cardiovascular renal and pns pharma

Question 1

What is the PNS composed of?

Answer 1

Cranial nerves
Spinal nerves

Question 2

What is afferent part of PNS?

Answer 2

Pathway that passes signals from tissues back to CNS via sensory neurons

Question 3

What are the two types of afferent?

Answer 3

Somatic afferents (body walls)
Visceral afferent (organs)

Question 4

What is the efferent pathway of PNS?

Answer 4

Signals from CNS to tissues:
- Somatic motor (voluntary)
- Autonomic (involuntary)

Question 5

3 sub-parts of autonomic (involuntary) nervous system?

Answer 5

1. Enteric
2. Sympathetic (fight or flight)
3. Parasympathetic (rest and digest)

Question 6

4 functions of autonomic nervous system?

Answer 6

1. Contraction and relaxation of smooth muscle in blood vessels and organs
2. Regulation of glandular secretion (mostly exocrine)
3. Heart rate control
4. Metabolism

Question 7

What is the enteric nervous system and how does it link to the sympathetic and parasympathetic nervous systems?

Answer 7

A system that controls the gut independently of CNS through cell bodies in the wall of the GI tract, with input from sym and parasym systems to innervate blood vessels, smooth muscle and glands:

• Sympathetic sends inhibitory signals to stop non-essential gut activity and sends blood elsewhere in perceived danger
• Parasympathetic sends excitatory signals to stimulate digestion — vagal fibres work with enteric neurons to ensure digestion is smooth

Question 8

Where are nicotinic receptors located?

Answer 8

Post-gangliac neurons

Question 9

Although sympathetic and parasympathetic stimulation often has opposing actions on the same systems, what systems are only stimulated by one?

Answer 9

Sympathetic only – sweat glands, blood vessels

Parasympathetic only – ciliary muscle of eye

Question 10

What do the sympathetic and parasympathetic systems look like?

Answer 10

Two-neuron systems (usually) pre- and post- ganglionic
— sympathetic has longer post-ganglionic
— parasympathetic has longer pre-ganglionic

Question 11

How are pre- and post- ganglionic neurons different?

Answer 11

Pre:
- cell body in CNS, small diameter, myelinated, synapse at autonomic ganglia, releases ACh which acts on nicotinic receptors on post-synaptic neuron

Post:
- cell body in eutonomic ganglion, small diameter, unmyelinated, synapse close to target organ

Question 12

What is an exception to the two neuron system?

Answer 12

Adrenal medulla — specialised ganglion with chromaffin cells as specialised post-synaptic neurons

Question 13

What is an autonomic ganglion?

Answer 13

Interface between pre- and post-ganglionic neurons
ACh is primary transmitter and most actions are excitatory (via ganglion-type nicotinic ACh receptors)

Question 14

How do pre and post ganglionic neurons link?

Answer 14

Pre produces ACh which excites post (usually many pre feeding into one ganglia)

Question 15

What are nicotinic receptors?

Answer 15

Ligand gated ion channels that generate a fast excitatory post synaptic potential

Question 16

How do nicotinic receptors generate action potentials?

Answer 16

ACh binds to alpha3 and beta subunits = Na+ entry = action potential generation in post-ganglionic cell once threshold is reached

Question 17

What does nicotinic receptor stimulation cause peripherally (3)?

Answer 17

1. Stimulation of skeletal muscle
2. Stimulation of autonomic ganglia (sym and parasym)
3. Secretion of adrenaline from adrenal medulla (modified sympathetic ganglia)

Question 18

What do automatic ganglia stimulants do?

Answer 18

Stimulate nicotinic receptors to activate peripheral ganglionic receptors = tachycardia, increased BP, increased secretions

Question 19

Examples of autonomic ganglia stimulants?

Answer 19

Nicotine, DMPP, ACh

Question 20

3 mechanisms of ganglion blocking drugs?

Answer 20

1. Interference of ACh release
2. Prolonged depolarisation of postsynaptic neuron
3. Intereference with post-synaptic action of ACh

Question 21

How is the postsynaptic action of acetylcholine in ganglion interferred with?

Answer 21

Through blockade of ganglionic nicotinic receptors:

• Trimetephan is a nicotinic antagonist that acts as a ganglionic blocker — emergency lowering of blood pressure and induction of hypotension
• Hexamethonium

Question 22

Effects of ganglion blocking drugs?

Answer 22

• Lowered BP due to inhibition of sympathetic tone (vasodilation)
• Postural hypotension, loss of sympathetic vasoconstrictor activity upon standing
• Tachycardia
• Reduced secretions
• Pupil dilation
• Sexual dysfunction

Question 23

What do most postsynaptic sympathetic fibres release?
— exceptions?

Answer 23

Noradrenaline
—- sweat glands (ACh), renal vessels (dopamine)

Question 24

What do postsynaptic parasympathetic fibres release?

Answer 24

ACh that acts on muscarinic receptors

Question 25

Difference between heterotropic and homotropic inhibition?

Answer 25

Heterotropic = SNS releases NA to inhibit ParaNS, ParaNS releases ACh to inhibit SNS Homotropic = they inhibit themselves

Question 26

What other substances act in pre and post synaptic modulation?

Answer 26

1. Tissue and plasma derived substances e.g. prostaglandins, histamine, adenosine, bradykinin 2. Co-transmitters = neurotransmitters releases from same neurons as ACh/NA

Question 27

Why is it not just ACh and NA involved in pre and post synaptic modulation?

Answer 27

Fine tuning of autonomic activity, different onset/duration of action, different ration of transmitters depending on stimuli

Question 28

What can co-transmission of molecules do?

Answer 28

ATP causes fast contraction, NA causes slow SO combined causes fast onset prolonged contraction

Question 29

3 examples of co-transmission between parasympathetic and sympathetic NS?

Answer 29

1. Rapid response = ACh and ATP 2. Intermediate = NO and NA 3. Slow = VIP and NPY

Question 30

What do most postsynaptic fibres release?

Answer 30

Noradrenaline

Question 31

What do post-ganglionic neurons end in?

Answer 31

Varicosities at the end of the axon which synthesis, store and release noradrenaline

Question 32

How is noradrenaline synthesised?

Answer 32

Multi-enzyme pathways starting with precursor molecule L-tyrosine ---- initial synthesis occurs in cytoplasm and ends on membrane of synaptic vesicle --- enzymes for this are made in cell body and transported to the nerve terminus

Question 33

3 steps of noradrenaline synthesis?

Answer 33

1. Tyrosine --> DOPA (uses tyrosine hudroxylase, occurs in cytosol of catecholamine containing cells) 2. DOPA --> dopamine (uses DOPA decarboxylase, cytosolic) 3. Dopamine --> noradrenaline (uses dopamine beta-hydroxylase, on membrane of synaptic vesicles) 4. ONLY IN ADRENAL CELLS Noradrenaline --> adrenaline (in chromaffin cells)

Question 34

What is the negative feedback inhibition in noradrenaline synthesis?

Answer 34

Noradrenaline inhibits DOPA formation

Question 35

- Clinical use of tyrosine hydroxylase inhibitors? - Side effects of tyrosine hydroxylase? - What inhibits it?

Answer 35

- Catecholamine-secreting tumours - Headaches, sweating, tachycardia, high BP, pale face, nausea, anxiety - alpha-methyl-p-tyrosine (metirosine)

Question 36

- Clinical use of DOPA decarboxylase inhibitors? - What inhibits it?

Answer 36

- In Parkinson's disease t prevent peripheral effects of levodopa (high BP and tachycardia) - Carbidopa, methyldopa

Question 37

What does parkinson's do?

Answer 37

Reduce dopamine neurons in ganglia --- as dopamine cannot cross the blood-brain-barrier the treatment is carbidopa to stop levodopa being converted to dopamine anywhere but the brain

Question 38

What inhibits dopamine beta-hydroxylase?

Answer 38

Nepicastat

Question 39

What is methyldopa?

Answer 39

A medication used to lower high blood pressure ---- works to inhibit noradrenaline release --- false precursor molecule that is metabolised to methyl-NA --- peripheral and central effects on blood pressure and inhibits DOPA decarboxylase

Question 40

What is the first part of the termination of noradrenergic transmission?

Answer 40

NA removed from synaptic cleft by neuronal epinephrine transporter (NET) -- located on presynaptic nerve terminals and actively transports NA back into nerve varcosities

Question 41

What happens to NA when it is back in the neuron?

Answer 41

Taken up by vesicular monamine transporter (VMAT), packed into vesicles with ATP (co-transmitter and prevents leak due to opposite charge)

Question 42

When noradrenergic transmission is being terminated, what happens to NA in postsynaptic cell?

Answer 42

Taken up by extraneuronal monoamine (EMT) transporter into the cell and then metabolised by catechol o-methyl transferase (COMT)

Question 43

How is noradrenergic release regulated?

Answer 43

Depolarisation of nerve ending opens calcium channels = vesicle exocytosis = NA release = activation of presynaptic receptors that inhibit adenylyl cyclase = prevention of calcium channel opening and further NA release

Question 44

How does guanethidine inhibit the release of noradrenaline?

Answer 44

- Is a substrate for NET and VMAT - Accumulates in vesicles, stabilises vesicles, displaces NA slowly, blocks adrenergic neurons

Question 45

How does reserpine cause depletion of NA?

Answer 45

Inhibits VMAT so NA cannot enter vesicles -- causes NA metabolism by MAO = lower vesicle levels Used as an antihypertensive

Question 46

Side effects of inhibiting NA synthesis/release?

Answer 46

Anti-sympathetic effects = hypotension, bradycardia, digestive disorders, nasal congestion, sexual dysfunction Central effects = sedation, mood changes

Question 47

2 ways NA is metabolised?

Answer 47

1. Monoamine oxidase (MAO) ---- in neurones, liver, GI tract ---- NA ---> DOMA 2. Catechol-o-methyl transferase (COMT) --- in neuronal and non-neuronal tissue --- also metabolised DOMA

Question 48

What does liver COMT also metabolise?

Answer 48

Catecholamines

Question 49

How do receptor subtypes mediate different responses?

Answer 49

By coupling to different second messenger systems

Question 50

- What are alpha 1 adrenoreceptors always coupled with? - Main effects?

Answer 50

- Gq/11 proteins - Positive effect, activates gq/11 = inositol triphosphate formation = calcium release = contraction in smooth muscle

Question 51

- What protein are alpha 2 adrenoreceptors always coupled with? - Main effects?

Answer 51

- Gi proteins - Negative effect, activates gi proteins = reduced adenylyl cyclase = reduce cAMP = no contraction (reduces same system that beta adrenoceptors increase)

Question 52

- What proteins are beta adrenoreceptors always coupled with? - Main effects?

Answer 52

- Gs proteins - Positive effect, activates gs, increase andenylyl cyclase = increased cAMP = kinase activation = protein phosphorylation = contraction

Question 53

Role of alpha 1 adrenoreceptor?

Answer 53

Constricts smooth muscle (except GI tract where it relaxes)

Question 54

Role of alpha 2 adrenoreceptor?

Answer 54

Presynaptic inhibition of neurotransmitter release in sym and parasym neurones

Question 55

Role of beta 1 adrenoreceptor?

Answer 55

Increases heart rate and force of constriction (contractility)

Question 56

Role of beta 2 adrenoreceptor?

Answer 56

Dilates/relaxes smooth muscle and increase NA release from sympathetic nerves, releases renin to increase sodium and water retention

Question 57

Role of beta 3 adrenoreceptor?

Answer 57

Thermogenesis

Question 58

What does it mean that adrenoreceptors are relatively unselective?

Answer 58

Have similar affinity for adrenaline and noradrenaline

Question 59

How does adrenaline and noradrenaline affinity vary at different adrenoreceptors?

Answer 59

Adrenaline more potent at beta and alpha 2 Noradrenaline more potent and alpha and beta 1

Question 60

What are agonists of sympathetic alpha and beta adrenoceptors called?

Answer 60

Sympathetic agonists, adrenergic agonists, sympathomimetic agonists Can act directly or indirectly

Question 61

Difference between agonists and antagonists?

Answer 61

Agonists enhance cellular activity upon binding, antagonists block it

Question 62

What do indirect acting sympathomimetic agonists do?

Answer 62

Do not activate receptors but they stimulate NA release

Question 63

Examples of direct acting agonists on catecholamine adrenoceptor?

Answer 63

1. Noradrenaline (non-selective but higher affinity for alpha, naturally occurring) 2. Adrenaline (non-selective but higher affinity for beta, natural) 3. Dopamine (little acitivity at adrenoceptors) 4. Isoprenaline (synthetic, beta selective)

Question 64

What is a selective alpha1 agonist?

Answer 64

Phenylephrine ---- used as a decongestant, dilates pupils, increases BP and relieves hemorrhoids

Question 65

What is a selective alpha2 agonist?

Answer 65

Clonidine ---- prevents noradrenaline release = reduced BP (lowers hypertension) ---- can be used for ADHD, anxiety, tic disorders, withdrawal, migraine, menopausal flushing

Question 66

What can adrenaline be used for?

Answer 66

Used in cardiac arrest and anaphylactic shock

Question 67

What can beta1 agonists increase?

Answer 67

Cardiac contractility Dobutamine is used to treat cardiogenic shock and severe heart failure

Question 68

Example of beta2 agonist and what it does?

Answer 68

Salbutamol relaxes bronchial smooth muscle (treats asthma)

Question 69

What beta2 agonist is abused in sport and food industry?

Answer 69

Clenbuterol -- increases lean protein mass and lipolusis as well as allowing for bronchodilation

Question 70

What may beta 3 agonists control?

Answer 70

Obesity as beta 3 adrenoceptors are found in adipose tissue Mirabegron is used to treat overactive bladder syndrome

Question 71

4 examples of indirectly acting sympathomimetics?

Answer 71

1. Substrates for VMAT and NET = rapid increase in cytosolic NA, increase NA in synapse 2. Amphetamine = reverses NET and VMAT transport, narcolepsy, obesity, ADHD treatments 3. Ephedrine, pseudoephedrine = nasal decongestant 4. Cocaine = inhibits NET, increases NA in synapse but can cause hypertension

Question 72

What does amphetamine do?

