Cardiovascular, Renal and PNS Pharmacology Flashcards Preview

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Flashcards in Cardiovascular, Renal and PNS Pharmacology Deck (343)
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0
Q

What does the somatic nervous system control?

A

Skeletal muscle and sensory inputs to CNS. Movement, pain, temperature touch etc.

Single neurone system with cell body in CNS, while axons project from spinal cord to synapse on skeletal muscle.

1
Q

What are the three divisions of the PNS?

A

Somatic efferent system
Somatic and visceral afferent system
Autonomic nervous system

2
Q

What doe the autonomic nervous system control?

A

An efferent nervous system.
Subconcious control of major organs and homeostasis.
Divided into two parts: parasympathetic and sympathetic.
It is a two neurone system with one called preganglionic neurone and the other the postganglionic neurone.
The pre has the cell body in the CNS and synapses at autonomic ganglia.
The post has the cell body in the autonomic ganglion and synapses on the target organ.

3
Q

In the parasympathetic autonomic nervous system where are the pre and post ganglion found?

A

Preganglionic cell bodies are in the cranial and sacral regions of the spinal cord and they send long axon projections to parasympathetic ganglia (In or near target organ)

Post ganglionic cell bodies send short axon projections which synapse on the target organ.

4
Q

In the sympathetic autonomic nervous system where are the pre and post ganglion found?

A

Preganglionic cell bodies and in the thoracic-lumbar region of the spinal cord and send axon projections to the paravertebral sympathetic chain.

Postganglionic cell bodies in the sympathetic chain send long axon projections that synapse onto the target organ.

5
Q

What is the function of the autonomic nervous system?

A

In many organs such as heart and GI the sympathetic and the parasympathetic nervous systems have opposing actions.

However in some organs they only receive innervations from one branch of the autonomic nervous system such as the blood vessels are mainly sympathetic and the kidneys and liver.

In some organs parasympathetic and sympathetic have the same effect eg in salivary glands they both increase secretion.

6
Q

What common response can the autonomic nervous system be related to?

A

The fight or fright response. Many of these effects are due to the sympathetic nervous system. Parasympathetic functions mainly during satiation and repose.

7
Q

What are the two main neurotransmitters in the autonomic nervous system?

A

Acetylcholine
Released from all autonomic preganglionic neurones and postganglionic parasympathetic neurones (cholinergic transmission)

Noradrenaline
Released from most postganglionic sympathetic neurones (adrenergic transmission)

8
Q

In general how are neurotransmitters synthesised?

A

Synthesised and stored in the pre junctional cell (releasing cell) of the nerve synapse.
Precursor molecules are actively transported (ATP dependant) into neurones where transmitter is then synthesised
Stored for future release in vesicles

9
Q

What happens when a neurotransmitter is released?

A

On nerve impulse the vesicles fuse with the plasma membrane. Transmitter diffuses to post junctional cell to cause effect. Transmitter signal then terminated by removal or destruction

10
Q

How is the neurotransmitter release regulated from the presynaptic neurone?

A

Two types of regulation both dependant on the activation of receptors of the presynaptic cell.

Homotrophic: transmitter released from neurone inhibits further release from the same neurone.

Heterotrophic: transmitter from a neurone inhibits release of a different transmitter from a different neurone.

11
Q

What are co-transmitters?

A

Neurones re,ease more than one transmitter and can modulate signal strength and duration.

They can increase (potentate) action of the neurotransmitter
OR
Mediate a different phase of a response
OR
indirectly increase the action of a neurotransmitter

12
Q

What is a separate nerve supply in the autonomic nervous system called?

A

Non adrenergic non cholinergic nerves NANCN.

13
Q

What is an example of a NANCN?

A

ATP in postganglionic sympathetic neurones for contraction of smooth muscle cells.
Dopamine in some sympathetic neurones in the kidney for vasodilation.

14
Q

What is the receptor for preganglionic neurones releasing acetylcholine?

Receptor for postganglionic parasympathetic neurones releasing acetylcholine?

Receptor for postganglionic sympathetic neurones releasing noradrenaline?

A

Acetylcholine nicotinic receptor

Muscarinic receptors

NA, adrenergic receptors

15
Q

What steps in the autonomic nervous system can be targeted by drugs?

A

All steps of transmitter synthesis (except diffusion released transmitter)

The transport mechanisms for transmitter re uptake of uptake of precursors.

Drugs that affect receptor and ion channels

16
Q

What is the autonomic ganglia?

A

Interface between pre and post ganglionic neurones of the autonomic nervous system.
Acetylcholine is the neurotransmitter
Most actions on nicotinic acetylcholine receptors

17
Q

What are the nicotinic effects?

A

Stimulation of autonomic ganglia
Stimulation of voluntary muscle
Secretion of adrenaline from the adrenal medulla

18
Q

What are the three classes of nicotinic receptors?

A

CNS,
Muscle
Ganglionic

All are ligand gated ion channels

19
Q

What does activation of nicotinic receptors cause?

A

Activation of nicotinic receptors cause depolarisation postganglionic cell body via influx of Sodium.

20
Q

What does a nicotinic receptor look like?

A

A 5 transmembrane domain that is ligand gated ie it can be opened and closed

21
Q

What do stimulants of the autonomic ganglia do?

An example?

A

They stimulate nicotinic receptors as well as activating peripheral ganglionic receptors
The effects are complex due to non specific stimulation of all the peripheral ganglia.

Lobeline and DMPP do this.

This causes tachycardia, increase in BP, increased secretions eg sweat and saliva.

22
Q

What are the three mechanisms of ganglion blocking drugs?

A

Interference of acetylcholine release
Prolonged depolarisation
Interference with post synaptic action of aceytlcholine.

Only used in labs never clinically.

23
Q

What drugs can interfere with aceytlcholine release?

A

Vesamicol.

This inhibits intracellular transporter responsible for accumulating newly synthesised acetylcholine into storage vesicles.

Botulinum toxin .

This prevents exocytosis of aceytlcholine. Clinical use at neuromuscular junction as BOTOX.

24
Q

What drugs can cause prolonged depolarisation blocking the ganglia?

A

Nicotine
Initial stimulation then prolonged exposure causes inactivation

Cholinesterase inhibition
Acetylcholine not broken down. Prolonged action of acetylcholine. Prolonged exposure cause inactivation.

25
Q

What two drugs interfere with the post synaptic action of acetylcholine?

A

Trimetaphan blocks the nicotinic receptor. It is sometimes used in surgery to lower blood pressure.

Hexamethonium blocks ion channel activity. It was the first clinically effective antihypertensive.

26
Q

What is the cardiac pacemaker?

