-1 and block / oppose its effects by maintaining the ETB negative feedback loop.

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27
Q

Angiotensin II on EC/SMCs?

A

ACE in pulmonary and renal endo converts I to II- which acts on AT-1 receptors on SMCs- IP3 increase Ca- CONTRACT.
MAPK activation- long term increase in contractility

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28
Q

4 main factors that impact contraction/relaxation of SMCs?

A
  1. Angiotensin II- CONTRACTS
  2. Prostanoids: PGI2-RELAX, TXA2- CONTRACT, PGE2 either.
  3. Endothelins- CONTRACTS (but neg feedback to relax)7
  4. NO- activated GC- RELAXATION
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29
Q

How does ageing and disease cause hypertension?

A 
Atherosclerosis
Damage to glycocalyx
Calcification
Loss of elastin
↓ NO (diet, smoking, hypoxia)
INCREASE BP
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30
Q

Atherosclerosis impact on SM/ECs?

A

Loss of coupling between ECs and SMCs.

Activates ECs further- constrcition- narrow- hypertension.

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31
Q

Pneumonia risk of HA?

A

Recruits more WBC’s to endothelial walls- increase rupture chance- Thrombus- MI risk

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32
Q

Ageing impact on vessels contraction etc?

A

Loss of elastin stretch/ compliance of vessels.

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33
Q

Infection impact on VSMC contraction?

A

Pathogens and inflammatory / immune response, activates endothelium, recruiting leukocytes to artery wall, weakens atherosclerotic plaque (↑ vulnerable to rupture).
These stimuli generally activate pathways → VSCM contraction

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34
Q

Raynauds syndrome is? treatment?

A

Inappropriate vasoconstriction of smaller arteries/arterioles, over activation of sympathetic NS
White then blue then fingers when get cold and v red when warm again.
Gangrene/ ulceration risk
VASODILATION DRUGS

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35
Q

Hypertension epidemiology?

A

High BP. 30% of people have got, and these have increased risk of HA or stroke.

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36
Q

Symptoms of hypertension?

A

breathlessness, fatigue, fluid retention oedema. O2 not sufficient to meet metabolic demands

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37
Q

Hypertension can be secondary to?

A

athersclerosis. Lose ability for EC to communicate with SMCs so NO not relaxing SMCs. And glycocaylx broken down, age loss of elasticity, loss of vasodilation

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38
Q

Diseases that the vasculature is targetted as treatment? (4)

A
  1. Heart failure- not enough CO to meet demands (seocndary to Atherosclerosis or HA)- VASODILATE.
  2. Angina- o2 to heart insufficent with exercise, chest pain. Coronary artery disease
  3. Pulmonary hypertension- poor gaseous exchange due to narrowing of pulmonary arteries.
  4. Raynauds syndrome
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39
Q

Pulomary hypertension epidemiology?

A

1-3 years life without treatment, 5-6 with treatment. increased pressure on R side of heart (increased afterload) , R heart failure.

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40
Q

Summary of healthy vs activated endothelium factors acting on SMCs

A

Healthy: NO- relaxation (decrease in Ca and K channels)
Activated: ET-1- constriction (Increase in Ca via secondary messangers and calcium channels)

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41
Q

6 categories of therapies for vasodilation?

A
  1. Nitric oxide donors
  2. Prostanoids
  3. Endothelin inhibitors
  4. Angiotensin II and ACE
  5. PDE inhibitors
  6. Others
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42
Q

Nitric oxide donors use? action?

A

Nitroglycerine- for angina, increase blood flow to ischaemic heart (converted to NO)

Sodium nitroprusside- IV at A&E for emergency hypertension- breaks down to NO by binding to oxyhaemoglobin.

Inhaled NO for severe pulmonary hypertension

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43
Q

Prostanoid manipulation as therapy? use? action?

A

Corticosteroids- supress prostanoids production- prevent shock Hypotension.

illoprost- PGI2 stable analogue mimics, relaxation for Reynauds and pulmonary hypertension (and general)

Epoprostenol- IP R agonist (same above)

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44
Q

Endothelin inhibitors as therapy? use? action?