Answer 72

It is an indirect acting sympathetic agonist - causes NA release from vesicles - CNS stimulant, appetite suppressant, drug of abuse - can cause hypertension, tachycardia and insomnia as well as addiction

Question 73

Example of alpha and beta adrenoceptor antagonists?

Answer 73

Alpha = prazosin Beta = propanolol

Question 74

What does alpha1 adrenoceptor blockade cause?

Answer 74

Hypotension (treat high BP)

Question 75

What does alpha 2 adrenoceptor cause?

Answer 75

Increases cardiac output and causes tachycardia - reflex due to hypotension and a2 blockade causes increased sympathetic output

Question 76

2 non-selective alpha adrenoceptor antagonists?

Answer 76

1. Phenoxybenzamine (long lasting, covalent binding also blocks other classes of receptor) 2. Phentolamine (more selective but short acting)

Question 77

2 mixed alpha and beta adrenoceptor antagonists used to treat hypertension?

Answer 77

Labetalol and carvedilol

Question 78

Which selective alpha1 antagonists cause vasodilation and a fall in arterial pressure?

Answer 78

Antihypertensive drugs like prazosin and doxazosin --- cause less tachycardia than non-selective but still cause postural hypotension

Question 79

What other effects do selective alpha1 antagonists have?

Answer 79

Relax bladder neck smooth muscle and prostate capsule (tamsulosin used to treat urinary retention associated with enlarged prostate)

Question 80

Example of selective alpha2 antagonist and role?

Answer 80

Yohimbine ---- vasodilator and stimulant effects (can treat male impotence, aphrodisiac, may increase fat burn when exercising) --- increases NA release

Question 81

Adverse effects of phenozybenzamine and phentolamine (non selective antagonists)?

Answer 81

Hypotension, flushing, tachycardia, nasal congestion, impotence

Question 82

Adverse effects of prazosin and tamulosin (and all -osin drugs)?

Answer 82

Failure of ejaculation

Question 83

Adverse effect of yohimbine?

Answer 83

Hypertension

Question 84

Use of labetalol and adverse effects?

Answer 84

Alpha/beta adrenoceptor antagonist used to treat hypertension in pregnancy - Broncho-constriction, postural hypotension

Question 85

Use of carvediol and adverse effects?

Answer 85

Alpha/beta adrenoceptor antagonist used to treat heart failure - bronchoconstriction, postural hypotension, renal failure

Question 86

What are beta-adrenoceptor antagonists (beta blockers) used for?

Answer 86

Hypertension, heart failure, heart attack and arrythmia treatment e.g. propanolol and atenolol

Question 87

What do beta 1 receptors do?

Answer 87

Increase heart rate and contractility

Question 88

Actions of beta antagonists?

Answer 88

Decrease heart rate, contractility, cardiac output and oxygen demand in heart muscle

Question 89

Difference between 1st , 2nd and 3rd generations of beta blockers?

Answer 89

1st = non-selective (propranolol) 2nd = beta1 selective (atenolol) 3rd= non-selective alpha1 and beta (labetalol, carvedilol)

Question 90

Clinical uses of beta blockers?

Answer 90

Hypertension, angina, cardiac dysrhythmias, glaucoma (timolol), hyperthyroid disease, anxiety, tremor, migraine

Question 91

Adverse effects of beta blockers?

Answer 91

Bronchoconstriction (b2 but can still occur with b1 selective) Cardiac failure (reduce sympathetic tone needed for cardiac output) Bradycardia Cold extremities, fatigue, depression, hypoglycaemia

Question 92

Way to remember if a drug is an alpha1 antagonist or beta?

Answer 92

Alpha = ends in -azocin Beta = ends in -olol

Question 93

Where do cholinergic neurones use ACh?

Answer 93

As a neurotransmitter in peripheral and central nervous system and ACh acts on both nicotinic (ion channels) and muscarinic (G protein coupled) receptors

Question 94

Where is ACh synthesised?

Answer 94

In presynaptic axon by choline acetyltransferase (ChAT)

Question 95

Where does ACh degradation occur?

Answer 95

In the synaptic cleft by acetylcholinesterase

Question 96

What does stimulation of muscarinic ACh receptors cause?

Answer 96

Bradycardia, bronchoconstriction, increase in GI motility, bladder constriction, fall in BP, salivation

Question 97

What does stimulation of nicotinic ACh receptors cause?

Answer 97

CNS stimulation, ganglionic stimulation, release of adrenaline, rise in BP

Question 98

What does ACh binding to muscarinic m1, m3 and m5 receptors cause?

Answer 98

Rise in phosphotidyl inositol = increased IP3 and DAG = excitation and Ca2+ increase causes muscle contraction

Question 99

What does ACh binding to muscarinic M2 and M4 receptors cause?

Answer 99

Reduced adenylyl cyclase = reduced cAMP = inhibition They open potassium channels which causes membrane hyperpolarisation which closes calcium channes to reduce the force and rate of contraction Gi coupled

Question 100

Where are M1 muscarinic receptors found?

Answer 100

Gastric and salivary glands

Question 101

Where are M5 muscarinic receptors found?

Answer 101

Periphery --- salivary glands, iris, ciliary muscle

Question 102

Where are M3 muscarinic receptors found?

Answer 102

Exocrine glands (salivary and gastric), smooth muscle (GI tract, eye, airways, bladder), blood vessels (endothelium)

Question 103

Where are M2 muscarinic receptors found?

Answer 103

Cardiac myocytes, presynaptic

Question 104

Where are M4 muscarinic receptors found?

Answer 104

CNS

Question 105

Parasympathetic effects (rest and digest)?

Answer 105

Increased pupillary sphincter constriction, tears, mucus secretion, salivation, bronchoconstriction, gastric secretion, GI motility, urination, erection Reduced HR and AVN conduction Muscarine poisoning will cause extreme symptoms Muscarinic antagonists will PREVENT these responses

Question 106

Types of drugs that have direct actions on muscarinic receptor?

Answer 106

1. Muscarinic agonists (parasympathomimetic) 2. Muscarinic antagonists (parasympatholytic)

Question 107

Type of drug that will indirectly affect the muscarinic receptor?

Answer 107

Inhibitors of ACh breakdown

Question 108

Main effects of muscarinic agonists?

Answer 108

Bradycardia, vasodilation, lowered BP, contraction of visceral smooth muscle, exocrine secretions, pupillary contraction

Question 109

5 agonists acting on muscarinic and/or nicotinic ACh receptors and what they can be used for?

Answer 109

1. ACh (m&n), cataracts 2. Methacholine (m&n), bronchial provocation test 3. Carbachol (m&n), glaucoma 4. Bethanechol (m), bladder hypotonia via M3 5. Pilocarpine (m), glaucoma

Question 110

What is pilocarpine used for?

Answer 110

It is selective for constrictor pupillae, sweat, salivary, lacrimal M receptors (minimally GI, smooth muscle and heart) --- used for glaucoma and dry mouth/eyes

Question 111

Main effects of muscarinic antagonists?

Answer 111

Inhibition of secretions, tachycardia, pupillary dilation and paralysis of accomodation, relaxation of smooth muscle, CNS effects, antiemetic and antiparkinsonian effect

Question 112

What is atropine and how is it used?

Answer 112

A non-selective competitive muscarinic antagonist that is readily absorbed and penetrates BBB barried = CNS depression/excitation, delirium Used clinically: adjunct to anaesthesia (dries secretions), treat anticholinesterase poisoning, treat bradycardia, treat GI hypermotility

Question 113

Side effects of atropine?

Answer 113

Urinary retention, dry mouth, blurred vision, constipation

Question 114

What is hyoscine and how is it used clinically?

Answer 114

A non-selective competitive muscarinic antagonist that relaxes the GI tract, suppresses secretions, sedation, CNS depression/excitation, blocks transmission from vestibular apparatus to vomiting centre Used adjunct to anaesthesia, bowel pain, motion sickness, similar to atropine Side effects are the same as atropine

Question 115

What is pirenzepine and what does it do?

Answer 115

An M1 selective antagonist that is used to treat peptic ulcers and slow gastric acid secretion Inhibits vagus-induced histamine release = blocks M1 on G cells = enhancement of parasympathetic ganglia signalling However M3-mediated acid release is still possible

Question 116

Steps of gastric acid secretion?

Answer 116

1. Initiated by activity of membrane-bound proton pump that exchanges H+ and K+ across the cell membrane 2. H+ obtained from carbonic acid (H2CO3) by carbonic anhydrase 3. HCO3- enters plasma in exchange for Cl- 4. Cl- secreted into stomach lumen with H+ via symport carrier 5. Activity of proton pump is affected by histamine, gastrin and acetylcholine

Question 117

What are DARIFENACIN, oxybutynin and tolterodine? What are they used for? Side effects?

Answer 117

- M3 selective muscarinic antagonists that inhibit involuntary bladder contraction and micturition (urine leaving bladder) - Treats uriniary incontinence - Less severe atropine-like effects, dry mouth, blurred vision, constipation

Question 118

How does cholinergic signalling work in airways?

Answer 118

Nerve impulse causes ACh release which binds to M3 and triggers contraction

Question 119

What is ipratropium and what is it used for?

Answer 119

An M3/2 competitive antagonist quaternary ammonium compound that is poorly absorbed, lacks CNS effects and does not inhibit mucocililary clearance from bronchi Treats irritant induced bronchospasm through inhalation/nebuliser, asthma, bronchitis, COPD

Question 120

How does ipratropium prevent bronchoconstriction?

Answer 120

Blocks M3 pathway to stop cascade of increased IP3 and Ca2+ release which normally causes that

Question 121

What inhibits neuronal ACh release and what can loss of this cause?

Answer 121

M2 receptor negative feedback Loss of feedback may lead to enhanced airway contraction

Question 122

What is an issue with ipratropium?

Answer 122

Although it blocks the postsynaptic M3 receptors to stop contraction, it also blocks the M2 receptors on the presynaptic membrane = no negative feedback = enhanced ACh production = effect of ipratropium is overcome as it is only a competitive antagonist

Question 123

Why is tiotropium more efficient than ipratropium?

Answer 123

It binds M3 but not M2 (M3 selective) so the feedback cycle can occur and ACh release is limited

Question 124

2 types of specialised cardiomyocyte?

Answer 124

1. Pacemaker (1%) -- generate electrical impulses spontaneously, depolarise adjacent cells through gap junctions 2. Contractile (99%) -- become depolarised and contract, passes cell to cell via gap junctions

Question 125

Steps of the conduction pathway in the heart?

Answer 125

1. Action potential produced by pacemaker cells in sinoatrial node (slow) spreads to contractile cells of myocardium 2. Depolarisation spreads through muscular walls of atria (contraction of left and right at the same time --- or interatrial bundle connects the atria to allow conduction of the action potential) (fast) 3. Impulse transduced down internodal pathways to AV node (slow), delays impulse by 0.12 seconds to allow full atrial ejection 4. Impulse moves to interventricular septum through bundle of His --- fibres divide into bundle branches leading to lower ventricles and Purkinje fibres which rapidly spread the impulse to cause ventricular excitation

Question 126

Define the parts of an ECG?

Answer 126

P wave = atrial systole (depolarisation and contraction) PR segment = atrial systole and conduction to vesicles and AV delay QRS = spreading from bundle of his through purkinje fibres, ventricular systole ST segment = ventricular plateau (depolarisation) T wave = ventricular diastole (repolarisation)

Question 127

How do vagus nerves affect the heart?

Answer 127

Release ACh (slows HR = bradycardia)

Question 128

How do thoracic spinal nerves affect heart?

Answer 128

Release noradrenaline (quickens HR = tachycardia)

Question 129

What is an action potential?

Answer 129

Brief reversal of polarity of cell membrane --- produced by voltage gated ion channels --- as membrane polarity increases the cell is depolarised

Question 130

Steps of a pacemaker cells action potential cycle?

Answer 130

1. FUNNY channels open when membrane potential is below -40mV = slow Na+ influx 2. FUNNY channels close just short of threshold for action potential 3. Voltage-activated T-type calcium influx at -55mV (slow depolarisation) 4. Voltage-activated L-type calcium influx at -45mV (rapid depolarisation) 5. Voltage-activated potassium efflux at the peak of depolarisation and calcium channels close = rapid repolarisation

Question 131

Steps of action potential in contractile cardiomyocytes?

Answer 131

1. Na+ moves through gap junctions from adjacent cell = increased voltage 2. Voltage-activated sodium channels open at -65mV = depolarisation (transient Na+ channels close near peak) 3. Voltage activated transient K+ efflux = early repolarisation phase 4. L-type voltage-activated calcium channels open at -40mV 5. K+ efflux via slow and rapid delayed rectifier potassium channels 6. Ca2+ influx and K+ efflux balance eachother out = plateau phase (more calcium obtained from SR for contraction) 7. Ca2+ channels slowly close, K+ remain open = repolarisation 8. Ca2+ actively transported back into SR 9. Stable membrane potential maintained by K+ efflux via inwardly rectifying potassium channels

Question 132

Differences between pacemaker and contractile cardiomyocytes action potential?

Answer 132

Pacemaker = slow depolarisation --> repolarisation ---> no true baseline due to spontaneous depolarisation) Contractile = rapid depolarisation --> initial repolarisation ---> plateau ---> repolarisation ---> stable baseline (shape of contractile is more abnormal and has straight bits)

Question 133

How does the duration of the cardiac action potential determine the refractoriness?

Answer 133

There are two parts of the cycle: - ABSOLUTE/EFFECTIVE refractory period (main part of cycle) where no second action potential can be generate regardless of stimulus - RELATIVE refractory period (end part of repolarisation) where a second action potential can be generated if a strong stimulus is applied

Question 134

What are FUNNY channels?

Answer 134

Tetramers made up of transmembrane helices only found in pacemaker cells --- transmembrane helix 4 is a voltage sensor, helix 6 has a cAMP binding site

Question 135

What is sympathetic input to the heart?