A

The sinoatrial node

27
Q

In the cardiac conduction system what is the order of conduction?

A
SA node
Atria
AV node
Purkinje system (bundle of his) 
Ventricular muscle
28
Q

What are purkinje fibres?

A

Modified myocytes. They are wide and have the highest current conductivity meaning fast impulse propagation.

29
Q

When is the only time that current can flow to the surface of the body?

A

When the cardiac muscle is partly polarised and partly depolarised.

30
Q

What does an ECG provide information about? What does in NOT provide information about?

A

Anatomical orientation of the heart, relative sizes of the heart chambers, heart rate, rhythm and origin of excitation, spread of impulse, decay of excitation

It does not provide information about the contractile properties and pumping action of the heart.

31
Q

What are the 3 sections of the cardiac cycle seen on an ECG?

What are the 2 different measurements taken from this?

A

The P wave: atrial depolarisation
QRS complex: ventricular depolarisation
T wave: ventricular repolarisation

PR interval: measure of AV conduction interval
RR interval: measure of cardiac cycle length. (HR= 60/RR interval in seconds)

32
Q

What is arrhythmia and what is it used interchangeably with?

A

Literally means no rhythm. Used interchangeably with dysrhythmia which means abnormal rhythm.

Can either be ventricular or supraventricular

Caused by tissue ischaemia- myocardial infarction

33
Q

What are arrhythmia’s associated with? (Clinically)

A
Heart failure
Hyperthyroidism
Electrolyte disturbances
Autonomic dysfunction
Genetic disorders
Therapeutic intervention
34
Q

Where is the most common site of Conduction block?

A

The AV node.

35
Q

What is bradydysrhythmia? What are the causes and treatments? 2 of them.

A

This is slow heart rate.

Caused by either structural disease and treated with permanent cardiac pacing
Or drug induced so treated pharmacologically. Eg digoxin can cause it so treat with anti digoxin.

36
Q

What is tachydysrhythmia? What can it be caused by?

A

Fast heart rate. Means there is a shorter phase 4 from hypokalemia or mechanical stress

Or there are afterdepolarisations from sodium or calcium channel mutations

Or there is impulse re entry.

Or it is drug induced- beta blocker withdrawal, theophylline, quinidine, digoxin etc.

37
Q

What are the five classes of antidysrhythmics and what phases do they act on?

A

Beta agonists- pacemaker potential PHASE 4
Class 1- rapid depolarisation PHASE 0
Class 2- pacemaker potential PHASE 4 and plateau PHASE 2
Class 3 (and 1a)- repolarisation PHASE 3
Class 4- plateau PHASE 2

38
Q

Give examples of class 1a drugs what do they do and what are the direct and secondary effects?

A

Quinidine, disopyramide, procainamide.
Bock fast voltage gated sodium channels. They immediately dissociate.
Direct effects are decrease phase 0 depolarisation, decrease Vmax and velocity and increase effective refractory period ERP
Secondary effects are block potassium channels causing decreased phase 3 repolarisation

39
Q

What are examples of class 1b drugs, what do they do and what are the direct effects?

A

Lidocaine and mexiletine

Block of sodium channels dissociate rapidly so inhibits premature beat but does not alter normal rhythm.
Direct effects of decreasing phase 0 depolarisation and increasing block of sodium channels (thus decreasing Vmax) at high heart rate as it binds preferentially to open channels.

40
Q

What are examples of class 1c drugs? What do they do? What are the direct effects and what are the side effects?

A

Flecainide and propafenone.
They dissociate from the sodium channel slowly so cause a steady state block
Direct effects of decreasing phase 0 depolarisation, decreasing Vmax in healthy tissue in sinus rhythm.
Side effects are pro arrhythmic, MI.

41
Q
What are examples of class 2 drugs.
What do they do?
What do they HAVE to be in the presence of to work?
A

Propranolol and esmolol.
They are beta adrenergic receptor antagonists.
They have no effect in the absence of catecholamines
They bind to beta adrenergic receptors on cardia cell membranes to competitively inhibit noradrenaline binding.
There main action is to decrease diastolic depolarisation.

42
Q

What do class 3 drugs do? Give an example?

A

Amiodarone, Sotalol, Ibutilide, dofetilide.
Common property is potassium channel blocker
It increases AP duration and increases ERP.
Side effect is pro-arrhythmic

43
Q

What specific effects does amiodarone have?

A

It is a potent potassium channel blocker
Modest sodium, calcium channel blocker
Modest alpha and beta adrenergic receptor blocker.
It decreases SAN automaticity
It decreases AVN conduction velocity
It increases the refractory period AVN and ventricle

It is used for all supraventricular and ventricular arrhythmia’s.

44
Q

What do class 4 drugs do?give an example. How does it act?

A

Calcium channel blockers

Diltiazem
Acts primarily on slow response cells which are dependant on calcium influx for phase 0 of the action potential.

45
Q

In what nervous system is there noradrenaline and adrenaline release?

A

The sympathetic nervous system.

46
Q

Where are peripheral noradrenergic neurones located?

Where is noradrenaline synthesised stored and released?

A

The postganglionic cells of the sympathetic nervous system.

Cell bodies are in sympathetic ganglion and have long axons ending in varicosities that release noradrenaline in target tissues.

Noradrenaline is synthesised stored and released at these varicosities.

47
Q
The synthesis of noradrenaline
Where are the initial stages?
Where are the final stages?
What is the precursor molecule?
How is the process regulated?
A

The synthesis of noradrenaline
Where are the initial stages? In the cytoplasm
Where are the final stages? On the membrane of synaptic vesicle
What is the precursor molecule? The amino acid L-tyrosine
How is the process regulated? Noradrenaline regulates synthesis via a negative feedback process on initial step of synthesis.

48
Q

What are the molecular steps in the synthesis of noradrenaline?

A
Tyrosine
Enzyme tyrosine hydroxylase
DOPA
enzyme DOPA decarboxylase
Dopamine
Enzyme dopamine beta hydroxylase
Noradrenaline
Enzyme phenylethanolamine N-methyltransferase
Adrenaline
49
Q

What can inhibit the first enzyme in the synthesis of adrenaline?

A

This is tyrosine hydroxylase and is inhibited by alpha methyl p tyrosine. This has an occasional clinical use in pheochromocytoma a catecholamine secreting tumour

50
Q

What can inhibit the enzyme in the second stage of synthesis?

A

This is DOPA hydroxylase and it is inhibited by carbidopa. This is used in Parkinson’s disease to prevent peripheral effects of levodopa (as this only has a wanted effect in the central brain. Everywhere else it causes high blood pressure and racing heart so carbidopa stops this)

51
Q

What is methyldopa what does it treat and what are the unwanted effects of the drug?