A
  • ETA/B inhibition with Bosenton for pulmonary hypertension, phase 3 trials for ischaemic optic neuropathy from glaucoma.

ECE inhibitor-as experimental tool (Phosphoramidon)

REDUCE CONTRACTION

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45
Q

Angiotensin II and ACE for hypertension therapy?

A

ACE inhibitors

  • captopril- blocks active site (side effects; hypotension, cough, proteinuria, change in taste)
  • Enalapril-longer lasting as reviews convertion into the active form.

AT1 antagonists (reduce IP3 therefore contraction)- sartans inhibit production of Angiotensins as well.

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46
Q

Phosphodiesterase inhibitors use?

A

Sildenafil (viagra), stop breakdown of CAMP and CGMP (which cause relaxation)
Dont use with NO donor- hypotension.

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47
Q

number 6- other therapies for hypertension?

A
  1. NorA- many sympathetic NS activators- many side effects rarely used
  2. Ca channel blockers- Verapamil etc
  3. K channel activators- Nicorandil (also NO donor)
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48
Q

WHy treat asymptomatic hypertension?

A

Preventaable cause of premature death- but if drugs give side effects less compliance of patients, hence why important too match drugs with the patient depending on if elderly etc or young and active.

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49
Q

hypertension is a risk factor for which diseases?

A

Stroke- ischaemic, haemorrhogic (bleed in brain due to microaneurism.
MI
HF (Increases afterload) CO down- L Ventricle HF
Chronic renal disease (also causes secondary hypertension- Renin from JGA)
Cognitive decline- small vessel bursting gives ischaemia
Premature death
Atrial fibrillation(stoke risk itself also)

50
Q

Each ….mmHg rise in …… BP is assoicated with … increase in mortality from …. and … increase of …

A

Each 2mmHg rise in systolic BP increases mortality from ischaemic HD by 7% and 10% increase in stroke

51
Q

Why is it hard to test if a patient is hypertensive?

A

White coat hypertension- patients anxiety rises BP, so can offer ambulatory BP monitoring over longer period of time when at home etc inflating every 30mins.

52
Q

Clinical thresholds for hypertension?

A 
Stage 1 (Mild)- 140/90 in clinic (135/85 ambulatory) (150/90 if over 80yrs)
Stage 2- 160/100 (150/95)
Stage 3(severe)- systolic above 180 or diastolic above 110mmHg
53
Q

Two types of hypertension? Treatments differ? (not pulmonry)

A

Primary (essential) hypertension: no obvious cause- treatment 1. lifestyle modification if mild, 2. Anti-hypersive drug therapy.

Secondary hypertension: Due to another disease e.g. adrenaline secreting/steroid tumor, overactive thyroid, renal artery stenosis- treat this.

54
Q

What makes the doctor more likely to think the hypertension is secondary?

A

If the patient is younger- 40x more likely an underlying cause.

55
Q

Why could renal artery stenosis cause hypertension?

A

(stenosis= narrowing)
If kidney belives poor perfusion to it, it will secrete renin (Increase EXV and BP increase). For this ACE inhibitors stop hypertension.

56
Q

If under 80 and only stage 1 hypertension also need one of what, to recieve antihypertensive drugs?

A
  1. Target organ damage- LV hypertrophy (pump harder against increased afterload), burst capillaries in eye, proteuria.
  2. Establushed cardiovascular disease e.g. past stroke.
  3. Renal disease
  4. Diabetes- substatial increase risk of stroke HD etc
  5. A 10yr cardicascular risk of above 20% due to other factors.

Stage 2 immediate treatment.

57
Q

WHy is the BP threshold higher for above 80years for hypertension?

A

Because as age vessels get less compliant and stiffer so naturally higher

58
Q

Two other types of hypertension? (not primary and secondary)

A

Systemic and Pulmonary, depending on which arteries the narrowing is in

59
Q

3 targets for pharmacology for systemic hypertension?