Answer 135

Binding of adrenaline and noradrenaline to beta adrenergic receptors = adenylyl cyclase activation = cAMP production = cAMP binding to helix 6 = opening of channel = Na+ influx = faster depolarisation = increased action potential frequency = HR increase (via beta adrenoceptors)

Question 136

What is parasympathetic input in the heart?

Answer 136

ACh binding to muscarinic ACh receptor = adenylyl cyclase inhibition = less cAMP = less FUNNY channel opening = slower depolarisation of pacemaker cells = reduced action potential frequency = HR decrease via muscarinic m2 receptors

Question 137

What do beta blockers do?

Answer 137

Inhibit beta adrenoceptors = inhibited cAMP production = reduced HR SYMPATHETIC DECREASE

Question 138

What does digoxin do to the heart?

Answer 138

Stimulates vagus nerve = less FUNNY channel opening = reduced HR PARASYMPATHETIC INCREASE

Question 139

What does ivabradine do to the heart?

Answer 139

Physically blocks FUNNY channels = lowered Na+ influx = reduced heart rate

Question 140

2 ways FUNNY channels are activated?

Answer 140

1. Membrane repolarisation 2. Increased intracellular cAMP (directly)

Question 141

Difference between dysrhythmia and arrhythmia?

Answer 141

Dysrhythmia = abnormal rhythm Arrythmia = no rhythm (irregular)

Question 142

How are arrhythmias classified?

Answer 142

1. Effect on HR (increase or decrease) 2. Effect on rhythm (regular or irregular) 3. Site of origin in the heart (supraventricular like SAN, atria, AVN or ventricular (bundles of his, purkinje fibres, ventricles) 4. Type of QRS complex (narrow or broad)

Question 143

Signs of arrythmias?

Answer 143

Palpitations, shortness of breath, fatigue, chest pain, dizziness, blackouts, cardiac arrest

Question 144

What is sinus bradycardia caused by?

Answer 144

Physiological causes like increased vagal tone or it occurs in trained athletes

Question 145

Extrinsic (non-cardiac) causes of bradycardia?

Answer 145

- Endocrine disorders (hypothyroidism) - An electrolyte imbalance (severe hyperkalaemia, hypo/hyper calcaemia) - Drugs -- anti-arrhythmic (beta-blockers, digoxin) and antihypertensives (clonidine) - Hypothermia

Question 146

Intrinsic causes of bradycardia?

Answer 146

1. Sick sinus syndrome (ischaemia and infarction of SAN) 2. Atrioventricular blockade or heart block

Question 147

How is sick sinus syndrome classified?

Answer 147

Sinus pause, sinus arrest and/or bradycardia-tachycardia syndrome on ECG

Question 148

Different types of AV block causing bradycardia?

Answer 148

1. First degree = slower AV conduction (mildest) 2. Second-degree = slowed HR, irregular ventricular contraction as some are missed 3. Third degree = complete block meaning no conduction to ventricles from atria = random ventricular contraction out of rhythm

Question 149

How is an AV block bradycardia case treated?

Answer 149

In emergencies: 1. Atropine to slow vagus input (competitive antagonist for ACh) = increased sympathetic input = increased HR 2. Isoprenaline = non selective beta-adrenergic agonist to increase HR LONG TERM = implantable transcutaneous pacemaker

Question 150

What are class I anti-arrhythmic drugs?

Answer 150

Sodium channel blockers that block the depolarisation phase in contractile cardiomyocytes to prolong action potentials and reduce HR Act on bundle of his, purkinje fibres and on ventricular/atrial myocytes E.g. disopyramide, lidocaine, flecainide

Question 151

What are class II anti-arrhythmic drugs?

Answer 151

Beta blockers that inhibit FUNNY channels to reduce Na+ influx, slow depolarisation and conduction to the AVN and reduce HR E.g. propanolol, atenolol, esmolol

Question 152

What are class III anti-arrhythmic drugs?

Answer 152

Prolong action potential in contractile cells by blocking K+ channels to slow repolarisation and action potential to reduce HR

Question 153

What are class IV anti-arrhythmic drugs?

Answer 153

Calcium channel blockers that inhibit depolarisation in pacemaker cells, extending the plateau phase in contractile cells to slow action potential and reduce HR

Question 154

Characteristics of disopyramide?

Answer 154

Class I drug with an intermediate dissociation rate that can also block repolarisation through blockage of K+ channels

Question 155

Characteristics of lidocaine?

Answer 155

Class I drug with fast dissociation rate meaning dissociation occurs at the start of an action potential in time for the next action potential to occur (block Na+ to prevent premature beats)

Question 156

Characteristics of flecainide?

Answer 156

Class I drug with a slow dissociation rate forming a steady block that doesnt change during the cardiac cycle = greater impact on upstroke of action potential (depolarisation) and it inhibits purkinje fibres

Question 157

Adverse effects of class I anti-arrhythmic drugs?

Answer 157

Disopyramide = atropine like effects, myocardial dysfunction causing reduced contractility (negative ionotropic effect cause by Ca2+ channel blockage), competitive antagonist of muscarinic ACh receptors causing higher HR Lidocaine = CNS effects like drowsiness, disorientation, convulsions, respiratory depression Flecainide = sudden cardiac death associated with ventricular fibrillation

Question 158

What are propanolol, atenolol, esmolol?

Answer 158

Propanolol = long-acting non-selective beta blocker Atenolol = beta1 selective, water soluble Esmolol = short acting beta1 selective blocker

Question 159

Adverse reactions of class II anti-arrhythmics?

Answer 159

Bradycardia, myocardial depression due to negative ionotropic effect, bronchoconstriction, increased risk of hypoglycaemia unawareness, sleep disturbances

Question 160

Mechanism of class III anti-arrhythmics?

Answer 160

Block voltage-activated potassium channels in repolarisation phase 3 of cardiac action potential causing prolonged cardiac action potential and increased refractoriness of heart (restore and maintain rhythm) Drugs are called amiodarone and sotalol

Question 161

Characteristics of amiodarone?

Answer 161

Class III drug that causes modest block of Na+ channels (class I effect), modest block of Ca2+ channels (class IV) effect, decrease in expression of beta-1 adrenoceptors (class II effect) and a modest alpha adrenergic receptor antagonist to reduce blood pressure NOT VERY SPECIFIC

Question 162

Characteristics of sotalol?

Answer 162

Class III drug that is a non-selective beta blocker

Question 163

Adverse effects of amiodarone?

Answer 163

Arrythmias, thyroid abnormalities, corneal deposits, pulmonary disorders, skin pigmentation

Question 164

What do class IV anti-arrhythmics do?

Answer 164

Block L-type voltage-activated calcium channels and they inhibit depolarisation in phase 0 in pacemaker cells (slows conduction at AV node) Types are phenylalkilamines like verapamil, or benzothiazepines like diltiazem

Question 165

Adverse effects of class IV anti-arrhythmics?

Answer 165

Bradycardia, reduced myocardial contractility, constipation (calcium channels in GI cells blocked = reduced contraction and peristalsis), hypotension

Question 166

Other anti-arrhythmic drugs?

Answer 166

Adrenaline, atropine, isoprenaline, adenosine, digoxin, magnesium chloride

Question 167

What is adrenaline used for and how does it work?

Answer 167

Cardiac arrest Stimulates beta adrenergic receptors = FUNNY channel activation = depolarisation = action potential = increased heart rate

Question 168

What is atropine used for and how does it work?

Answer 168

Treats 2nd and 3rd degree AV block Competitive antagonist of muscarinic ACh receptors = slower vagal input = increased sympathetic input = higher HR

Question 169

What is isoprenaline used for and how does it work?

Answer 169

2nd and 3rd degree AV block Beta adrenergic receptor agonist that works the same as adrenaline

Question 170

What is adenosine used to treat and how does it work?

Answer 170

Supraventricular tachycardia (SVT) Binds adenosine A1 receptors (linked to same cardiac K+ channel as ACh and has a similar mode of action to AVN) = slower pacemaker potential

Question 171

What does digoxin treat and how does it work?

Answer 171

Rapid atrial fibrillation Stimulates vagus nerves, activating M2 receptors = less FUNNY activation = reduced HR

Question 172

What does magnesium chloride treat and how does it work?

Answer 172

Ventricular tachycardia due to hyperkalaemia Slows conduction and is a vasculature vasodilator

Question 173

What certain diseases can cause tachyarrhythmias through hypoxia/scarring of heart changing the conduction properties of the heart?

Answer 173

Congenital heart defects, hyperthyroidism, pheochromocytoma Also electrolyte imbalances like hypokalaemia and hypomagnesemia

Question 174

What drugs can cause tachyarrhythmias?

Answer 174

Asthma inhalers (stimulate beta adrenoceptor), anti-arrhythmic drugs, anti-hypertensive, antifungal (QT prolongation), antibiotics, antihistamines

Question 175

Emotional and lifestyle factors causing tachyarrythmias?

Answer 175

Stress, anxiety, lack of sleep, excess alcohol/caffeine, recreational drug use

Question 176

Genetic disorders associated with tachyarrhythmias?

Answer 176

1. Channelopathies (mutations in cardiac voltagve-activated Na+, Ca2+ and K+ channels) such as long QT syndromes and brugada syndrome (Na+ channel mutation) 2. Mutations in proteins associated with storage and release of calcium from the SR like catecholaminergic polymorphic ventricular tachycardia

Question 178

What is automaticity (spontaneous depolarisation in SAN) like in tachyarrhythmias?

Answer 178

Enhanced due to sympathetic overactivity and abnormal due to ectopic pacemaker

Question 179

What is the mechanism of Atrioventricular nodal re-entrant tachycardia (AVNRT)?

Answer 179

Normal people have a fast conducting pathway with a longer refractory period, but this condition has an abnormal accessory slow conducting pathway with a shorter recovery period but slower conduction --- a premature atrial beat enters slow pathway whilst fast pathway is refractory = ventricular contraction and stimulation of fast pathway (before refractory period ends due to looping around) = atrial contraction Visible as P wave following the QRS complex due to the shortened refractory period

Question 180

What is the mechanism of atrioventricular reciprocating tachycardia (AVRT)?

Answer 180

Re-entry via congenital accessory pathways between atria and ventricles common in adolescents --- causes narrow QRS complex tachycardia Visible as shorter PR intervals, longer QRS and delta waves preceding QRS

Question 181

What is re entry?

Answer 181

Electrical impulse re-circulates in a loop within the heart, reactivating tissue that has already been depolarised (it should die out)

Question 182

What do AVNRT and AVRT commonly cause?

Answer 182

Paroxysmal SVT

Question 183

What is the therapeutic strategy to stop paroxysmal SVT and how is it dealt with?

Answer 183

Increase AVN delay and slow down conduction via the AVN --- Short episodes = vagal maneuvers like Valsalva's maneuver to increase vagus tone at AVN --- Long episodes = adenosine IV

Question 184

What are the ways of managing paroxysmal SVT long term?

Answer 184

1. Catheter ablation of slow pathway (AVNRT) and accessory pathway (AVRT) 2. Rate control drugs that act on AVN such as class ii beta blockers, verapamil, digoxin 3. Rhythm control drugs like flecainide, sotalol, amiodarone

Question 185

Difference between macro and micro re-entry?

Answer 185

Macro = conduction from the atrium to ventricle via accessory pathways (rare) causing antidromic circular tachycardia Micro = ischaemic damage of purkinje fibres = two pathways with different properties (similar to slow and fast pathways in AVNRT) but at micro level causing ventricular tachycardia

Question 186

Treatment and management of ventricular (broad QRS complex) tachycardia?

Answer 186

If pulse is present then amiodarone, flecainide and lidocaine If no pulse = CPR and defib Manage = rate control drugs = adenosine, verapamil, beta blockers, digoxin

Question 187

What is triggered activity early after depolarisation (EAD)?

Answer 187

Reactivation of L-type voltage activated calcium channels during the plateau phase of the cardiac action potential (depolarisation of cell when it is not fully repolarised) = arrhythmias as premature action potentials are triggered

Question 188

What can promote EAD?

Answer 188

Slow HR, drugs that prolong the QT interval, genetics (multiple genotypes with different triggers)

Question 189

How are EADs linked to Torsades de Pointes (TdP)?

Answer 189

A longer QT interval in the heart which allows more EADs to occur during the repolarisation phases = polymorphic ventricular tachycardia (known as TdP) This results in dangerous twisting ventricular arrhythmias that can be fatal

Question 190

What is delayed after depolarisation (DAD)?

Answer 190

Build up of intracellular Ca2+ = activation of electrogenic 3Na+/Ca2+ exchanger = membrane depolarisation during diastole

Question 191

What factors promote DADs?

Answer 191

Fast HR, drugs like digoxin and caffeine, and genetics

Question 192

What is the difference between atrial fibrillation and flutter?

Answer 192

Fibrillation = fast irregular heartbeat Flutter = fast regular heartbeat

Question 193

Most common causes of atrial fibrillation?

Answer 193

Random focal ectopic activity from the pulmonary vein in the left atrium like EADs and AVRT

Question 194

Most common causes of atrial flutter?

Answer 194

One or more foci of excitation in the atria due to micro re-entry or EADs

Question 195

What is atrial fibrillation the main cause of? Treatment?

Answer 195

Stroke Rhythm control - electrical cardioversion, pharmacological cardioversion like flecainide or amiodarone Rate control - beta blockers, diltiazem, digoxin

Question 196

4 steps of excitation-contraction coupling?

Answer 196

1. Depolarisation due to fast Na+ influx via Na+ channels (Phase 0 - stimulus) 2. Activation of L-type voltage gated calcium channels = influx of extracellular Ca++ (phase 2 - trigger of start of contraction not the full) 3. Activation of ryanodine receptors on the SR by Ca++ and Ca++ induced Ca++ release (triggers contraction fully) 4. Ca++ influx via reverse mode of Na+-Ca++ exchanger

Question 197

What is the ryanodine receptor (RyR)?

Answer 197

Large homotetrameric protein complex with a large cytoplasmic N-terminus domain that acts as an intracellular calcium release channel on the SR

Question 198

What are the 3 main isoforms of RyR?