A

This is a drug used to treat hypertension as it blocks the second stage of synthesis of noradrenaline (DOPA to dopamine).
Noradrenaline increases heart are so inihibiting synthesis will decrease heart rate.

It has unwanted effects centrally as it crosses the blood brain barrier causing sedation and depression so is no commonly used. It can also cause diarrhoea and impotence.

52
Q

Where is noradrenaline stored and what is it stored with? Why?

A

Stored in vesicles along with ATP. ATP is co released with noradrenaline and is a co transmitter. As the molecules have opposite charges it is thought that ATP helps keep noradrenaline in the vesicle and prevent leakage.

53
Q

What does reserpine do?

A

This prevents transport of noradrenaline into vesicles and leads to depletion of noradrenaline stores. It is an antihypertensive sold as a herbal hypertensive. It has side effects similar to methyldopa but also causes Parkinsonism.

54
Q

How is noradrenaline release regulated?

A

Depolarisation of the varicosities opens calcium channels stimulating the release of noradrenaline by exocytosis.

Noradrenaline regulates its own release by activating presynaptic alpha receptors inhibiting adenylyl cyclase, preventing calcium channel opening.

55
Q

What does the drug guanethidine do?

A

Prevents noradrenaline release.

56
Q

How is the noradrenergic transmission terminated?

A

By removal of noradrenaline from the synaptic cleft.

Either by NET located on presynaptic nerve terminals, actively transports noradrenaline back into nerve varicosities causing recycling.

Or by EMT, noradrenaline and adrenaline are actively transported then metabolised

57
Q

What drugs inhibit NET? X2

A

Imipramine clinically used in depression to increase catecholamine in the synaptic cleft. It has atropine like side effects.

Cocaine is a drug of abuse. Side effects include hypertension, convulsions, excitement and dependence. It has a local anaesthetic effect.

58
Q

When noradrenaline signal is terminated by EMT what is noradrenaline metabolised by?

A

By either monoamine oxidase (MAO) found mainly in neurones also liver and GI tract. Metabolises it to DOPA.

or by catecholamine-O-methyl transferase in neuronal and non neuronal tissue. It also metabolised DOPA produced by MAO.

Liver COMT metabolises circulating catecholamines.

59
Q

What are the 5 different adrenoceptors and what do they do?

A

Alpha 1: constrict most smooth muscle (except in GI tract where it relaxes)
Alpha 2: presynaptic inhibition of neurotransmitter release in sympathetic and parasympathetic neurones
Beta 1: increases heart rate and force of constricting
Beta 2: dilates/relaxes smooth muscle and increases noradrenaline release from sympathetic nerves
Beta 3: thermogenesis in skeletal muscle

60
Q

What adrenoceptor does adrenaline use? Noradrenaline?

A

Both can go to any adrenoceptor however:
Adrenaline has slightly more affinity for beta 2 and alpha 2
Noradrenaline is slightly more selective for alpha 1 and beta 1

61
Q

Which are positive adrenoceptors and which are negative?

A

Negative alpha 2.

All the rest are positive.

62
Q

What receptors are for each of these drugs?

Isoprenaline
Adrenaline
Dobutamine
Salbutamol
Salmeterol
Phenylephrine
Clonidine

Indirect action
Tyramine
Amphetamine
Ephedrine

A
Isoprenaline- beta
Adrenaline- beta over alpha
Dobutamine- beta 1
Salbutamol- beta 2
Salmeterol- beta 2
Phenylephrine- alpha 1
Clonidine- alpha 2

Tyramine- noradrenaline release
Amphetamine- noradrenaline release and MAO inhibitor
Ephedrine- noradrenaline release and beta agonist.

63
Q

What is another name for a agonist of sympathetic alpha and beta receptor

A

Sympathetic agonist
Adrenergic agonist
Sympathy mimetic agonist

64
Q

What are the effects of alpha adrenoceptor agonists and clinical uses?

A

Effect depends on receptor type activated
Selective alpha 1 agonists cause smooth muscle constriction, used as nasal decongestants
Eg phenylephrine, methoxamine
Stimulate mydriasis
Clinically useful

Selective alpha 2 prevent noradrenaline release and hence reduce BP. eg clonidine.

65
Q

What is the clinical use of adrenaline?

A

Used in cardiac arrest and anaphylactic shock

66
Q

What type of drug is dobutamine? What is it used for clinically?

A

It is a beta 1 agonist. It can increase cardiac contractility and is used to treat cardiogenic shock.

67
Q

What is salbutamol and what does it treat?

A

It is a beta 2 agonist. It relaxes bronchial smooth muscle and is used to treat asthma.

Can increase lean protein mass and lipolysis.

68
Q

Where are beta 3 receptors found?

What can the drug do?

A

Found in adipose tissue

May control obesity.

69
Q

Give an example of an antagonist of adrenoceptor?

A

A B receptor antagonist is propranolol

70
Q

What do alpha adrenoceptor antagonists cause?

A

Alpha 1 cause hypotension, postural hypotension

Alphav2 cause increased cardiac output and cause tachycardia

An example is phenoxybenzamine which causes long lasting covalent binding.

Phentolamine more selective but short acting

71
Q

What ending do drugs that are selective alpha 1 antagonists have?
What do they cause?

A

Azosin for example prazosin doxazosin terazosin.

Causes vasodilation and fall in arterial pressure clinically used as an antihypertensive drug

Also as a treatment for urinary retention.

72
Q

Give an example of selective alpha 2 antagonist and its use.

A

Yohimbine and synthetic analogue idazoxan are mainly experimental-the effects are debated.

It has vasodilator and stimulant effects. Used to treat male impotenance.

73
Q

What ending do beta adrenoceptor antagonists have? (Beta blockers)

What do they do within the body?

What are the clinical uses?

What are the side effects?

A

The olol drugs, such as propranolol, atenolol and metoprolol.
Have effects on the cardiovascular system. They reduce the effect of exercise or excitement on cardiovascular parameters. They reduce cardiac output, reduce renin release and reduce sympathetic activity. They also prevent tremor.

Side effects include bronchoconstriction- patients with asthma can be effected seriously.
Cardiac failure due to too much reduction in sympathetic tone
Brachycardia (low heart rate)
Reduce tremor
Hypoglycaemia- glucagon release is stimulated by adrenaline, this is blocked. Symptoms of hypoglycaemia (tremor) blocked by beta blockers so this side effect is often missed
Fatigue- due to CO and muscle perfusion during exercise
Cold extremities- loss of beta induced dilation of subcutaneous blood vessels
Erectile dysfunction
Lucid dreams

Used to treat hypertension, angina and cardiac dysrhythmias. Also glaucoma, hyperthyroid disease, anxiety,tremor, migraine.