A
  1. Cardiac output (rarely) and peripheral resistance (dilation)
  2. Balance between Renin Angiotensin II, Aldosterone system and sympathetic NS (norA)
  3. Local vascular vasoconstrictive/dilation mediators
60
Q

hypertension afro-carribbean patients personalisation?

A

Often have low renin levels so renin inhibitor of little use.

61
Q

Drug options for systemic hypertension? (8)

A
  1. ACE inhibitors (decrease EXCVol- BP down)
  2. ARB/Sartans (Angiotenin II receptor antagonists)
  3. Ca channel blocker (reduce constriction)
  4. Beta blockers- phased out- block b adrenergic R (adrenaline to sympathetic) Brings HR down
  5. Aldosterone antagonists. (salt retention EXCV up)
  6. Alpha blocker- causes vasoconstriction
  7. Renin inhibitors
  8. NorA recetor blockers
62
Q

ACE inhibitors examples and side effects?

A

Ramipril, enalapril etc,

side effects: diabetic nephropathy, hypotension, HF

63
Q

What are sartans? Use? Examples?

A

ARBs (Angiotenin II receptor blockers) hypertension

Condesartan, Valsartan, losartan

64
Q

Sartans side effects?

A

Risk:
Hypotension, especially in vol depleted patients e.g. HF if on diuretics already
Hyperkalaemia
Potential for renal dysfunction
Rash
Contraindicated in pregnancy (false indication)
but generally well tolerated.

65
Q

Problem with using ACE inhibitors and sartans together?

A

Angiotensin I accumulates as not converted to II. This starts to compete with the sartan (Angiotensin receptor), so not combined, but Sartans can be used with Ca blockers.

66
Q

Calcium channel blockers for?

A

arrhythmias, angina and hypertension.
Hypertension E.g. amlodipine, nifedipine, felodipine etc di-hypropyradine group of drugs.

Angina and anti-arrhythmia e.g. Verapamil, diltiazem.

67
Q

3 classes of calcium blockers?

A
  1. Dihydropyridines: nifedipine- 3 tablets a day (others only 1) peripheral arterioal vasodilators.
  2. Phenylalkylamines- e.g. verapamil
    Major impacts on heart so useful for angina and ischaemic heart disease. negative chronoropic and inotropic.
  3. Benzothiazepines e.g. diltiazem, effects- half way between impacts on vessels and heart.
68
Q

calcium channel blockers adverse effects?

A

Due to peripheral vasodilatation (mainly dihydropyridines)
Flushing
Headache
Oedema
Palpitations (reflex sinus tachycardia heart tries to maintain BP)

Due to negatively chronotropic effects (mainly verapamil/diltiazem)
Bradycardia- if too slow faint.
Atrioventricular block

Due to negatively inotropic effects (mainly verapamil)
Worsening of cardiac failure
Verapamil causes constipation

69
Q

adrenoreceptors different varieties impact on vessels?

A

alpha- constriction-sympathetic tone on peripheral vessels.
B2-inotropic dilators (bronchioles and arteries of skeletal muscle)
B1 inotropic both (heart)- NorA, adrenaline constrict but others may dilate

70
Q

Alpha blockers medicine for? How?

A

Hypertension.
e.g Doxazosin, indoramin Prazosin (short acting) etc
Noradrenaline in sympathetic NS to alpha receptors which cause vasoconstriction of peripheral vessels under sympathetic tone.

71
Q

Risk with alpha blockers?

A

Postural hypotension- stand up suddenly feel dizzy, natural BP decreases if sitting but normally increased when stand up as HR speeds up and peripheral vessels constrict to maintain BP but this cannot happen if cannot constrict perphery vessels.

72
Q

Alpha blockers also used for..?

A

Prostate disease- hypertrophy. with Alfuzosin and Tamsulosin.
There are alpha receptors here and these drugs relax prostate smooth muscle and help stop postanism (the pushing against bladder neck obstructing the outlet).

73
Q

Centrally acting drugs for systemic hypertension work how?

A

Block sympathetic drive out from the brainstem to the periphery.