Answer 198

RyR1 = skeletal muscles, RyR2 = cardiac muscles, RyR3 = brain and other tissues

Question 199

What activates and inhibits RyR2? What keeps it closed? What opens it?

Answer 199

Activated by low cytosolic Ca++ Inhibited by high cytosolic Ca++ Kept closed by calstabin-2 (endogenous stabiliser) and calmodulin (inhibits opening) Increased opening caused by phosphorylation by PKA and CaMKII

Question 200

What is RyR2 linked to?

Answer 200

Calsequestrin-2 (a low affinity, high capacity Ca++ binding protein) that stores Ca++, buffers its concentration and helps regulate its release via RyR2 (needed for heart muscle contraction and rhythm)

Question 201

Difference between RyR1 and RyR2?

Answer 201

RyR1 physically arranged in tetrads with voltage activated Ca++ channel that acts as a voltage sensor RyR2 arranged in loose clusters, calcium influx via L-VACC that activates RyR2 and triggers calcium induced calcium release

Question 202

Mechanism of calcium induced calcium released causing a contraction?

Answer 202

Ca++ enter via L-VACCs = activation of RyR2 clusters = local Ca++ release (calcium spark) = rapid summation of local events = global raise in Ca++ (calcium wave) = contraction

Question 203

What is ryanodine?

Answer 203

Drug with high-affinity binding site that activates RyRs at low concs and inhibits at high concs

Question 204

How does caffeine affect RyRs?

Answer 204

Makes them 'leaky' At low concs it increases RyR sensitivity to Ca++ At high concs it can cause rapid calcium release

Question 205

What is FKBP and how does it link to RyRs?

Answer 205

FK506 binding protein part of immunophilin family that stabilises RyR2 channel in closed state to prevent leaky calcium release during diastole

Question 206

What drugs affect immunophilins?

Answer 206

Drugs like tacrolimus (FK506) and rapamycin that bind FKBP and disrupt the association with RyR2

Question 207

What can cause cytosolic calcium overload that triggers DAD and lead to cardiac tachyarrhythmia?

Answer 207

Drugs that make RyR leaky like caffeine and immunosuppressants, cardiac glycosides, genetics or acquired abnormal function in RyR2, calsequestrin-2 or calmodulin

Question 208

4 steps of Ca++ removal leading to cardiac relaxation?

Answer 208

1. Reuptake into SR by Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) (70-80%) 2. Extrusion by Na+-Ca++ exchanger (NCX) (20-30%) 3. Uptake by mitochondrial Ca++ uniporter (1%) 4. Extrusion by sarcolemmal Ca2+ ATPase (1%)

Question 209

What is the relationship between SERCA and phospholamban?

Answer 209

Phospholamban is bound to SERCA and inhibits it normally to keep cytosolic Ca++ levels high to sustain muscle contraction However under stimulus phospholamban is phosphorylated by PKA = no inhibition = greater Ca2+ uptake = relaxation

Question 210

What drives NCX activity?

Answer 210

Increased cytosolic concentration of calcium or sodium

Question 211

What is the function of NCX like?

Answer 211

Exchanges 1 Ca++ for 3 Na+ (electrogenic) and can operate in: - forward (normal Ca++ removal) during repolarisation but cause depolarisation which triggers DADs in Ca++ overloaded myocytes - reverse (Na+ removal) during depolarisation

Question 212

What are the major phosphorylation targets for cAMP/PKA?

Answer 212

Cav1.2 (increased calcium influx), RyR2 (increased Ca release), troponin I (increased calcium sensitivity) = increased Ca++ = increased force of contraction The increased Ca++ = increased CaMKII = Increased PLN-mediated increased SERCA which negatively feedsback to Ca++ levels (removal)

Question 213

How do catecholamines cause contraction?

Answer 213

Increase cytoplasmic Ca++ through PKA activation = PKA mediated phosphorylation of L-VACCs (increases calcium influx) and RyR2 (increased calcium release) = contraction This is a positive inotropic effect

Question 214

How do catecholamines cause relaxation?

Answer 214

Increase calcium reuptake into the SR through activation of PKA = PKA-mediated phosphorylation of PLN = SERCA pumps Ca++ into SR faster = relaxation This is positively lusitropic

Question 215

4 catecholamines?

Answer 215

Noradrenaline, adrenaline, dobutamine, isoprenaline

Question 216

3 cardiac glycosides?

Answer 216

Digoxin, digitoxin, ouabain

Question 217

Example of a calcium sensitiser?

Answer 217

Levosimendan

Question 218

What are some features of cardiac glycosides?

Answer 218

1 to 4 sugars residues for pharmocokinetics (solubility, binding), steroid with lactone ring (biological activity)

Question 219

What is the mechanism of cardiac glycosides?

Answer 219

Inhibition of Na+/K+ ATPase pump by binding to an extracellular K+ binding site in a competitive manner = blocked potassium binding sites = blocked pump activity = sodium build up = NCX triggered in reverse mode = calcium in = contraction (inotropy) They act as positive inotropes

Question 220

Mechanism of action of calcium sensitisers?

Answer 220

Binds to troponin C in Ca++-dependent manner to prolong the active state by making the contractile proteins more responsive to the existing Ca++ (not adding more)

Question 221

Cardiac benefits of calcium sensitisers?

Answer 221

- Do not increase ATP consumption - Do not increase cytosolic Ca - Can synergise with PKA-dependent phosphorylation of troponin i

Question 222

Other benefits of levosimendan?

Answer 222

- Inhibits PDE3a = increased cAMP - Activates potassium ATP sensitive channels in blood vessels = vasodilation

Question 223

Equation for blood pressure?

Answer 223

Blood pressure = cardiac output (CO) x total peripheral resistance (TPR)

Question 224

Equation for cardiac output?

Answer 224

Cardiac output = heart rate x stroke volume

Question 225

What does total periphery resistance influence?

Answer 225

Cardiac afterload (pressure the heart must work against to eject blood during systole) BUT TPR is influenced by arteriolar constriction (increases) or dilation (reduces)

Question 226

What influences stroke volume?

Answer 226

Blood volume (influences by venoconstriction and venodilation = the venous return = cardiac PRELOAD)

Question 227

What is the tunica media?

Answer 227

A layer of smooth muscle in blood vessels --- veins have less to house more blood --- arteries have more to control the amount of blood

Question 228

What is the tunica adventitia?

Answer 228

A protective layer of blood vessels

Question 229

What is the tunica intima?

Answer 229

The inner endothelial cell lining of blood vessels

Question 230

What does it mean to say blood vessels act as a functional synctyium?

Answer 230

They are a group of cells that function as a single unit because they are electrically and mechanically coupled --- coupled in each layer via intercellular gap junctions --- coupled between layers (smooth muscle and endothelial cells via myoendothelial gap junctions) --- chemical coupling by release of neuromediators and local mediators

Question 231

How is contraction of blood vessels caused by regulation of receptor agonists?

Answer 231

GPCRs (bound to gq proteins like Gq11) sit on smooth muscle cells --- agonists like noradrenaline, angiotensin ii, vasopressin, endothelin-1, thromboxane A2 and ATP --- they bind to GPCRs and activate Gq protein = PLC-beta activation = IP3 generation = Ca++ release = MLCK activation via calmodulin = myosin light chain phosphorylation = smooth muscle contraction

Question 232

How is contraction of blood vessels regulated by membrane voltage?

Answer 232

Blockage of L-type Voltage Activated Ca++ channels (L-VACCs) by calcium channel blockers = reduced intracellular Ca++ = reduced myosin light chain phosphorylation = RELAXATION If they open due to membrane depolarisation = contraction due to raised Ca++

Question 233

What are RhoA and ROCK and how do they cause contraction?

Answer 233

They sustain contraction by increasing calcium sensitisation by inhibiting MLCP so myosin light chain stays phosphorylated

Question 234

How can relaxation be induced?

Answer 234

Statins inhibit RhoA PKC inhibitors and ROCK inhibitors promote relaxtion (preserves MLCP activity)

Question 235

Mechanisms of blood vessel relaxation?

Answer 235

1. Phosphorylation-dependent inhibition of MLCK through agonist binding to Gs-receptor-coupled increase of cAMP = increased PKA = MLCK inhibition = less MLC phosphorylation 2. PDE inhibitors (PDE inhibits cAMP and cGMP) 3. Potassium channel activators to cause hyperpolarisation 4. Activation of MLCP via cGMP-PKG mediated pathway (via GC-coupled receptors or nitric oxide activated sGC = increased cGMP = increased PKG = increased MLCP = relax)

Question 236

Agonists of Gs coupled GPCRs?

Answer 236

Adrenaline, prostaglandin, adenosine and histamine

Question 237

Main ways of decreasing cytosolic calcium levels in vascular smooth muscle?

Answer 237

1. Reduction of agonist-activated Ca++ release 2. Reduced calcium influx via L-type VACCs (hyperpolarisation-mediated --- opening of K+ channels by voltage, phosphorylation or NO AND phosphorylation dependent inhibition) 3. Reuptake by SERCA2 3. Extrusion via plasmalemmal Ca++-ATPase pump, NCX (very small role compared to cardiac muscles)

Question 238

What is endothelium-derived relaxing factor?

Answer 238

Another name for nitric oxide (NO)

Question 239

3 nitric oxide synthase isoforms?

Answer 239

1. Neuronal NOS (nNOS) --- calcium dependent for neurotransmission, gastric emptying and more 2. Inducible NOS (iNOS) --- calcium independent, acts as a host defence in macrophages, neutrophils and leukocytes 3. Endothelial NOS (eNOS) --- constitutively expressed, calcium dependent, causes vasodilation, reduced platelet adhesion, anti-inflammatory, anti-proliferative

Question 240

What activates eNOS?

Answer 240

Agonists like acetylcholine, bradykinin, histamine, and endothelin-1(as it is gq11 coupled, via cAMP-PKA pathway), stress, insulin

Question 241

What does eNOS do in endothelial cells?

Answer 241

Has basal activity, activation is enhanced by increased cytosolic Ca++ (dependent on calmodulin), synthesises NO from L-arginine and O2 ---- then NO diffuses out of cell

Question 242

What does NO do in smooth muscle?

Answer 242

Activates soluble Guanylyl cyclase (sGC) ---> sGC converts GTP to cGMP ---> cGMP stimulates MLCP via activation of protein kinase G (PKG)

Question 243

What are competitive NOS inhibitors (endogenous)?

Answer 243

Molecules like asymmetric dimethylarginine (ADMA) that compete with L-arginine for the active site of NOS enzymes to prevent NO synthesis

Question 244

What are high plasma levels of ADMA linked with?

Answer 244

Hypercholesterolemia, atherosclerosis, hypertension, chronic renal and heart failure A MARKER OF ENDOTHELIAL DYSFUNCTION AND A RISK FACTOR FOR CARDIOVASCULAR DISEASES

Question 245

Other competitive NOS inhibitors (experimental)?

Answer 245

Nitroarginine (L-NNA) and L-NAME

Question 246

Examples of NO donors that bypass endothelial cells?

Answer 246

Glyceryl trinitrate and sodium nitroprusside

Question 247

Example of PDE5 selective inhibitors that prevent cGMP breakdown?

Answer 247

Sildenafil

Question 248

What enzymes produce prostanoids?

Answer 248

COX-1 (constitutive) and COX-2 (inducible except in kidneys) by converting arachidonic acid to them Inhibited by NSAIDS

Question 249

Examples of protanoids?

Answer 249

Prostaglandin i2, E2, D2, F2 and thromboxane A2

Question 250

Steps of synthesis of prostandoids?

Answer 250

1. Membrane phospholipids into arachidonic acid (cPLA2 increases rate) 2. Arachidonic acid into PGG2 (COX-1 increases) 3. PGG2 into PGH2 4. PGH2 into prostagladins in endothelial cells (prostacyclin synthase) or thromboxane 2 in platelets (thromboxane synthase)

Question 251

What are the characteristics of IP, DP, EP2 and EP4 prostanoid receptors?

Answer 251

General inhibitory actions like smooth muscle relaxation and anti-aggregatory platelet effects and anti-inflammatory

Question 252

What are the characteristics of TP, FP and EP1 prostanoid receptors?

Answer 252

General excitatory actions like smooth muscle contraction and pro-inflammatory and platelet aggregatory actions

Question 253

Characteristics of EP3 prostanoid receptor?

Answer 253

General inhibitory actions

Question 254

What are the therapeutic targets in systemic hypertension?

Answer 254

Calcium channel blockers, receptor antagonists, K channel activators

Question 255

Therapeutic targets in angina?

Answer 255

Nitrates, calcium channel blockers, K channel activators

Question 256

Therapeutic targets in heart failure?

Answer 256

Calcium channel blockers, K channel activators, receptor antagonists, PDE inhibitors

Question 257

Therapeutic targets in pulmonary hypertension?

Answer 257

Calcium channel blockers, prostaglandin agonists, endothelin receptor antagonists, PDE5 inhibitors

Question 258

Kidney functions?

Answer 258

1. Regulation of water, salts, acid-base balance 2. Removal of metabolic waste 3. Removal of foreign chemicals 4. Gluconeogenesis 5. Production of hormones/enzymes --- erythropoietin, renin, activates vitamin D

Question 259

Role of erythropoietin?

Answer 259

Controls red blood cell production

Question 260

Role of renin?

Answer 260

Controls blood pressure and sodium balance

Question 261

3 functions of nephrons?

Answer 261

Glomerular filtration, tubular secretion and tubular reabsorption

Question 262

How does glomerular filtration work?

Answer 262

Endothelial cells in capillaries and the podocytes in the capsule only let in specific molecules and leave cells, proteins and protein-bound drugs out in the blood

Question 263

What is glomerular filtration rate?

Answer 263

Volume of fluid filtered from glomeruli to bowmans space per unit time ---- regulated by adjusting blood pressure --- one way of maintaining water and salt balance

Question 264

How is GFR reduced?

Answer 264

Afferent flow is constricted, efferent flow is dilates Reduces water and salt loss via excretion

Question 265

How is GFR increased?

Answer 265

Afferent flow is dilated, efferent flow is constricted Increases water and salt loss via excretion

Question 266

Steps of decreasing salt and water excretion?