74
Q

What do cholinergic receptors mediate?

A

The effects of acetylcholine

75
Q

What type of receptor are nicotinic receptor?

What are the two main types?

A

Ligand gated ion channels two main types are neuronal and neuromuscular

76
Q

What type of receptors are muscarinic?

A

G protein coupled receptors

77
Q

What do M1 muscarinic receptors control?
What do they do?
What does this cause?

A

They are neural receptors.
They control autonomic ganglia, and the gastric and salivery glands
They increase IP3 and DAG
They are coupled to Gq to activate the IP3 pathway

They cause CNS excitation, memory and gastric secretion.

78
Q

What do M2 muscarinic receptors control?
What do they do?
What does this cause?

A

They Are cardiac receptors
They control the atria in the heart

They decrease cAMP

They cause cardiac inhibition, neural inhibition and central effects such as tremor.

79
Q

What do M3 muscarinic receptors control?
What do they do?
What does this cause?

A

They are smooth muscle glandular receptors
They control they exocrine glands such as salivery, gastric
They contol smooth muscle such as the GI tract the eye and airways and bladder

They increase IP3 stimulation by being coupled to Gq.

They cause glandular secretion and visceral smooth muscle contraction

80
Q

What do M4 muscarinic receptors control?
What do they do?
What does this cause?

A

They are in the CNS
They decrease cAMP
They cause enhanced locomotion

81
Q

What do M5 muscarinic receptors control?
What do they do?
What does this cause?

A

They control the periphery: salivary glands, iris and ciliary muscle. Also CNS.
they cause increased IP3 secretion as they are coupled to Gq.

82
Q

Name some parasympathetic effects

A

Increased mucus secretion
Increased salivation
Increased gastric secretion
Increased GI motility

83
Q

What agonists act on muscarinic and nicotinic aceytlcholine receptors?

A

Acetylcholine used for cataract
Carbachol used for glaucoma
Methacholine used for bronchial provocation test.

84
Q

What symptoms are associated with muscarinic toxicity? Think SLUDGE.

A
Salivation
Lacrimation
Urination
Diarrhoea
Gastric upset
Emesis ie vomiting
85
Q

Name two muscarinic agonists that are still used clinically

A

Bethanecol used to assist bladder emptying
and pilocarpine used to constrict pupil, sweat, salivery and lacrimal.

They both cross the blood brain barrier causing central effects.

86
Q

What is another name for a muscarinic antagonist?

A

Parasympatholytics

87
Q

What type of drug is atropine?
What are its clinical uses?
What are the side effects?

A

Non selective competitive antagonist.
Used for anaesthesia, to treat anticholinesterase poisoning, to treat GI hyper motility
Side effects of urinary retention, dry mouth and blurred vision.

88
Q

What type of drug is scopolamine?
What are its clinical uses?
What are the side effects?

A

It is a non selective competitive antagonist
It is used to treat motion sickness and same as atropine ie GI motility etc
Side effects are the same as atropine ie blurred vision dry mouth and urinary retention constipation also amnesia.

89
Q

What type of drug is pirenzepine?
What are its clinical uses?
What are the side effects?

A

It is an M1 selective antagonist

90
Q

What type of drug is ipratopium?
What are its clinical uses?
What are the side effects?

A

It is a muscarinic antagonist.
It is used to treat irritant induced bronchospasm and asthma. BROWN INHALER!
Few side effects.

91
Q

In what muscarinic receptor type can negative feedback occur?

A

M2 receptors ie acetylcholine mediates its effects on acetylcholine.

92
Q

What are darifenacin, oxybutynin and tolterodine in clinical trials to be used for?

A

To treat stress incontinence
M3 selective
Side effects of dry mouth, blurred vision and constipation

93
Q

What nervous system response do antagonists of muscarinic receptors prevent?

A

Prevent parasympathetic responses.

94
Q

What are the two sections of smooth muscle in the eye? What do they do?

A

Iris- radial and sphincteric regulate pupil size and hence amount of light reaching the retina
Ciliary muscle- change refractive index of lens, accommodation.

95
Q

If there is increased activity in the parasympathetic nervous system what does this cause in the eye?
Decreased activity?

A

Increased causes pinpoint pupils miosis

Decreased causes dilated pupils mydriasis.

96
Q
In bright light what are the pupils?
In low light?
With an M3 antagonist?
With an a1 adrenoceptor agonist?
With an a1 adrenoceptor antagonist?
A

In bright light what are the pupils? Miosis
In low light? Mydriasis
With an M3 antagonist? Mydriasis
With an a1 adrenoceptor agonist? Mydriasis
With an a1 adrenoceptor antagonist? Miosis

97
Q

Name two uses of mydriatics?

A

Ocular examination

Prevention of synechia- adhesion of iris and lens

98
Q

What is glaucoma?

What does aqueous humour do?

A

A damaged optic nerve as a consequence of raised intra-ocular pressure. This pressure is determined by rate of production and drainage of aqueous humour.

Aqueous humour is produced continuously by ciliary body epithelium. It maintains intra ocular pressure, provides nutrients to cornea, lens etc and is released into posterior chamber.

99
Q

What pressure in the eye causes glaucoma?

A

Above 20mmHg

100
Q

What is open angle glaucoma?

What is closed angle glaucoma?

A

Open angle glaucoma is common. Obstruction of drainage through trabecular mesh work and into canal of schlemm.

Closed angle glaucoma is when the iris touches the cornea.
It blocks flow of aqueous humour from posterior to anterior chamber.

101
Q

What drugs improve drainage of aqueous humour?

What drugs inhibit formation of aqueous humour?

A

Miosis, muscarinic agonists, prostaglandin analogs

Beta blockers, alpha agonists, carbonic Anhydrase inhibitors

102
Q

What drugs specifically are used to improve drainage of aqueous humour?

A

Carbachol- mixed muscarinic and nicotinic agonist

Pilocarpine- muscarinic agonist, slow release formulation

103
Q

How is aqueous humour formation decreased?

What drugs do this?

A

A2: directly inhibits AH formation, decreases cAMP.
A1: vasoconstriction, decreased blood supply to ciliary body
Presynpaptic a2 auto receptors: decreases NE release and decreases beta stimulation

Adrenaline
Dipiverfrin.

104
Q

What do carbonic Anhydrase inhibitors do?

A

Decrease formation of aqueous humour by active transport of sodium.

For example acetazolamine and methazolamine.

105
Q

What beta adrenergic antagonist do for glaucoma? Give examples.

A

They block beta receptors, decrease the action of adrenaline and noradrenaline which decreases aqueous humour formation. It is topical not systematic.