74
Q

Centrally acting drugs for systemic hypertension examples? (3)

A
  1. Moxonidine
    - Imidazoline type 1 receptor agonist (natriuretic effect, vasodilation)
  2. Methyldopa- activates presynaptic alpha 2 receptors to decrease NorAdrenaline release (sympathetic) can be used with pregnant (also decreases dopamine)
  3. Clonidine- Alpha 2 receptor agonist to reduce norAdrenaline release.
75
Q

Word for sodium excretion?

A

Natriuresis (water follows so reduces EXCV therefore BP-)

76
Q

Renin inhibitors for hypertension action? example? side effects?

A

For example: Aliskiren,

Hyperkalaemia
Dizziness
Arthralgia- joint pain
Diarrhoea
Caution with other RAAS inhibitors
Concomitant use not recommended
77
Q

WHat are the NICE guidelines for hypertension treatment? (under 55)

A

Under 55:

  1. ACE inhibitor (or Angiotensin II blocker if not tolerated not together)
  2. Dual therapy ACE/ARB +CCB
    • Thiazide-like diuretic
  4. Resistant hypertension

(but personalisation depending on heart rate (beta blockers if high) etc

78
Q

WHat are the NICE guidelines for hypertension treatment? (over 55)

A

Or Afrocaribbean

  1. Calcium channel blocker e.g. Amlodipine
  2. Dual therapy ACE/ARB +CCB
    • Thiazide-like diuretic
  4. Resistant hypertension
79
Q

What is ischaemic heart disease? Chain of events?

A
  • Atherosclerosis blocks the coronary artery lumen, restricting Blood flow to tissues (here heart)
  • Oxygen demand of the myocardium exceeds supply (Ischaemia)This often presents in patients as chest pain.
  • Chest pain can be due to angina or myocardial infarction (heart attack).
  • Ischaemia can cause HF due to tissue death.
80
Q

What group of diseases kills the most people?

A

Disease of coronary arteries kills more people worldwide than any other disease

81
Q

Ischaemic heart disease epidemiology?

A

Leading cause of death in the world,

Decreasing due to decrease in smoking. (deaths halved in last 10 years)

82
Q

IHD Risk factors?

A

Non-modifiable: Age, male, family history of before 65.

Modifiable:Diabetes, high cholesterol, smoking, diet, obesity, kidney disease

83
Q

What is stable angina? Ischaemia?

A

Stable angina isnot to do with acute coronary syndrome ie in high stress situations appears, not ischamia which is unstable angina (Pre MI)

84
Q

NSTMI vs STEMI?

A

Non-ST elevation myocardial infarction (NSTMI) caused by a severly narrowed arterywhereas ST elevation MI happens after a complete block of a coronary artery ie when a plaque ruptures and thrombus blocks.

85
Q

IHD patietns ECGs?

A

Can be normal if dont have ischaemia currently, or not had an MI before.

86
Q

What is a stable atheroma?

A

One where the plaque does not contact the blood in the artery. e.g. there is a fibrous cap between stabilising the plaque, narrowing the artery but not risking thrombus formation and MI yet.

87
Q

Acute coronary syndrome?

A

Umbrella term for the risks that patients with IHD face.
These are unstable angina, NSTEMI and STEMI.
The syndrome only presents when the plaque ruptures.

88
Q

Epidemiology of Acute coronary syndrome?

A

rare in under 35s -0.6%.

NSTEMI ncreasing, 75% of ACS are NSTEMI or unstable angina, whereas STEMI only 5 in 1000 people a year in Uk

89
Q

Stable vs unstable angina?

A

Unstable is when get pain at rest (non predictable, whereas stable is only upon exercise when the hearts O2 demand increases.

90
Q

What is Angina?

A

Heavy or central crushing pain in chest upon exertion and relief with rest. But as it progresses, less and less exercise is needed for the agina pain (1-4).

91
Q

treatment of stable angina?

A

Reduce the cardiac work.
e.g. Nitrates (vasodilation) Ca anatgonists etc. Treat underlying condition (statin) and drugs to prevent MI e.g. anti platelet drug aspirin.

92
Q

Treatment for unstable angina?