Answer 266

Increased water and salt loss = decreased plasma volume = increased renal sympathetic nerve activity and blood pressure = constriction of afferent renal arterioles = reduced GF pressure = decreased GFR = reduced water and salt excretion

Question 267

Where is salt and water reabsorbed?

Answer 267

Salt = all parts of nephron Water = all parts of nephron except distal convoluted tubule

Question 268

Where do different diuretics affect?

Answer 268

Water permeable parts of nephron = osmotic diuretics Proximal convoluted tubule = carbonic anhydrase inhibitors Ascending loop of henle limb = loop diuretics Distal convoluted tubules = thiazide and thiazide-like Collecting duct = potassium sparing diuretics

Question 269

Example of osmotic diuretic and how it works?

Answer 269

Mannitol -- freely filtered and increases osmolarity of tubular filtrate to decrease water reabsorption and increases sodium excretion through retention

Question 270

How is mannitol used?

Answer 270

Weak diuretic that is not really used, increases osmolarity of blood plasma so used to reduce pressure in cerebral oedema and glaucoma

Question 271

How is sodium reabsorbed in proximal convoluted tubule?

Answer 271

Moved through tubule cells through Na+/H+ counter-transport Moved from tubule cell to interstitial space by Na+/K+ ATPase pump

Question 272

How does H+/Na+ counter-transport work?

Answer 272

Carbonic anhydrase produces H2CO3 from H2O and CO2 Breaks down into H+ and HCO3 H+ promotes Na+ reabsorption HCO3 reabsorbed and replaces the HCO3 lost in absorption + controls acid-base balance

Question 273

How does carbonic anhydrase inhibitors work?

Answer 273

Drugs like acetazolamide inhibit carbonic anhydrase to shut down Na+/H+ counter-transporter = moderate Na+ reabsorption decrease

Question 274

What can carbonic anhydrase inhibitors cause?

Answer 274

Mild plasma acidosis and urine alkalosis

Question 275

How are carbonic anhydrase inhibitors used?

Answer 275

Rarely as diuretics as they are weak and self limiting --- reduced carbonate reduces water retention and increases sodium reabsorption elsewhere in the nephron Glaucoma to reduce production of aqueous humour Altitude sickness to reduce respiratory alkalosis by making plasma more acidic

Question 276

How is sodium reabsorbed in ascending loop of henle?

Answer 276

Na+ moved through tubules into cells through cotransport with K+ and Cl- (Na-K-Cl cotransporter) Na+/K+ ATPase moves Na+ into interstitial space

Question 277

How do loop diuretics work?

Answer 277

Drugs like furosemide and bumetanide inhibits NKCC co-transported to decrease Na+ and Cl- reabsorption and increase K+ excretion They are absorbed in gut, secreted into tubular filtrate by organic anion transporters in proximal convoluted tubule

Question 278

Therapeutic uses of loop diuretics?

Answer 278

Most powerful diuretics Treats acute pulmonary oedema, resistant oedema, resistant hypertension, impaired kidney function and liver cirrhosis with ascites

Question 279

How does sodium reabsorption work in the distal convoluted tubule?

Answer 279

Na+ moved from tubules into cells with Na/Cl cotransporter Into interstitial space with Na+/K+ ATPase

Question 280

Examples of thiazide and thiazide like diuretics?

Answer 280

Thiazide = hydrochlorothiazide and bendroflumethiazide Thiazide-like = chlortalidone, inapamide, metolazone

Question 281

How do thiazide and thiazide-like diuretics work?

Answer 281

Inhibit Na/Cl co-transporter, decreases Na+ and Cl- reabsorption and increases Ca2+ reabsorption

Question 282

Therapeutic uses of thiazide and thiazide-like diuretics?

Answer 282

Less powerful diuretics but have more prolonged action and better tolerated Hypertension, mild heart failure, severe resistant oedema, prevention of kidney stones in idiopathic hypercalciuria, nephrogenic diabetes insipidus

Question 283

Adverse effects of loop and thiazide/thiazide like diuretics?

Answer 283

Hypotension Volume contraction alkalosis (reduced plasma volume increases plasma bicarbonate concentration) Gout --- due to hyperuricaemia, increased uric acid reabsorption as a consequence of compensation for low plasma volume Hypokalaemia --- low plasma K+ causing tachyarrythmia (impaired repolarisation of heart action potentials) and hyperglycaemia (K+ required for insulin release) --- occurs because inhibited sodium reabsorption in nephron forces more sodium through collecting duct which causes hypokalemia (compensatory)

Question 284

How is sodium reabsorbed in collecting duct?

Answer 284

Na+ moves into cell and K+ moves out through ion channels Na+/K+ ATPase moves Na+ into interstitial space and K+ into cells Increased Na+ delivery increases reabsorption in collecting duct = increased K+ secretion

Question 285

What process further contributes to hypokalaemia?

Answer 285

Increased salt and water loss activates the renin angiotensin aldosterone system as a compensatory mechanism --- aldosterone action further contributes

Question 286

How does aldosterone affect collecting duct?

Answer 286

Acts on mineralocorticoid receptors = increased expression of ENaC, ROMK and Na+/K+ ATPase = increased ROMK causing K+ secretion/excretion

Question 287

Two groups of potassium sparing diuretics?

Answer 287

1. Mineralocorticoid receptor antagonists that block action of aldosterone such as spironolactone and eplerenone 2. ENaC blockers such as amiloride and triamterene

Question 288

Therapeutic uses of potassium sparing diuretics?

Answer 288

Not potent diuretics Hypokalaemia, heart failure, resistant essential hypertension, aldosteronisms (too much aldosterone)

Question 289

Adverse effects of potassium sparing diuretics?

Answer 289

Hyperkalaemia

Question 290

What does antidiuretic hormone (ADH) (vasopressin) do?

Answer 290

Increases blood pressure by acting on V1 receptor to cause blood vessel constriction and on V2 receptor to cause fluid reabsorption to increase plasma volume

Question 291

How is water reabsorbed in the collecting ducts?

Answer 291

Vasopressin acts on V2 GPCR on cells = aquaporin-2 vesicles to fuse to apical cell membrane and aquaporins 3 and 4 are constitutively expressed on basolateral side = more channels for water to cross through

Question 292

Related disorder to ADH?

Answer 292

Diabetes insipidus (production of copious amounts of diluted water (two forms): 1. Neurohypophyseal (reduced ADH, normal kidney response, caused by surgery, genetics and brain injury) 2. Nephrogenic (normal ADH, impaired kidney response, caused by lithium poisoning, kidney disease and genetics)

Question 293

Treatment of neurohypophyseal diabetes insipidus?

Answer 293

Desmopressin and synthetic ADH

Question 294

Treatment of nephrogenic diabetes insipidus?

Answer 294

Thiazides, paradoxically reduced urine volume, compensatory increase in proximal reabsorption allows kidneys to reabsorb water in nephron prior to collecting duct

Question 295

How is hypertension defined?

Answer 295

>140mmHg systolic bp >90mmHg diastolic bp

Question 296

Why is high blood pressure dangerous if left untreated?

Answer 296

- Risk factor for CHD and stroke - Endothelial cell damages = atherosclerosis - Internal organ damage - Extra strain on heart = left ventricular hypertrophy = pulmonary oedema and congestive heart failure = peripheral oedema

Question 297

What are the cardiovascular risk factors?

Answer 297

MODIFIABLE: high BP, smoking, high salt intake, alcohol, lack of exercise, obesity, dyslipidaemias, diabetes NON-MODIFIABLE: genetics, gender, age

Question 298

3 types of systemic hypertension?

Answer 298

1. Essential (primary) hypertension -most common, no apparent cause 2. Secondary hypertension - many causes 3. 'White-coat' hypertension - anxiety in situation of having BP measured but not at all times

Question 299

3 causes of secondary hypertension?

Answer 299

1. Endocrine gland disorders -- Cushing's disease (increased ACTH), hyperaldosteronism, pheochromocytoma (abnormal catecholamine expression) 2. Kidney diseases 3. Drug induced -- anti-inflammatory corticosteroids, weight loss pills, birth control pills, cold medicines

Question 300

What is ABPM/HBPM?

Answer 300

A measurement of BP over 24 hours of normal life

Question 302

What are the stages of systemic hypertension and how is treatment initiated?

Answer 302

If clinic BP <140/90 and ABPM/HBPM <135/85: Stage 1 = lifestyle changes and treatment should be considered if the individual is <80, has a CVD, renal diseases, diabetes Stage 2 = initiate treatment and life style changes

Question 303

What is the therapeutic strategy for treating systemic hypertension?

Answer 303

Reduce TPR to reduce afterload Reduce SV to reduce blood volume and preload Reduce HR

Question 304

How does RAAS affect blood pressure?

Answer 304

Increases both arterioconstriction and venoconstriction to increase preload and afterload which raises BP

Question 305

How is the RAAS activated?

Answer 305

1. Low tubular NaCl is detected by macula densa cells -- indicated low filtration = PGE2 release by COX-2 --- PGE2 acts on granular cells to trigger renin release 2. Low blood pressure detected by granular cells = renin secretion 3. Increased sympathetic stimulation is detected by beta-adrenergic receptors on granular cells --- increased renin release during stress/shock

Question 306

How does renin allow angiotensin ii release?

Answer 306

Renin cleaves angiotensinogen to angiotensin i ACE then cleaves that to angiotensin ii Angiotensin ii then raises BP

Question 307

What is the role of ACE2 in the RAAS?

Answer 307

Converts angiotensin ii to angiotensin (1-7), converts angiotensin i to angiotensin (1-9) then to (1-7) via ACE Angiotensin (1-7) then acts on the Mas receptor = vasodilation, anti-fibrotic and anti-inflammatory OPPOSITE OF WHAT ACE CAUSES

Question 308

What does angiotensin ii act on and what does this cause?

Answer 308

Acts on AT1 receptors: - Heart --- hypertrophy and fibrosis - Vascular growth --- hyperplasia and hypertrophy (long term) - Vasoconstriction --- direct on blood vessels, sympathetic NA release - Salt retention --- increased aldosterone and Na+ reabsorption

Question 309

What drugs are the first choice of treatment in caucasian patients below 55 and patients with type 2 diabetes?

Answer 309

Angiotensin II receptor blockers (ARBs) and ACE inhibitors

Question 310

3 groups of anti-hypertensive drugs that act on the RAAS?

Answer 310

1. ACE inhibitors (all end in -pril) 2. Angiotensin II receptor blockers (ARBs) 3. Renin inhibitors

Question 311

How do ACE inhibitors work?

Answer 311

Enter ACE active site and prevent angiotensin i from binding to the binding sites

Question 312

2 examples of ACE inhibitors and what they are like?

Answer 312

1. Captopril = short acting but poorly tolerated due to taste disturbance and skin rashes due to -SH moiety 2. Enalapril = long acting prodrug with carboxyl moiety

Question 313

Common adverse effects of ACE inhibitors?

Answer 313

Hypotension, reflex tachycardia and palpitations, hyperkalaemia (due to reduced aldosterone), taste disturbances and skin rashes, peristent dry cough, angioedema

Question 314

How do ACE inhibitors cause angioedema?

Answer 314

Reduce angiotensin ii = decreased vasoconstriction = more vasodilation Increased bradykinin (ACE normally decreases this) = vasodilation

Question 315

What do ARBs cause?

Answer 315

Reduced aldosterone and vasoconstriction = lowered BP

Question 316

Examples of ARBs and benefits of them over ACEIs?

Answer 316

Losartan and valsartan Reduced angioedma, no cough, improved tolerance

Question 317

Example of a renin inhibitor?

Answer 317

Aliskiren (good pharmacological properties) --- not as good as other drugs

Question 319

When are anti-hypertensive drugs that act on the RAAS not recommended?

Answer 319

In pregnancy (teratogenic = defects), in the elderly or African-American/Caribbean origin patients (low RAAS activity)

Question 320

Direct acting vasodilators?

Answer 320

Calcium channel blockers, potassium channel openers, hydralazine, ethanol, various GPCRs on smooth muscle cells, natriuretic peptide receptors

Question 321

How does calcium channel blockers work?

Answer 321

Block L-VACCs' calcium influx in vascular smooth muscle cells to cause arterial dilation and venodilation Main group = dihydropyridines like nifedipine (fast acting) and amlodipine (slow acting)

Question 322

3 main groups of calcium channel blockers, their tissue specificity and clinical applications?

Answer 322

1. Dihydropyridines are vascular and used anti-hypertensively 2. Benzothiazepines are cardiac and vascular and are used antiginally and anti-arrhythmically 3. Phenylalkylamines are cardiac and used anti-arrhytmically

Question 323

Who are calcium channel blockers the first choice of treatment for?

Answer 323

Individuals with hypertension who are: elderly, of African-American or Caribbean origin or in pregnancy

Question 324

6 adverse effects of calcium channel blockers and why they occur?

Answer 324

1. Hypotension 2. Postural hypotension (decreased ability of arteries to constrict rapidly when someone suddenly stands) 3. Reflex tachycardia and palpitations (increase in sympathetic activity when BP is lowered) 4. Peripheral oedema (dilation of peripheral arteries and veins, increased fluid accumulation in low extremities) 5. Headache and flushes (vasodilation) 6. Constipation (blocked peristalsis)

Question 325

Cellular mechanism of potassium channel activators?

Answer 325

Open ATP-sensitive potassium channels in vasculature (they are normally regulated by intracellular ATP:ADP ratio = metabolism dependent SO higher cytosolic ATP keeps them closed)

Question 326

Anti-hypertensive mechanism of action of potassium channel activators?

Answer 326

Activation of ATP-sensitive potassium channels = membrane hyperpolarisation = closure of L-VACCs = vasorelaxation

Question 327

Differences between ATP-dependent potassium channels in pancreatic beta cells and in vascular smooth muscle?

Answer 327

Pancreatic beta cells = higher ATP and inhibitor sensitivity Vascular SM = lower ATP sensitivity but high activator sensitivity

Question 328

Examples of potassium channel activators and inhibitors?