Examples are timolol and betoxolol.

106
Q

In closed angle glaucoma emergency what drugs are used? What do they do?

A

Glycerin, urea. Both increase blood osmolarity causing water to go out of vitreous humour

107
Q

What other alternative treatments are there for glaucoma when pharmacology is not enough?

A

Use of lasers in trabeculoplasty and iridectomy.

Surgery to make a sceral flap.

108
Q

What is the somatic effect system layout?

A

Single motor neurone connecting CNS to skeletal muscle. Cell bodies are in the brain stem.

109
Q

How wide is the synaptic cleft of the NMJ?

A

50 to 70nm wide.

110
Q

What do the synaptic clefts lie opposite? What do they contain high concentrations of?

A

Opposite the release points for aceytlcholine

Contain high concentrations of acetylcholinesterase

111
Q

How is acetylcholine synthesised?

What does acetylcholinesterase make?

A

Acetate plus coenzymeA makes acetylCoA with acCoaA synthase
AcCoA plus choline makes acetylcholine with choline acetyltransferase

Acetylcholinesterase makes choline and acetate.

112
Q

How is aceytlcholine released from storage?

A

The action potential conducted along the motor nerve causes depolarisation and an influx of calcium. The influx of calcium stimulates the release of acetylcholine from storage vesicles into the synapse.

The nicotinic receptor at the neuromuscular junction contains 5 subunits, which surround the sodium channel. ACh binds to two of these subunits; (alpha) binding of acetylcholine results in opening of the sodium channel for one millisecond

113
Q

Where does the muscle type of nicotinic receptor occur?

What does it look like?

A

Occurs at the skeletal NMJ.

Just acetylcholine to nicotinic receptor (alpha1)

114
Q

Where does the neuronal type of nicotinic receptor occur?

What does it look like? (The pathway)

A

Occurs at the autonomic ganglia and also in the brain.

Acetylcholine to nicotinic receptor then along again to the sympathetic system.

Ie the nicotinic receptor is not in the sympathetic system

115
Q

What are focal innervated muscle fibres?

A

Muscle fibres that receive their innovation at a single end plate region.

Fibres of mammaliammuscles are focally innervated

116
Q

What are multiply innervated muscle fibres?

A

Receive dense innervation eg muscles of amphibia and birds.

117
Q

What happens when acetylcholine is applied to the neuromuscular junction?

What happens when it is applied to the nerve or the muscle apart from the junction?

A

In low quantities it elicits a muscular contraction

It does not cause any effect

118
Q

What do NMJ blocking drugs do?

What are the two types?

A

They interfere with post-synaptic action of ACh.

There are either:
Non depolarising agents which act by blocking ACh
Depolarising blocking agents which are weak agonists of ACh receptors.

119
Q

Give an example of a non depolarising agent, its effects on the body, what it binds to and what effect it has

A

Competitive antagonist of ACh receptor
Turbocurarine
Causes paralysis by blocking neuromuscular transmission but not nerve conduction or muscle contractility
Blocking receptors causes a decrease in end-plate potential

120
Q

What are all depolarising blocking agents? What number of carbons produces a ganglionic block?

What number of carbons block NMJ

what do they act on?

What is the action due to?

What side effect do the drugs have?

A

Symmetrical bisquarternary ammonium compounds
5 or 6 carbons ganglionic block
9 or 10 carbons that block NMJ

They act on the end plate just like ACh..

Action is due to a maintained depolarisation at the end plate region and loss of electrical exciteability.

The drugs produce a transient twitching of skeletal muscle.

121
Q

What are the three key differences between non-depolarising and depolarising blocking drugs?

A

Non depolarising block is reversible by increasing ACh concentration, depolarising is not.

Depolarising block produces initial fasciculations.

Suzamethonium is hydrolysed by cholinesterase and is short acting than tubocararine.

122
Q

How can suxamethonium be distinguished from tubocurarine?

A

Suxamethonium (depolarising) injected into chicks causes powerful extensor muscle spasms

Tubocurarine (non depolarising) causes a flaccid paralysis.

This happens in chicks because they have multiply innervated nerves. So one nerves goes to manny end plates however in mammals it’s only one end plate per fibre so end plate depolarisation is too localised to cause contraction on its own.

123
Q

Way can suxamethonium be used for?

A

Used as an adjunct to general anaesthesia when artificial ventilation is available.

Emergency intubation

C-sections (it does not cross the blood placenta barrier so does not affect the foetus’ respiration.

Lethal injections.

124
Q

What are some unwanted side effects of non depolarising drugs?

A

Hypotension due to ganglion block

Histamine release from mast cells:bronchospasm in sensitive individuals

Respiratory failure: assisted ventilation used.

125
Q

What are unwanted side effects and dangers of depolarising drugs?

A

Bradycardia: due to direct muscarinic action

Potassium release: increase in cation permeability at end plate causes net loss of K+

Increasing intraocular pressure: contraction of extraocular muscles

Prolonged paralysis: in small group of cholinesterase deficient individuals, when using anti-cholinesterase drug in liver diseases where plasma cholinesterase levels are low.

126
Q

What does hemicholinium do?

A

Act as a competitive inhibitor of choline uptake

127
Q

What does vesamicol do?

A

Blocks acetylcholine transport into synaptic vesicles

128
Q

What is a false transmitter?

A

A compound that has no depolarising actions

129
Q

What agents inhibit acetylcholine release through inhibition of calcium entry?

A

Agents that inhibit calcium entry such as mg2+, streptomycin and neomycin.

130
Q

What drugs inhibit acetylcholine release by presynaptic toxins?

A

The neurotoxins botulinum toxins; beta-bungarotoxin.

131
Q

Where can the botulinum toxin live?

What does it cause?

What is the main problem with it?

A

It lives in preserved food

It causes progressive parasympathetic and motor paralysis, dry mouth, blurred vision and difficulty in swallowing. Respiratory paralysis

Once the toxin is bound it is irreversible. So very high mortality.

132
Q

What is the main use of the botulinum toxin?

A

Injected into muscles locally as Botox.

Used to treat a form a persistent and disabling eyelid spasm.

133
Q

What does the alpha bungarotoxin do?

And the beta bungarotoxin?

A

Irreversible binding to nACh receptors at the NMJ competitively inhibiting acetylcholine binding post synaptic and consequently inhibiting the acetylcholine induced electrical response.

Toxin that acts on the presynaptic motor nerve terminals to block the release of acetylcholine

134
Q

How can there be increased acetylcholine or aceytlcholine effect at the NMJ?

A

By inhibiting cholinesterase the compound that hyrolyses acetylcholine to choline and acetate.

135
Q

What two distinct regions are there is acetylcholinesterase?