A
  • Prevent MI= DAPT (dual anti-platelet therapy- aspirin + another)
  • Nitrates
93
Q

How can test for MI be done in clinic?

A

Detection of troponin in blood 12h after MI. Troponins are cardiac muscle specific and are needed to diagnose an MI – they indicate myocyte death.
ECG- NSTEMI or STEMI not normal.

Angina has neither of these, unless got angina at that specific time may have ECG changes.

94
Q

Broad aims of treatment for ischaemia?

A 
Broad aims of treatments are:
Reopen blocked arteries (Cardiologist)
Reduce the coagulability of blood
Control risk factors
Reduce myocardial oxygen demand
95
Q

IHD: Intervention after MI?

A

Non surgical PCI (percutaneous coronary intervention: Catheter into the heart vessels to dilate them from within. A drug coated metal stent is inserted (e.g. drugs that inhibit cell proliferation taxol or rapamycin). Balloon inflated inside the stent to open it up and then balloon removed. Nitrates added to increase flow.

STEMI door to balloon in 2hours to prevent heart failure.

96
Q

Stent risk?

A

Thrombosis- 1% so need to reduce blood coagubility.
E.g. Aspirin+ for 1 year+ (DAPT dual anti platelet therapy- aspirin + another drug).
or
Anticlotting e.g. PLAVIX (clopidogrel) or ticagrelor.

But excess bleeding now risk, but Pleiotropic postive effects.

97
Q

What is the main aim of pharmacological treatments of ischaemic heart disease?

A

“To keep the coronary plaques as stable as possible to avoid an acute clot blockage (occlusion) which can be partial or full”

+ REDUCE PAIN

98
Q

Pharmacological treatments are either to reduce … or improve…..

A 
reduce symptoms (ie pain) 
or improve prognosis (long term outcomes ie death)
99
Q

Symptomatics as treatment for IHD?

A

Symptomatics – reduce strain on the heart and increase vasodilation of arteries and veins

Nitrates e.g. nitroglycerin (short acting) and isosorbide mononitrate (long acting) Vasodilation 
Aspirin and antiplatelet drugs 
Ca channel blockers e.g. amlodipine
K channel activators  e.g. Nicorandil 
Analgesia e.g. morphine
100
Q

Prognostics as treatment for IHD?

A

Prognostics – alleviate future negative outcomes

Aspirin, Statins/PCSK9 inhibitors, beta blockers or an ACE inhibitor. Anti-inflammation approaches are being developed.

101
Q

IHD first line agent for?

A

NItrates- Nitroglycerin (GTN) as a short acting spray given sublingually ( effective in 1-2mins fro 30mins)

102
Q

How do nitrates for IHD work?

A

Primary mechanism to relax smooth muscle (all) and also veins. Main effect is on the larger muscular arteries – coronary vasodilation, increases coronary flow.

Secondary effects: reduces cardiac work(by reducing afterload), redirection of flow towards ischaemic areas of heart muscle through collateral vessels, improves coronary artery spasm.

Mechanism of action: GTN/nitroglycerin metabolism releases NO (nitric oxide), a free radical gas
NO activates soluble guanylyl cyclase and increases cGMP which activates protein Kinase G leading to relaxation effects in smooth muscle.

103
Q

Which scientist suggested what drug for IHD? why?

A

Brunton- saw that blood loss relieved angina- BV down, BP down, so more can divert to the heart.

104
Q

Adverse effects of nitrates for IHD?

A

Adverse effects – possible hypotension so administer sitting down. Headaches
Tolerance can occur, possibly because of depletion of –SH groups and is more common with longer acting agents.

105
Q

Problem with short acting nitrates?

A

nitroglycerin is inactivated by hepatic metabolism and only lasts 30minutes.

Isosorbide Mononitrate (longer acting) –can be orally administered 2x day with a nitrate free period at night to avoid tolerance

106
Q

Ca channel blockers for IHD?

A

Nitrates don’t help mortality but these disrupt Ca movement through heart tissue, non selectively blocking SM contraction (L type Ca channels)
e.g. Verapamil- phenylalkamines (more active in heart), dihydropyradines (more efficient in smooth muscle in vessels) etc

107
Q

Ca channel blockers side effects?