Answer 328

Activators = diazoxide (no longer licensed) and minoxidil (used in severe resistant hypertension) Inhibitor = glyburide

Question 329

Adverse effects of potassium channel activators?

Answer 329

Hypotension, reflex tachycardia, fluid retention, hyperglycaemia and excessive hair growth

Question 330

What does hydralazine do?

Answer 330

Dilates arteries and arterioles, decreases TPR and cardiac afterload

Question 331

Therapeutic uses of hydralazine?

Answer 331

- In severe hypertension in pregnancy (alongside beta blocker and diuretic) - In heart failure in African-Americans (alongside nitrates)

Question 332

Adverse effects of hydralazine?

Answer 332

Lupus-like syndrome, tachycardia and palpitations, hypotension and peripheral oedema

Question 333

What anti-hypertensive drugs act on the sympathetic nervous system?

Answer 333

Beta blocker (all end in olol), alpha1-adrenoceptor antagonists Central acting (brainstem) = - alpha2-adrenoceptor agonists like clonidine and methyldopa - imidazoline receptor agonists like moxonidine - ganglion blockers like trimetephan - adrenergic neuron blockers like guanethidine and reserpine

Question 334

Cellular mechanism and benefits of beta blockers as anti-hypertensives?

Answer 334

- Block beta1 adrenoceptors in heart and kidney --- used in resistant hypertension and severe hypertension in pregnancy - Reduce reflex tachycardia and renin release (that leads to RAAS activation)

Question 335

Benefit of using nebivolol?

Answer 335

Beta1 selective and stimulates NO release in vascular endothelium = vasodilation, and less fatigue, bradycardia and impotence

Question 336

Benefit of using pindolol?

Answer 336

Beta1-selective and partial agonist at low sympathetic activity = less bradycardia in patients with dysrhythmias

Question 337

Benefit of using carvedilol and labetalol?

Answer 337

Non selective beta blockers with alpha 1 adrenoceptor antagonism = vasodilation and decrease in TPR with little changes in HR and CO

Question 338

Adverse effects of beta blockers?

Answer 338

Bronchoconstriction, bradycardia, fatigue, cold extremities

Question 339

Mechanism of alpha1-adrenoceptor antagonists as anti-hypertensives?

Answer 339

Inhibit postsynaptic alpha1-adrenoceptors on vascular smooth muscle cells to cause arterial dilation and venodilation

Question 340

Adverse effects of alpha1-adrenoceptor antagonists?

Answer 340

Postural hypotension, dizziness, fatigue However there is LESS reflex tachycardia

Question 341

When is moxonidine used?

Answer 341

In resistant hypertension (when first line drugs fail)

Question 342

When is alpha-methyldopa used?

Answer 342

In severe hypertension in pregnancy

Question 343

When is clonidine used?

Answer 343

Rarely as an antihypertensive --- but used to treat migraines, insomnia and opiod detox

Question 344

Adverse effects of central-acting anti-hypertensives?

Answer 344

Rebound hypertension upon withdrawal, dry mouth, bradycardia, sedation and drowsiness, respiratory depression

Question 345

Mechanism of ganglion blocking drugs?

Answer 345

Competitive nicotinic acetylcholine receptor antagonist at autonomic ganglia = non-depolarising block

Question 346

Adverse effects of ganglion blocking drugs?

Answer 346

Reflex tachycardia, postural hypotension, cycloplegia

Question 347

Mechanism of adrenergic neuron blocking drugs?

Answer 347

Guanethidine = taken up by NET and VMAT = depletion of vesicles of NA in adrenergic synapse (used in hypertensice crises) Reserpine = taken up by NET, irreversibly inhibits VMAT = preventing uptake+accumulation of NA in synapse (not used)

Question 348

What occurs in the early stages of atherosclerosis development (atherogenesis)?

Answer 348

Endothelial dysfunction

Question 349

How do monocytes contribute to atherogenesis?

Answer 349

They are recruited to the atherosclerotic lesion, differentiate into macrophages which transform into foam cells filled with lipids and they contribute to plaque development

Question 350

What is atherosclerosis?

Answer 350

A chronic and progressive inflammatory disease of large/medium-sized blood vessels where there is accumulation of fatty/fibrotic tissue (atheromatous plaque) in inner most layer of arteries (intima)

Question 351

How does atherosclerosis cause serious harm?

Answer 351

Plaque develops a fibrotic cap and accumulates calcified material --- advanced plaques then disrupt blood flow as blood vessel lumen is reduced = tissue ischemia (lack of o2)

Question 352

Related diseases to atherosclerosis?

Answer 352

Coronary heart disease Carotid artery disease Peripheral artery disease Chronic kidney disease

Question 353

Risk factors of atherosclerosis?

Answer 353

Diabetes, smoking, gender, dyslipoproteinemia (abnormal lipid balance in circulation), age and genetic conditions

Question 354

What are lipoproteins and how do they relate to atherosclerosis?

Answer 354

- Lipoproteins are lipid-protein complexes formed to allow lipid transport in the blood (hard to carry lipids alone) --- two types = low density lipoproteins (a risk factor), high density lipoproteins (protective, anti-inflammatory)

Question 355

Steps of lipid transport?

Answer 355

1. Niemann pick C1 like protein takes up cholesterol into intestinal cells and fatty acid transporters take up fatty acids 2. Chylomicron is produced which enters bloodstream 3. Endothelial cells express lipoprotein lipase which digests chylomicron to produce chylomicron remnant which enters liver 4. HMG-CoA reductase generates cholesterol which combines with triglycerides to form VLDL particles (very low density lipoproteins) 5. VLDL particles enter circulation, broken down by lipoprotein ligases into intermediate and then low density lipoproteins which are taken back up by liver via LDL receptor 6. ATP binding cassette transporter transports cholesterol out and combines it with apolipoprotein 1 to form high density lipoprotein (returns to liver)

Question 356

What happens when endothelial cells dysfunction in the early stages of atherosclerosis?

Answer 356

Reduced bio-availability of nitric oxide, upregulation of endothelial adhesion receptors, increase endothelial permeability to LDL particles

Question 357

What happens when LDLs become oxidised in intima?

Answer 357

Scavenger receptors on macrophages bind to oxLDLs and engulf them to form foam cells = cell death and cholesterol deposition

Question 358

How does lipoprotein accumulation occur?

Answer 358

ApoB100 (present in LDLs) binds to negatively charged extracellular matrix proteoglycans = retention of LDL particles in subendothelial layer

Question 359

Why do monocytes accumulate in atherosclerosis?

Answer 359

Endothelial VCAM-1 is abnormally highly expressed on endothelial cells in the lumen of blood vessels in atherosclerosis which attracts monocytes Then diapedesis occurs (attachment and migration through endothelial layer) AND THEN THEY DIFFERENTIATE INTO MACROPHAGES (macrophage colony-stimulating factor)

Question 360

What do monocyte derived macrophages do?

Answer 360

Produce pro-inflammatory mediators, reactive oxygen species and tissue factor pro-coagulants that amplify local inflammation and promote thrombotic complications

Question 361

What are scavenger receptors?

Answer 361

Highly expressed in monocytes/macrophages during differentiation and they bind and internalise oxidised LDLs to help foam cell formation

Question 362

What happens when macrophages ingest oxLDLs?

Answer 362

Cholesterol is released and transformed into cholesterol ester which moves through transporter (if in excess)

Question 363

How do cholesterol crystals in atherosclerosis in intima affect the cytoskeleton?

Answer 363

Disrupts it in vascular cells --- contributing to plaque progression and instability

Question 364

How do cholesterol crystals affect atherosclerosis?

Answer 364

Activate inflammasomes which cleave proIL-1beta into bioactive IL-1beta This triggers the activation of caspase 1 and amplified local inflammation which further destabilises the plaque

Question 365

What was the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)?

Answer 365

Study that used canakinumab (monoclonal antibody that blocks IL-1beta) Exhibited anti-inflammatory benefit at 150mg dose

Question 366

What is the end point of atherosclerosis?

Answer 366

Recruitment of smooth muscle cells that become foam cells and collagen A lesion rupture can occur if cap is degraded or collagen is exposed = thrombosis

Question 367

What is the necrotic core in atherosclerosis?

Answer 367

Accumulation of apoptotic cells, debris and cholesterol crystals

Question 368

What is the fibrous cap made of in atherosclerosis?

Answer 368

Collagen and smooth muscle

Question 369

How are lipoproteins classified?

Answer 369

By size --- smallest to largest: HDL, LDL, VLDL, Chylomicrons

Question 370

What inhibits niemann pick C1 like proteins?

Answer 370

Ezetimibe

Question 371

What enhances lipoprotein lipase?

Answer 371

Fibrates

Question 372

What inhibits HMG-CoA reductase and why?

Answer 372

Statins to prevent de novo cholesterol production to reduce LDL cholesterol AND increase expression of hepatic LDL receptors to increase LDL clearance from the blood

Question 373

What is PCSK9 and what inhibits it?

Answer 373

Has a role in LDL receptor recycling Evolcumab

Question 374

What metabolises VLDLs into LDLs?

Answer 374

Lipoprotein lipases and hepatic lipases (LDLs are then the source of cholesterol for cell membranes)

Question 375

What is protein prenylation and how does it relate to statins?

Answer 375

Part of the cholesterol synthesis pathway that HMG-CoA reductase regulates can be modified to form proteins that increase inflammation and destabilise atherosclerotic plaques Statins stop this pathway, stopping this modification and therefore improving CV health through reducing the impacts above

Question 376

Other benefits of statins?

Answer 376

Improved endothelial function, reduced vascular inflammation, reduced platelet aggregation, increase neovascularisation of ischemic tissue, stabilise plaque and have antithrombotic actions

Question 377

What do fibrates do?

Answer 377

Increase lipoprotein acitivity, decrease plasma VLDL and increase plasma HDL

Question 378

What are bile acid resins and what do they do?

Answer 378

Anion exchange resins that are orally administered to sequester bile acids and decrease their reabsorption via the enterohepatic circulation to increase their synthesis (from endogenous cholesterol = reduction) which increases LDL receptor expression = increased clearance of LDL-cholesterol

Question 379

Side effects of bile acid resins?

Answer 379

Bind other lipid soluble factors like vitamins and some drugs, unpalatable, diarrhoea

Question 380

How do PCSK9 inhibitors (like evolocumab) work?

Answer 380

PCSK9 post-translationally regulates hepatic LDL receptors by binding them and causing their degradation SO inhibitors would increase LDL receptor levels = decreased plasma LDLs

Question 381

How is PCSK9 mutated and what does it cause?

Answer 381

Can have: - Gain of function mutations = reduced hepatic LDL receptor = hypercholesterolemia and increased CVD - Loss of function = lower LDL cholesterol lifetime = reduced CVD

Question 382

What is ezetimibe?

Answer 382

A cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border --- targets Nieman pick c1 like 1 protein

Question 383

What was the MENDEL-2 trial?

Answer 383

Action of evolocumab compared to placebo or ezetimibe treatment Evolocumab reduced LDL-C from baseline more than either of the other treatments Adverse events were muscle related

Question 384

What was the FOURIER trial?

Answer 384

Just showed Evolocumab reduced LDL cholesterol

Question 385

What is lipoprotein a and why are high levels of it a risk factor is CVD?

Answer 385

A cholesterol-rich LDL particle with one molecules of apolipoprotein B100 and apolipoprotein (a) attached via a disulfide bond Risk factor as it has anti-fibronolytic effects and accelerates atherogenesis due to intimal deposition of Lp(a) cholesterol

Question 386

What reduces lipoprotein a?

Answer 386

PCSK9 inhibitors

Question 387

What is the role of plasminogen in atherosclerosis?

Answer 387

It is the inactive precursor of plasmin -- when it is activated, plasminbreaks down fibrin in clots and prevents thrombosis over a ruptured plaque and limits excessive fibrous tissue build up

Question 388

How does lipoprotein a affect plasminogen?

Answer 388

Blocks activation so clots cannot be dissolved

Question 389

What is Tangiers disease?

Answer 389

A rare severe deficiency or absence of HDL in a remote isolated island community causing orange tonsils, englarged lymphoid tissuem hepatosplenomegaly, neuropathy, corneal opacities and increased atherosclerosis risk

Question 390

What causes tangiers disease?

Answer 390

Mutations to the ABCA1 transporter on chromosome 9q31 --- abnormal lipid trafficking meaning cholesterol does not leave the cell to form HDLs and it accumulates meaning cholesterol distribution is abnormal

Question 391

What is familial hypercholesterolemia?

Answer 391

Severely elevated LDL cholesterol levels = atherosclerotic plaque development in coronary arteries at young age ---- leads to coronary artery disease (manifests as angina and myocardial infarction)

Question 392

What is the most common mutation in familial hypercholesterolemia?

Answer 392

Mutations in gene that expresses the LDL receptor (absent LDL receptor = elevated LDL cholesterol) Homozygotes die in childhood, heterozygotes are more variable

Question 393

Effects of familial hypercholesterolemia?

Answer 393

Cholesterol deposits, nodules of cholesterol (xanthoma) in skin, development of arcus coneae before 45, arthropathies associated with cholesterol crystals in synovial fluid (leading to inflammatory signalling)

Question 394

Treatment of familial hypercholesterolemia?

Answer 394

Statins, LDL apheresis (removal), liver transplant

Question 395

What is a common mouse model for visualising atherogenesis?

Answer 395

LDL receptor knockout to see the pathways and study size and cellular makeup

Question 396

What have GWAS showed in atherosclerosis?

Answer 396

Lipid modifying pathways, inflammatory signalling pathways

Question 397

What do macrophages do to make caps more likely to rupture?

Answer 397

Release proteolytic enzymes, like MMPs, to digest collagen and thinnen the caps

Question 398

What are the two ways thrombosis occurs in atherosclerosis?

Answer 398

1. Plaque rupture 2. Superficial erosion = layer of endothelial cells covering plaque die = collagen exposure = thrombosis that is normally non-occlusive

Question 399

What are the steps of the platelet activation pathway?