A

An esteratic site in which histidine imidazole ring and a serine OH group play important roles in activity

An anionic site that possesses a glutamate residue that binds the choine moiety of acetylcholine

136
Q

What happens in the three steps of cholinesterases action?

A

1- acetylcholine binds to anionic site via the choline moiety.
2- acetylcholine group is transferred to serine -OH group, choline is released
3- acetyl-serine is spontaneously hydrolysed to reveal enzyme in resting conformation.

137
Q

What is edrophonium?
What does it do?
Why is it not useful?

A

It is a short acting anticholinesterase
Forms a reversible ionic bond with aceytlcholinesterase at the anionic site and has very brief action.
Too short for clinical use

138
Q

What can carbamates be used as? Give examples? What do they do? What are they used for therapeutically?

A

They are medium duration anticholinesterases

They are competitive inhibitors at anionic and esteratic sites. Action is quite long lasting.

Used to reverse neuromuscular block

Neostigmine, physostigmine.

139
Q

What are irreversible anti-cholinesterases used for?why?

A

Used as war gases and pesticides

Very volatile and absorbed through the lungs and skin.

140
Q

What is the mode of action of irreversible anti-cholinesterases?

How can the enzyme be re activated faster?

A

They convalently bind the serine OH group at the esteratic site. There is no spontaneous hydrolysis of bound complex.
Recovery of the enzyme activity depends on re synthesis of the enzyme which can take weeks.

Reactivated faster using pralidoxime which brings an oxime group into close proximity with phosphorylated esteratic site. Basically rips off bound organophosphate from enzyme.

141
Q

What are anticholinesterase drugs used to treat?

A

Myasthenia gravis which is an autoimmune disease affecting the NMJ.
They block nicotinic receptors and prevent the interaction between acetylcholine and nicotinic acetylcholine receptors.

142
Q

What is the main functional unit of the kidney?

A

The nephron

143
Q

How is urine formed? 3 processes.

A

Glomerular ultrafiltration where blood pressure forces molecules from glomerular capillaries into glomerular capsule

Tubular reabsorption where diffusion and active transport return some of the molecules to the blood

Tubular secretion active transport moves molecules from blood to tubule.

144
Q

Where is 70% of sodium rebsorbed?

A

The proximal tubule.

145
Q

What kind of process is sodium reabsorption?

A

Active

146
Q

Where does sodium reabsorption occur? Where does it not occur?

A

In all tubular segments except the descending loop of Henle.

147
Q

When does water follow the movement of sodium?

A

It will follow passively if the segment is permeable

148
Q

What is the vasa recta?

A

The capillaries that surround the loop of Henle. Takes blood into medulla and back to cortex.

149
Q

What does urea recycling help maintain?

A

Hypertonic medullary interstitium.

150
Q

How can the collecting duct permeability to water be increased?

A

With ADH reabsorption. This increases permeability of collecting duct to water, by increasing number of water channels (aquaporins) in apical membrane.

151
Q

What is the main disorder of ADH secretion? What is it due to?

A

Diabetes insipidus- production of copious amounts of urine.

Due to either impaired ADH secretion or impaired response to normal ADH levels.

152
Q

What is the macula densa?
What is its functions?
What is it part of?
What does this do?

A

What is the macula densa? Patch of cells in wall of tubule near the end of the ascending loop of Henle and start of distal tubule.
What is its functions? Senses change in rate flow and decrease in sodium concentration
What is it part of? The juxtaglomerular apparatus.
What does this do? This secretes the hormone renin into the blood in the afferent arteriole.

153
Q

What does a decrease in sodium and choride concentration and blood pressure result in? In terms of renin release.

A
Decreased concentration 
Renin release
Angiotensin 1
Angiotensin 2
Aldosterone release from adrenal cortex
Increases sodium reabsorption.
154
Q

What does atrial natriuretic peptide cause?

What are the effects of this?

A

Causes an increase in blood volume and pressure released from stretched atrial myocytes

Effects of increasing dieresis by decreased renin secretion and sodium reabsorption, also dilating arterioles and increasing capillary permeability.

155
Q

What effects does aldosterone have on the collecting duct?

A

It opens sodium channels on the luminal membrane.

It increases number of sodium pumps on basolateral membrane.

156
Q

If too much potassium is ingested what happens?

A

This stimulates aldosterone secretion from the adrenal cortex, aldosterone increases sodium reabsorption at the expense of increased potassium secretion.

157
Q

What do diuretics do?

A

Increase the excretion of sodium and water from the body by acting on the kidney by decreasing the reabsorption of sodium and chloride from the filtrate.

Normally only 1% of filtered sodium is excreted, certain diuretics can increase this to 15-20%

158
Q
There are 5 types of diuretics what do they act on?
Loop diuretics
Thiazides
Potassium sparing diuretics
Carbonic Anhydrase inhibitors 
Osmotic diuretics
A

Loop diuretics act on thick ascending limb of the loop of Henle
Thiazides act on the early distal tubule
Potassium sparing diuretics act on the late distal tubule and collecting duct
Carbonic Anhydrase inhibitors act on the proximal tubule
Osmotic diuretics act of the proximal tubule.

All act on those parts of the nephron where active and selective solute reabsorption occurs.

159
Q
What do loop diuretics act on?
How powerful are they? 
Give an example of the drug? 
How do they act?
What are the clinical uses?
A

What do loop diuretics act on?thick segment of loop of Henle
How powerful are they? Most powerful diuretics cause torrential urine flow
Give an example of the drug? Furosemide.
How do they act? Sodium pump is the primary active transport mechanism. More sodium and chloride and potassium enter by a cotransporter system. Chloride levels through basolateral chloride channels and electroneutral potassium/chloride co transport. Some potassium enters lumen via potassium channels.
What are the clinical uses?hypertension complicated by renal impairment. Salt and water overload associated with acute pulmonary oedema, chronic heart failure renal failure etc.

160
Q
What do thiazides act on?
How powerful are they? 
Give an example of the drug? 
How do they act?
What are the clinical uses?
What is an adverse effect?
A

What do thiazides act on? Early distal tubule
How powerful are they? Moderate diuretic action
Give an example of the drug? Benzofluazide
How do they act? Same as loop diuretics
What are the clinical uses? Hypertension, mild heart failure, severe resistant oedema, to help prevent stone formation in idiopathic hypercalciuria.
What is an adverse effect? Causing erectile dysfunction.

161
Q

What is the main unwanted effect of loop diuretics and thiazides?

A

They cause potassium loss eg hypokalemia.
This occurs by 2 mechanisms
Blocks sodium reabsorption in earlier parts of the nephron and increased delivery to the collecting ducts
High flow rate produced by diuretics will favour potassium excretion

Ie continual flushing away results in increased potassium gradient from cell to lumen.