A

Few: flushing, headache (vaodilation in head), half life varies and personalised dose.

108
Q

Aspirin mechanism of action?

A

NSAID. Acetylsalicyclic acid
It irreversibly acetylates COX-1 in platelets, inactivating the enzyme until new platelets are made.
COX-1 converts arachadonic to thromboxane A2 (which causes platelet aggregation)

109
Q

Aspirin use?

A

Treat pain, inflammation or fever. But also decreases risk of HA by anti-platelets. Given immediately on presentation of heart symptoms e.g. angina IHD.

110
Q

How long does aspirin action last?

A

Irreversibly acetylates COX-1 so lasts as long as platelets regenerate, which is 10 days. New platelets are made from the bone marrow. PLatelets have no nucleus so cannot synthesise more COX-1

111
Q

Aspirin side effects?

A

GI bleeding and ulcers. Interaction with warfarin very serious so it increases warfarin comcentration and has separate effects on platelets as well.
deafness/tinnitus (with larger doses/overdoses)
Risk of self poisoning
Resistance to aspirin is known but there are no genetic tests available.

112
Q

metabolism of aspirin after taking?

A

Taken orally, weak acid so protonated (proton transferred to) in the stomach, then able to cross ilium to be absorbed.
Esterases in the liver (75%) and plasma hydrolyse aspririn to salicylate.

113
Q

Issue with Anitcoagulants/antiplatelet drugs? Overcome?

A

Stop clotting if bleed, say if going into surgery anti-dotes can be given to reverse the drugs.
e.g. Protamine sulphate for heparin. Binds to heparin

114
Q

Heparins are? Work how?

A

Anticoagulant, activate anti-thrombin IIa which inactivates thrombin and factor Xa.
Prevents formation of a stable clot.

Heparins are glycosaminoglycans found in mast and basophils preventing thrombus formational naturally.

115
Q

Opiates work how?

A

Morphine: Blocks Mu opiod receptors used in ACS. receptors (Gi/G0 coupled to ion channels) in the brain as a partial agonist

116
Q

Opiates side effects?

A

Side effects: respiratory depression, nausea and vomiting (40%)- affects the postrema in the medulla.

reduced tone and motility in the gut, histamine release, tolerance
anti-emetic (anti-vomiting drug)e.g. metclopramide IV

117
Q

Summary of treatments for unstable angina?

A

DAPT - aspirin plus clopidogrel or ticagrelor
Heparin (usually)
Analgesics
Secondary prevention : statin, ACE inhibitor or beta blocker
Once stabilised, then elective (planned) PCI e.g. stent

118
Q

Summary of treatments for NSTEMI?

A

Antiplatelet and anti-thrombotic therapy (DAPT - aspirin plus clopidogrel or ticagrelor)
Heparin (usually)
Possibly an additional platelet inhibitor if ECG changes are rapidly changing
Analgesics
PCI within 72 hours to determine lesion severity and suitability for stenting or bypass surgery.

119
Q

Summary of treatments for STEMI?

A

Primary PCI first at a local heart attack centre
If the above centre is too far then a clot buster drug is used intravenously.
Antiplatelet medications – aspirin and ticagrelor for example
Lifelong medications after STEMI are: aspirin 75mg/day, antiplatelet agent for 1 year, statins, ACE inhibitors and beta blockers to aid myocardial recovery.

120
Q

Mortality if get to hospital with STEMI is… compared to … if don’t

A

4.4%, compared to 30%.

121
Q

Personalisation for STEMI?

A

Platelet based or physiology based, maybe inflammation in the future
- use a bedside device at the time of PCI after STEMI to measure individual platelet reactivity and assigned the anti-platelet medication on the basis of this.

Individualised maps of a patient’s coronary arteries help decide which of the lesions within an artery needs attention. Can put stents in on computer to estimate effect.
-CANTOS study 2017- which has proved that inhibition of inflammation prevents repeat heart attacks and reduces all cause mortality.

BMS 109 (20 decks)

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