Answer 399

1. Adhesion of platelets to exposed subendothelial matrix proteins like collagen 2. Platelets activate and express P-selectin on their surface, and release their contents which attracts more platelets and stimulates vasoconstriction and onflammation 3. Aggregation --- platelets stick together, expose integrin alphaiibeta3 which binds fibrinogen which bridges adjacent platelets 4. Prothrombinase complex assembles (promthrombin converted to thrombin and fibrinogen is converted to fibrin

Question 400

What receptors are involved in platelet activation?

Answer 400

Thrombin receptors and purinergic receptors (P2Y) Platelets also express scavenger receptors

Question 401

Types of purinergic receptors?

Answer 401

P2X1, P2Y1, P2Y12

Question 402

Characteristics of P2X1 purinergic receptors?

Answer 402

ATP gated ion channel, causes calcium influx that changes platelet shape and causes small arterial thrombosis

Question 403

Characteristics of P2Y1 purinergic receptors?

Answer 403

Gq protein coupled receptors, activated by ADP, release internal calcium stored to change platelet shape and cause aggregation

Question 404

Characteristics of P2Y12 purinergic receptors?

Answer 404

Gi protein coupled receptors that inhibit adenylyl cyclase and activate PI3Kinase to cause platelet aggregation, inhibited by clopidogrel cangrelor (used to treat unstable angina)

Question 405

How do oxidised LDLs activate platelets?

Answer 405

Bind scavenger receptors (CD36) which upregulates P-selectin and intraplatelet ROS formation Also makes them hyperactive (more sensitive to ADP)

Question 406

How do LDL particles affect platelets?

Answer 406

Increase their sensitivity to agents that induce activation

Question 407

Final card of atherosclerosis summarising whole process of atherogenesis:

Answer 407

Endothelial cell dysfunction ---> increased permeability to LDL cholesterol ---> adhesion and transendothelial migration of monocytes ---> differentiation of monocytes into macrophages ---> oxidation of LDL cholesterol ---> uptake of oxLDL by macrophages ---> foam cell formation ---> lipid rich necrotic core forms ---> migration of smooth muscle cells ---> formation of collagen rich cap over lipid rich necrotic core ---> plaque rupture and erosion ---> adhesion, activation and aggregation of platelets ---> thrombosis

Question 408

If metabolic needs are not met how does the heart suffer?

Answer 408

Poorly perfused and at higher risk of ischaemia (lack of blood supply)

Question 409

What is coronary blood flow linked to?

Answer 409

Aerobic myocardial oxygen consumption

Question 410

What do the left and right coronary vessels supply?

Answer 410

Left = all of the heart (85% of blood) Right = SAN and AVN and some of right side of heart

Question 411

Where does venous blood return to?

Answer 411

Right atrium (95%) via coronary sinus and anterior cardiac vein AND rest directly into chambers via thebesian veins

Question 412

When does coronary blood flow occur and what affects this?

Answer 412

During diastole ---- shortened diastole in tachycardia or reduced perfusion pressure in aortic valve stenosis

Question 413

What does decreased coronary blood flow cause?

Answer 413

Ischaemic chest pain (ANGINA)

Question 414

How do catecholamines both increase and decrease coronary blood flow?

Answer 414

Decrease it as it decreases diastolic time Increase due to increased cardiac workload = increased cardiac metabolism = local release of metabolites (adenosine) and hypoxia (potassium) = vasodilation = increased coronary blood flow

Question 415

How does increased adenosine due to increased heart rate cause increased coronary blood flow?

Answer 415

Increased HR and cardiac workload = ATP breakdown = increased AMP = increased adenosine = activation of A2a receptors = increased cAMP = vasodilation This also involves negative feedback to reduce HR via cardiac adenosine A1 receptors

Question 416

How are potassium and oxygen involved in increased coronary blood flow?

Answer 416

Increased cardiac workload = increased o2 extraction and consumption = reduced o2 = decreased ATP in coronary smooth muscle = opening of ATP sensitive K+ channels = hyperpolarisation = inhibition of L-VACCs = vasodilation Increased AP frequency = increased extracellular K+ = activation of electrogenic Na+/K+ ATPase in coronary SM = hyperpolarisation etc

Question 417

How does athersclerosis disrupt the balance between supply and demand of oxygen?

Answer 417

Reduces coronary blood flow and increases cardiac workload = increased oxygen demand but a decreased oxygen supply (ANGINA)

Question 418

What causes angina and how does it manifest?

Answer 418

Exertion, cold or excitement and can be stable, variant/vasoplastic or unstable (STEMI/non-STEMI) Pain in chest, arms and neck

Question 419

What is acute coronary syndrome?

Answer 419

Reduced coronary blood flow due to platelet-fibrin thrombus from ruptured atheromatous plaque --- can be fatal due to dysrhythmia or mechanical failure of ventricle Characterised as unstable angina or myocardial infarction

Question 420

Cause of stable angina?

Answer 420

Partial narrowing of coronary artery due to atheromatous obstruction that is worse during exertion or stress

Question 421

How is stable angina treated?

Answer 421

Reduced oxygen demand by reducing heart rate Increase oxygen supply to increase coronary blood flow Reduce obstruction First line = beta blockers or calcium channel blockers Second line = organic nitrate vasodilators, potassium channel activators, inhibitors of cardiac late Na current

Question 422

How do calcium channel blockers relieve angina?

Answer 422

Slow HR, arterial and coronary vasodilation, reduce contractility

Question 423

How do beta blockers relieve angina?

Answer 423

Reduce cardiac o2 and energy consumption However can cause bradycardia

Question 424

How do organic nitrates reduce stable angina?

Answer 424

Reduce cardiac workload, relax smooth vascular muscle, dilate veins, arteries and coronary vessels, divert blood from normal to ischaemic areas, increase heart relaxation

Question 425

Negatives of organic nitrates as stable angina treatment?

Answer 425

Patients gain tolerance Can cause postural hypotension, reflex tachycardia, headache, dizziness

Question 426

What causes variant angina?

Answer 426

Coronary vasospasm at rest

Question 427

Therapeutic aim with variant angina?

Answer 427

Dilate coronary blood vessels using nitrate vasodilator and calcium channel blockers

Question 428

What causes unstable angina and what are the types?

Answer 428

Myocardial ischaemia due to thrombus formation in a coronary artery -- NSTEMI = partial occlusion -- STEMI = full occlusion ----- STEMI = ST segment- Elevation Myocardial Infarction

Question 429

Treatment of NSTEMI unstable angina?

Answer 429

Aim to prevent future adverse CV events using antiplatelet and anticoagulants

Question 430

Treatment of STEMI unstable angina?

Answer 430

Aim to open coronary vessels using coronary angioplasty, stenting, thrombus removal, coronary artery bypass, fibrinolytics

Question 431

How is a secondary myocardial infarction prevented?

Answer 431

Mediterranean diet, exercise, low alcohol, no smoking, weight control ACE inhibitors, dual antiplatelet therapy, beta blockers, statins

Question 432

Big issue with antiplatelet drugs?

Answer 432

Bleeding as platelets are required

Question 433

Implications of thrombus formation?

Answer 433

Ischaemic stroke (part of thrombus breaks off and blocks vessels in brain = reduced blood flow and o2) Deep vein thrombosis --- swelling, pain, reddening, can lead to pulmonary embolism

Question 434

As well as platelet aggregation, what else occurs when an atherosclerotic plaque ruptures?

Answer 434

Blood coagulation as thrombin activates fibrinogen into fibrin

Question 435

3 triggers of platelet activation?

Answer 435

Endothelial cell damage Exposure of collagen Release of von Willebrand factor

Question 436

How do platelets adhere?

Answer 436

Von Willebrand factor bridges subendothelial collagen and platelet receptors

Question 437

What does the exposure of acidic phospholipids when platelets aggregate cause?

Answer 437

Adhesion of prothrombin and factor Xa on platelet surface = thrombin and fibrin formation

Question 438

What drugs stop platelet aggregation?

Answer 438

COX inhibitors like aspirin P2Y12 receptor antagonists Glycoprotein iib/iia receptor inhibitors Phosphodiesterase inhibitors

Question 439

How does aspirin work?

Answer 439

Irreversible COX inhibition by acetylation of serine residues = antiplatelet activation and aggregation agent Also blocks PGI2 synthesis= decreased anti-thrombotic effect (BUT endothelial cells can resynthesise COX1 unlike platelets) Also reduces TxA2 as it is a vasoconstrictor

Question 440

Adverse effects of COX inhibitors?

Answer 440

GI bleedng Hypersensitivity/bronchospasm

Question 441

How do P2Y12 receptor antagonists act as antiplatelet drugs?

Answer 441

Inhibit platelet activation and aggregation by preventing ADP binding which normally activates platelets

Question 442

Mechanism of action of P2Y12 antagonists?

Answer 442

Primary drug metabolised to active form with thiol group --- thiol forms disulphide bond with cysteine residues in receptor = irreversible inhibition

Question 443

Adverse effecs of P2y12 antagonists?

Answer 443

Dysepsia Diarrhoea Rashes

Question 444

Cons of first generation p2y12 antagonists and pros of second gen?

Answer 444

Cons = longer onset of action, complex drug interactions Pros = less dependence on metabolism, quicker

Question 445

Why do glycoprotein iib/iia receptor inhibitors work?

Answer 445

When the receptors are activated by platelet agonists, fibrinogen can create cross-linked bridges between the receptors to induce platelet aggregation SOOOO blocking them prevent aggregation

Question 446

Adverse effect of glycoprotein iib/iia receptor inhibitors?

Answer 446

Thrombocytopenia

Question 447

How do phosphodiesterase inhibitors act as anti-platelet drugs?

Answer 447

Inhibit PDE so cAMP/cGMP increase = inhibited platelet activation and prolonged cAMP and cGMP mediated vasodilation in smooth muscle cells Also block adenosine uptake into platelets and endothelial cells = increasing extracellular adenosine concentration = vasodilation

Question 448

Adverse effects of phosphodiesterase inhibitors?

Answer 448

GI disturbances Headaches Dizziness angina pectoris Rashes

Question 449

Treatment of stable angina and primary prevention of acute coronary syndrome?

Answer 449

Aspirin low dose or P2Y12 antagonist

Question 450

Treatment of unstable angina (NSTEMI) and myocardial infarction (STEMI)?

Answer 450

Aspirin Aspirin + P2Y12 antagonist + more

Question 451

Secondary prevention of myocardial infarction treatment?

Answer 451

Low dose aspirin and P2Y12 antagonist (12 months)

Question 452

Treatment in percutaneous coronary intervention (angioplasty)?

Answer 452

Short term = aspirin + iib/iia inhibitor + heparin In prep for PCI = low dose aspirin and p2y12 antagonist

Question 453

What is thrombotic thrombocytopenic purpura?

Answer 453

Formation of small blood clots in blood vessels that appear as small purple bruises below the skin due to low platelet count

Question 454

2 main types of thrombotic thrombocytopenic purpura?

Answer 454

1. Inherited = mutations in ADAMTS12 gene or immunodeficiency in ADAMTS13 enzyme that breaks down von William factor 2. Acquired = drug induced or diseases or pregnancy

Question 455

Key aspects of the clotting cascade i must know?

Answer 455

Endothelial damage activates FX FX activates thrombin Thrombin activates fibrinogen to for fibrin clot

Question 456

Endogenous anticoagulants?

Answer 456

Anti-thrombin III and heparins

Question 457

What do anticoagulants do?

Answer 457

Inhibit factor X (FX)

Question 458

How do heparins work?

Answer 458

Can be unfractionated (UFH) and low molecular weight (LMwH) --- both bind antithrombin III and enhance its bind to factor Xa (inhibits)

Question 459

Negative of using heparins?

Answer 459

Hyperkalemia (aldosterone suppression) Osteoporosis

Question 460

What do heparins need to do to inhibit thrombin as well as factor Xa?

Answer 460

Bind antithrombin III AND factor IIa (thrombin) ---- but most LMWHs are too short to bind to exosite 2 of thrombin so they only inhibit factor Xa ---- UFH can do it SOOO activity decreases when molecular weight does

Question 461

Antidote that UFH has to reverse bleeding?

Answer 461

Protamine sulfate (a positively charged protein) --- binds to negatively charged UFH forming stable inactive ion pairs

Question 462

Cons of protamine sulfate as an antidote to reverse bleeding?

Answer 462

- Hypersensitivity and anaphylactic reaction - Less effective against LMWHs - Can cause immune thrombocytopenia (reduced platelets)

Question 463

What is fondaparinux?

Answer 463

An anticoagulant that mimics the binding sequence of heparin to antithrombin iii to enhance interactions of ATIII with factor Xa active site without causing thrombocytopenia

Question 464

Con of fondaparinux?

Answer 464

No antidote

Question 465

How do direct oral anticoagulants work?

Answer 465

Directly inhibit factor Xa to block conversion of prothrombin to thrombin ---- lasts 8-10 hours and has an antidote

Question 466

What are hirudin peptide analogues?

Answer 466

Bind and inhibit the free form of active thrombin --- lepirudin is an irreversible thrombin inhibitor, bivalrudin can be cleaved and displaced by fibrinogen

Question 467

What is dabigatran?

Answer 467

Oral anticoagulant that is taking in an inactive form and hydrolysed to active form Rapid and reversible thrombin inhibitor that inhibits both free and fibrin bound forms of thrombin as well as thrombin-idnuced platelet aggregation Has an antidote Success depends on metabolism

Question 468

How does warfarin act as an anticoagulant?

Answer 468

Inhibits vitamin K epoxide reductase to prevent vitamin k reduction so the factors involved in clotting cannot be carboxylated (activated) so they cannot bind to platelets

Question 469

How is warfarin activated?

Answer 469

Drugs that unbind it from albumin in the plasma (inactive when bound)

Question 470

Cons of warfarin?

Answer 470

Narrow therapeutic window Teratogenic

Question 471

5 things that increase action of warfarin?

Answer 471

1. Alcohol excess (decreased liver function) 2. Liver disease 3. Plasma protein binding displacement (NSAIDs) 4. CYP polymorphisms/inhibitors 5. VKORC polymorphisms (type a)

Question 472

4 things that decrease warfarin activity?