162
Q

What are the two types of potassium sparing diuretics?

A

Sodium channel blockers

Aldosterone antagonists

163
Q

What is the mechanism of action of potassium sparing diuretics?

A

Cells impermeable to water in the absence of ADH and sodium in the absence of aldosterone
Sodium pump in the basolateral membrane is the main source of energy for ion movement
Pottassium ions added to filtrate
Amiloride blocks luminal sodium channels normally activated by aldosterone.

164
Q

What do sodium channel blockers do?
what are drug examples?
Where do they act?Why is this an issue?

A

Remove the driving force for potassium secretion
Net effect is reduced sodium reabsorption and decreased potassium secretion.

Examples are amiloride and triamterene.

They act on collecting tubules and collecting ducts

This is only a small amount of the nephron so only small amount of efficacy.

165
Q

How do carbonic Anhydrase inhibitors work?
What is an example of a drug?
What is it used in?

A

Sodium ions are absorbed and hydrogen is secreted at luminal surface by an antiport mechanism.

Primary active transport mechanism is sodium pump,

166
Q

How do osmotic diuretics work?

Give a drug example.

What is it used to treat?

A

They are freely filtered at the glomerulus and increase osmotic pressure of tubular fluid and reduce reabsorption of water, acts on regions freely permeable to water such as proximal tubule, descending limp of loop of Henle and collecting tubules.

Mannitol.
Used in extreme cases of cerebral oedema and glaucoma, increase plasma osmolarity without entering brain or eye.

167
Q

What does caffeine do in the body?

A

It increases heart rate and blood pressure leading to increased renal blood flow and increased GFR leading to decreased re-absorption of sodium in the renal tubules.

The diuretic effect of caffeine is dependant on the amount consumed and duration of intake.
Eg 5 to 6 cups of tea.

168
Q

Why does alcohol have a diuretic effect?

A

It inhibits release of ADH from the pituitary gland.

169
Q

What are the common causes of chronic renal failure?

What is this treated by?

A

Severe hypertension, diabetes mellitus, glomerulonephritis, obstruction of the urinary tract.

Treated by loop diuretics to increase urine volume and sodium excretion
Also acetazolamine to correct alkalosis associated with the vomiting of renal failure
Also antihypertensive drugs
Angiotensin converting enzyme inhibitors are particularity effective.

170
Q

What happens in nephrotic syndrome?

What is it treated with?

A

Increased permeability of the glomerular basement membrane to proteins, particularily albumin, leading to proteinuria (protein in the urine)

Leads to an increase in the volume of interstitial fluid leading to tissue swelling.

Increases blood volume and venous and capillary pressures, and subsequently further Edema formation.

Treat with thiazides or loop diuretics to reduce fluid retention.

171
Q

What is Glomerulonephritis?
What are the symptoms?
What is used to treat it?

A

Range of kidney diseases characterised by inflammatory changes to the glomerulus.
Patients exhibit hematuria and proteinuria as well as diminished function.

Thiazides or loop diuretics to reduce fluid retention
Antihypertensives to contol blood pressure
Immunosuppressives

172
Q

What is oliguria?
What is it a feature of?
What is used to treat it?

A

What is oliguria? Reduced urine volume
What is it a feature of? Acute renal failure
What is used to treat it? Diuretic options are mannitol or furosemide

173
Q

What is the main function of the cardiovascular system?

What is the sub function?

A

The supply organs and tissues with sufficient blood, at a high enough pressure to maintain normal function.
To remove waste products from organs and tissues and deliver them to sites of elimination.

Us function:
Secretory function:release of atrial natriuretic peptide (ANP)

174
Q

How is cardiac output calculated?

A

Heart rate x stroke volume

175
Q

What 3 factors does cardiac function depend on?

A

Cardiac electrical activity
Cardiac contractility
Coronary blood flow

176
Q

What does atrial natriuretic peptide do? (ANP)
How many amino acids does it contain?
When is it released?

A

28 amino acid peptide
Released by atrial myocytes when stretched by increased blood volume

Acts on natriuretic peptide receptors linked to guanylyl cyclase causing increase in intracellular cGMP
increases glomerular filtration rate…increases dieresis and natriuresis.
Decreases renin and decreases aldosterone
Decreases sodium reabsorption
Causes vasodilation and increase in capillary permeability.

177
Q

What does adrenaline do to the heart?

A

Increases SAN and AVN beats per minute.

178
Q

What is the receptor in the heart for the sympathetic system? What is the second messenger systems?

What does it do to:
Heart rate
Force
Conduction velocity
Ap duration
A

Adrenoceptor Beta1

Increases cAMP/PKA

What does it do to:
Heart rate increase
Force increase
Conduction velocity increase
Ap duration  increase
179
Q

What is the receptor in the heart for the parasympathetic system? What is the second messenger systems?

What does it do to:
Heart rate
Force
Conduction velocity
Ap duration
A

Muscarinic M2

Decreases cAMP and K+ channel activation

What does it do to:
Heart rate decrease
Force no affect or decrease in atria
Conduction velocity decrease
Ap duration decrease
180
Q

What are the phases of cardiac action potential?

0
1
2
3
4
A

What are the phases of cardiac action potential?

0 rapid depolarisation
1 initial rapid depolarisation
2 plateau
3 repolarisation 
4 baseline
181
Q

During depolarisation what happens with the various ions?

A

Sodium influx and calcium influx

182
Q

What happens with the various ions during hyperpolarisation/repolarisation

A

Potassium efflux

183
Q

How does calcium enter the cardiac myocytes?

A

Calcium channels during AP phase 2 plateau.

184
Q

What are the two types of voltage dependant calcium channels in the heart?

A

L-type VDCC (dihydropyridine receptors)
Slow activating and low inactivating current
Present in all cardiac cells
Important in maintaining cardiac plateau phase
Activity is enhanced by sympathetic stimulation via cAMP dependant phosphorylation, directly by Galpha subunit
Activity is inhibited by parasympathetic stimulation

T-type VDCC
Slow activating and rapidly inactivating current
Present In atrial cells, generally less common than L-type

185
Q

In SAN cells what is different about the threshold potential?
What is the unstable resting potential called?

A

Threshold potential is more positive
Slow upstroke of AP causes slow conduction

Unstable resting potential-called pacemaker potential

186
Q

What is the funny current selective to? How is it activated? How is it modulated?

A

No selective to monovalent cations sodium and potassium. At physiological conditions mainly sodium influx

Activated by hyperpolarisation or directly by cAMP

Modulation is
Sympathetic stimulation via beta 1 adrenoceptors
Parasympathetic inhibition via muscarinic receptors

187
Q

What happens in the absolute and relative refractory periods?