Answer 472

1. Chronic alcoholism (increases CYP activity) 2. Diet (vitamin K rich foods) 3. CYP enzyme inducers 4. VKORC polymorphisms (type b)

Question 473

What are the therapeutic applications of anticoagulants?

Answer 473

- Unstable angina and prevention of STEMI - Prophylaxis (prevent) of stroke in TIA (transient ischemic heart attack) - Prophylaxis and treatment of deep-vein thrombosis and pulmonary embolism - Thromboprophylaxis (prevent blood clots) - Warfarin is used in haemodialysis patients - Heparins are used after hip/knee replacements

Question 474

What is tranexamic acid and what is it used for?

Answer 474

A fibrinolytic agent that competively inhibits plasminogen activators by blocking lysine binding sites on plasminogen and it can block plasmin noncompetitively at high concentrations (inhibits fibrinolytic pathway)

Question 475

Therapeutic uses of tranexamic acid?

Answer 475

Haemorrhage complications Prophylaxis and treatment in patients at high risk of pre and post operative haemorrhage Periods

Question 476

Therapeutic uses of fibrinolytics?

Answer 476

In acute myocardial infarction to dissolve thrombus and prevent further ischaemic damage Acute thrombotic stroke Life-threatening thromboembolisms

Question 477

What do fibrinolytics do?

Answer 477

Decrease bleeding by inhibiting fibrinolytic pathway

Question 478

Define heart failure

Answer 478

When the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return

Question 479

Why has the incidence of heart failure increased?

Answer 479

Treatment of disease is better so the risk of getting heart failure is greater as it increases with age This is causing a heavy burden on the NHS

Question 480

Potential causes of heart failure?

Answer 480

- Ischaemic heart disease and MI - Cardiomyopathy (dilated or hypertrophic) --- reduces ability to pump blood - Systemic hypertension - Diabetes and obesity - Arrhythmias - Congenital heart defects like family history of enlarged heart, damage to heart valves or history of heart murmur - Inflammatory cardiomyopathy (myocarditis) - Pulmonary hypertension, COPD = right ventricle failure - Drugs and toxins (alcohol, cocaine, cytotoxic agents)

Question 481

4 types of heart failure?

Answer 481

1. High output heart failure 2. Low output heart failure 3. Systolic heart failure 4. Diastolic heart failure 2-4 are congestive 3 and 4 can be left or right sided

Question 482

What is high output heart failure?

Answer 482

Increased cardiac output DUE TO peripheral vasodilation (e.g. in anaemia, sepsis or hyperthyroidism) OR systemic arterio-venous shunting OR arterio-venous fistulae OR insufficiency of vitamin B1

Question 483

What is arteriovenous shunting?

Answer 483

Direct passage of blood from an artery to a vein (bypassing capillary network)

Question 484

What is arteriovenous fistula?

Answer 484

Abnormal connection or passageway between an artery or vein (bypassing capillaries)

Question 485

What causes low output heart failure?

Answer 485

Reduced cardiac output

Question 486

What is systolic heart failure?

Answer 486

Heart fails to contract properly = heart failure with reduced ejection fraction (HFREF)

Question 487

What is diastolic heart failure?

Answer 487

Heart fails to relax and fill properly during diastole = HF with preserved ejection fraction (HFPEF)

Question 488

Symptoms of right sided low output heart failure?

Answer 488

Fluid build up in abdomen (ascites) and swelling in legs and feet (pitting oedema)

Question 489

Symptoms of left sided low output heart failure?

Answer 489

Fluid build up in the lungs = shortness of breath, dyspnoea, cough Low tissue perfusion = fatigue, tiredness and exercise intolerance

Question 490

How does congestive heart failure progress?

Answer 490

Normal (no symptoms, normal exercise, normal left ventricle function) -----> Asymptomatic left ventricle dysfunction (no symptoms, normal exercise, abnormal left ventricle function) -----> Compensated congestive heart failure (no symptoms, reduced exercise, abnormal left ventricle function) -----> Decompensated congestive heart failure (symptomatic, further reduced exercise, abnormal left ventricle function) -----> Refractory congestive heart failure (symptoms cannot be controlled with treatment)

Question 491

Classification levels of heart failure?

Answer 491

Class I (mild) --- no limitations Class II (mild) --- slight limitation of physical activity causing fatigue, palpitation or dyspnoea Class III (moderate) --- marked limitation of physical activity Class IV (severe) --- cannot carry out physical activity without discomfort, issues at rest

Question 492

Symptoms of heart failure?

Answer 492

Fatigue Exercise intolerance Abdominal and peripheral oedema Breathing difficulties on exertion or at rest in sleep Cough

Question 493

4 pathogenesis factors of heart failure?

Answer 493

1. Impaired cardiac contractility and reduced cardiac output --- normally body could respond, but CHF means it is inefficient and only weakens heart further 2. Increased sympathetic activity (due to reduced cardiac output and activation of baroreceptors) 3. Activation of RAAS 4. Fluid and salt retention

Question 494

5 therapies for heart failure?

Answer 494

1. Positive inotropes = enhance cardiac output 2. Beta blockers = decrease cardiotoxicity of catecholamines (reduce sympathetic activity) 3. ACE inhibitors/Angiotensin ii receptor blockers = reduce RAAS activation 4. Diuretic = reduce fluid retention and oedema 5. Vasodilators = decrease total peripheral resistance and central venous pressure

Question 495

What is the first line treatment for congestive heart failure?

Answer 495

ACEI or ARB + beta blocker + diuretic

Question 496

Potential benefits of beta blockers in congestive heart failure treatment?

Answer 496

Inhibition of cardiotoxicity of catecholamines via increase in the density of beta1 adrenoceptors (increased contractility), anti-hypertensive, anti-anginal, anti-arrhythmic, antioxidant, antiproliferative

Question 497

What drugs may be added to first line therapy of congestive HF?

Answer 497

Aldosterone antagonists and/or hydralazine + nitrate vasodilators If the HF is associated with angina then a calcium channel blocker may be effective +positive inotropic agent

Question 498

Examples of positive inotropes used in the treatment of CHF?

Answer 498

- Catecholamines (beta1 adrenoceptor agonist) --- used in acute decompensated HF - PDE3 inhibitors --- used in short term treatment of acute decompensated HF (long term use = mortality) - Cardiac sensitisers --- used in acute decompensated HF - Cardiac glycosides --- used in worsening/severe HF

Question 499

How do catecholamines treat heart failure?

Answer 499

Stimulate beta1-adrenergic receptors = increased cAMP = calcium influx = stronger and faster contractions

Question 500

How do PDE3 inhibitors treat HF?

Answer 500

Inhibit PDE3 = increased cAMP = calcium influx = increased contractility and vascular vasodilation Increase cardiac output, reduce right atrial pressure and total peripheral resistance

Question 501

Adverse reactions of PDE3 inhibitors?

Answer 501

Lethal dysrhythmias, hypotension, headache

Question 502

Benefts of digoxin in CHF?

Answer 502

Anti-arrhythmic, positive cardiac inotrope, mild diuretic, reduces sympathetic activity

Question 503

Adverse effects of digoxin in CHF treatment?

Answer 503

Cardiac toxicity, GI issues, yellow vision, blurriness, dizziness, headache, bradycardia

Question 504

What conditions affect plasma levels and toxicity of digoxin?

Answer 504

1. Hypokalaemia (increased binding to Na-K-ATPase = increased toxicity and arrhythmia) 2. Hyperkalaemia (increased plasma levels = increased CNS and GI effects) 3. Hyperthyroidism (increases digoxin clearance) 4. Impaired kidney function (reduced excretion) 5. Drugs affecting excretion

Question 505

What conditions would reduce plasma digoxin?

Answer 505

Cytotoxic agents/radiotherapy = GI lining damage Chronic inflammatory bowel diseases

Question 506

How is digoxin toxicity prevented?

Answer 506

1. Low doses and monitoring of plasma levels 2. Oral K+ supplements in hypokalaemia 3. Steroid-binding resins 4. Digoxin-specific antibody fragments

Question 507

What is the NP system and how does it help counteract HF?

Answer 507

A system that releases natuiretic peptides which promote vasodilation to reduce BP, increase sodium and water excretion, inhibit RAAS and sympathetic activity

Question 508

How can BNP and NT-proBNP be used as HF biomarkers?

Answer 508

Levels of these indicate severity of heart failure and left ventricle dysfunction

Question 509

How can NP system be utilised in HF treatment?

Answer 509

Drugs could prolong beneficial effects of NPs

Question 510

How can angiotensin receptor-neprilysin inhibitor (ARNI) be used to treat heart failure?

Answer 510

Modulates NP system and RAAS Inhibits NEP and reducing breakdown of BNP and ANP to enhance beneficial effects Block AT1 recepotrs to inhibit Angiotensin ii's effects Basically enhances protective effects of NP system and blocks damaging effects caused by angiotensin ii

Question 511

What is the somatic nervous system?

Answer 511

Component of PNS associated with voluntary control of body movements via the use of skeletal muscles and is responsible for the reflex arc Cell bodies in brain stem, single motor neuron connecting CNS to skeletal muscle

Question 512

What is a motor unit?

Answer 512

The motor neuron and the muscle fibre it innervates (one axon innervates many fibres)

Question 513

What is the neuromuscular junction?

Answer 513

Synaptic connection between the terminal end of a motor nerve and a muscle where an action potential is transmitter (and it is a site of many diseases and a site of action for many drugs)

Question 514

How do nicotinic receptors on skeletal muscle motor end plate look and work?

Answer 514

Ligand-gated ion channel with many subunits --- ACh binds at two sites and triggers opening of cation channel = Na+ in, K+ out = depolarisation

Question 515

What does end plate depolarisation trigger?

Answer 515

Opening of proximal voltage-gated Na+ channels = action potential in muscle cells

Question 516

What does Na+ driven action potential open?

Answer 516

L-type calcium channels which stimulates Ca++ induced Ca++ release from intracellular stores = contraction

Question 517

How can the neuromuscular junction be interfered with?

Answer 517

- NMJ blockers to block nicotinic cholinergic receptors - Decrease ACh by inhibiting its synthesis or release - Increase ACh or ACh effect to enhance the nicotinic effects

Question 518

Why must the area under investigation be immobilised during anaesthesia?

Answer 518

Muscle spasm can occur due to mechanical manipulation of limbs and nerves --- reflexes are not suppressed until deep anaesthesia

Question 519

What drugs block NMJ?

Answer 519

Non-depolarising agents (nACh receptor antagonists) and depolarising blocking agents (weak nicotinic agonists) that interfere with post-synaptic action of ACh

Question 520

What are non-depolarising agents?

Answer 520

Competitive antagonists of ACh receptors at endplate e.g. d-tubocurarine

Question 521

How does d-tubocurarine work?

Answer 521

Binds nicotinic receptor as antagonist (must block 90% for an effect) --- causes decrease in end-plate potential by reducing the epp amplitude so no action potential is generated Causes paralysis by blocking NMJ transmission but not nerve conduction or muscle contractility

Question 522

Why do newer non-depolarising blockers have shorter durations of action?

Answer 522

It is determined by susceptibility to cholinesterases and clearance (safer and paralysis fades quicker after surgery)

Question 523

How does alpha-bungarotoxin work?

Answer 523

Irreversible binding to nACh receptors at NMJ to inhibit ACh binding and inhibit the ACh-induced electrical response

Question 524

Unwanted effects of non-depolarising blockers?

Answer 524

- Hypotension due to ganglion blockade - Histamine release from mast cells --- bronchospasm in sensitive individuals, not related to nicotinic receptor - Respiratory failure - Autonomic ganglion block at high doses - M2 blockade = tachycardia

Question 525

How do depolarising blocking agents work?

Answer 525

Mimic acetylcholine and bind and activate nicotinic receptors to cause persistent stimulation at the nicotinic receptors in muscles --- leads to initial muscle contraction followed by paralysis as receptor cannot reset They have a quaternary nitrogen group which helps them bind to the alpha-subunit of nicotinic receptors at the neuromuscular junction Causes initial twitching prior to the block

Question 526

What is phase i of depolarising blocking agents?

Answer 526

Depolarising phase --- muscle held in depolarised state, voltage-gated Na+ channels are refractory (no longer open in response to transmitter binding) ---- muscle becomes flaccid as Ca++ is taken into stores

Question 527

What is phase ii of depolarising blocking agents?

Answer 527

Desensitisation block --- persistent stimulation leads to receptor desensitisation (cannot occur with ACh as it is rapidly removed) --- muscle partially repolarises but transmission remains blocked --- may be a safety mechanism to prevent overexcitation

Question 528

How is depth of anaesthesia assessed?

Answer 528

Train of four that monitors degree of neuromuscular blockade by delivering electrical stimuli --- muscle response is observed

Question 529

What are the advantages of depolarising neuromuscular blockers like suxamethonium?

Answer 529

Rapid onset, useful for intubation, surgery during pregnancy/caesarian (they are ionised so cannot cross blood-placenta barrier), less likely to elicit histamine release

Question 530

Adverse effects of depolarising drugs?

Answer 530

Bradycardia Potassium release (causes hyperkalemia = dysrhythmia) Post operative pain Increased intraocular pain Prolonged paralysis (in plasma cholinesterase deficient individuals) Malignant hyperthermia

Question 531

Other uses of neuromuscular blockers?

Answer 531

Electroconvulsive therapy e.g. mental health issues Lethal injections (better if non-depolarising)

Question 532

How can a non-depolarising block be reversed?

Answer 532

By increasing ACh concentration

Question 533

Key differences between non-depolarising and depolarising blockers?

Answer 533

Depolarising are hydrolysed by plasma cholinesterase and are shorter acting Nondepolarising work on closed channels, depolarising work on open channels

Question 534

Way of reversing neuromuscular blockers?

Answer 534

Neostigmine --- acetylcholinesterase inhibitor, raises ACh in synapse, reverses non-depolarising block and potentiates depolarising block

Question 535

Another way of reversing neuromuscular blockers?

Answer 535

Sugammadex --- chelates aminosteroid non-depolarising blockers