A

In absolute there is no propagation of second stimulus

In relative propagation of two stimulus but strong second stimulus required

188
Q

What two factors does cardiac contractility depend on?

A

Level of cytosolic calcium and the sensitivity of myofilaments

189
Q

What do positive inotropes do?

What do negative inotropes do?

A

Positive increase contractility so increase force of contraction

Examples are noradrenaline from sympathetic nerves, adrenaline from the circulation and digoxin

Negative decrease contractility so decrease force of contraction

Examples are intracellular acidosis (decrease in pH, occurs during ischaemia)

PARASYMPATHETIC STIMULATION DOES NOT AFFECT CONTRACTILITY

190
Q

How does contraction in cardiac muscle happen? Ie calcium.

A

Opening of L-type voltage dependant calcium channels
Calcium induce d release of calcium from the sacroplasmic recticulum
Binding of calcium to trogon in C and activation of actin-myosin interactions causes contraction
Removal of calcium from to cytosolic causes relaxation

191
Q

What is CICR?

A

Calcium induced calcium release.

Activation of RyR causes calcium release, activation of more RyRs causes more calcium release.

Not sure what RyR is???!!!

192
Q

What are the two ways to terminate the intracellular rise of calcium in cardiac muscle?

A

Elimination of calcium influx through L type VDCC by membrane repolarisation due to potassium efflux, or inactivation by intracellular calcium.

Elimination of calcium release from the SR by local depletion of SR calcium of ryanodine receptor inactivation.

193
Q

What are the two major mechanisms of calcium removal from the cytosol to cause relaxation?

A

Calcium reuptake into the SR by SERCA.

Calcium extrusion by sacrolemmal

194
Q

What is the calcium reuptake into the SR by SERCA regulated by? What is it activated by?

A

Regulated by phospholamban

Activated by calcium with the threshold of between 100-200nM.

195
Q

How does phospholamban regulate calcium reuptake into the SR by SERCA?

A

Dephosphorylated phospholamban (PLB) reduces SERCA affinity for calcium so reduces calcium reuptake into the SR

phosphorylated PLB increases SERCA activity so calcium uptake is increases and the relaxation rate of the heart is increased

196
Q

What is the process of calcium extrusion by sacrolemmal? (Sodium/calcium exchange) what does its activity depends on? Where does it remove calcium from?

A

Removes calcium from outside the side.
Activity depends on ion gradients. Exchanges 3 sodium for 1 calcium.

During repolarisation (phase 3) there is an increase in intracellular calcium, so calcium effluxs by the exchanger so intracellular calcium decreases and causes relaxation.

During depolarisation (phase 0) there is an increase in intracellular sodium, so sodium effluxs by the exchanger and calcium influxes from the exchanger, causing increase in intracellular calcium so contraction.

197
Q

What is frank starlings law of the heart?

What are the three most significant physiological outcomes?

A

The more cardiac muscles are stretched, the greater the force of contraction.

The stroke volume on the left and right side of the heart are matched.
Prevent accumulation of blood in the heart and veins
Important compensatory mechanism in heart failure.

198
Q

In skeletal muscle what determines muscle tension?

In cardiac muscle what determines muscle tension?

A

The degree of overlap determines the active muscle tension in skeletal muscle.

In cardiac muscle calcium sensitivity of myofilaments is length dependant. An increase in sacromere length increases sensitivity of myofilaments to calcium so increases force of contraction.

199
Q

How does the drug levosimendan work?

What is it used to treat?

A

It increases cardiac contractility by binding to troponin C in calcium dependant manner stabilising it and the actin-myosin cross bridges without increases myocardial consumption of ATP.

Used the treat severe acute decompensated heart failure.

200
Q

What causes occurs during ischaemia?

A

Acidosis (decrease in pH)
Increased phosphate concentration
Increased magnesium concentration.

201
Q

What are the energy sources for aerobic respiration?

A

Fatty acid oxidation

Oxidation of carbohydrates

202
Q

How is the oxygen consumption of cardiac muscles spread out? As in what consumes the most and the least

A

50% contraction
20-30% basal activity
20% relaxation

203
Q

What does coronary flow occur primarily during? Systole or diastole?

A

During diastole

204
Q

What are collateral vessels for?

A

Provide an alternative route for blood if primary vessels are occluded.

205
Q

What happens when cardiac workload is increased? Answer in relation to AMP and adenosine

A

Increased cardiac workload causes increased ATP breakdown causing an increase in AMP. Because of this more adenosine is released, which causes adenosine receptor activation on smooth muscle cells which increases cAMP and leads to vasodilation

206
Q

What is hyperaemia?

A

An increase in blood flow to different tissues in the body.

207
Q

How do hypoxia and potassium cause vasodilation?

A

Hypoxia is a decrease in oxygen levels, this opens ATP sensitive K channels in SM. causing membrane hyperpolarisation and vasodilation.

Potassium increases extracellularily. This activates sodium potassium ATPase in SM causing membrane hyperpolarisation and vasodilation.

208
Q

How is cardiac blood flow indirectly regulated by neurones?

A

Main effect of sympthatic stimulation is vasodilation. Through increases contractility and increased heart rate leading to increased oxygen demand.

209
Q

How many layers of smooth muscle cells do capillaries have?

What does this mean?

A

Have only one layer of smooth muscle cells and so are unable to constrict.

210
Q

What do perivascular nerves release?

A

Noradrenaline

211
Q

How are actin and myosin arranged in a smooth muscle cell?

A

Arranged like a mesh.

212
Q

What complex is not present in smooth muscle?

A

Troponin complex. Control is by myosin light chain (MLC)

213
Q

What Are the two ways in which contraction occurs in smooth muscles?

A

By calcium dependant pathways (calcium release and calcium entry)

And by calcium independent pathway (calcium sensitisation)

214
Q

What happens in the voltage idependant pathway of calcium contraction?

A

Noradrenaline binds to alpha 1 adrenoceptor coupled to Gaq/11 protein subunit.
this activates PLC which breaks down PIP3 into IP3 and DAG.
IP3 binds to the IP3 receptor in the SR. This causes calcium to be released
Increases cytosolic calcium causes contraction.

215
Q

What is the voltage dependant pathway of calcium dependant contraction?

A

Calcium passes through the voltage dependant calcium channel which causes increase in cytosolic calcium causing contraction.

216
Q

What happens when nitric oxide gets into a smooth muscle cell?

A

It causes convention of GTP to cGMP
This activates protein kinase G.
This causes MLC phosphatase to not phosphorylate MLC which causes relaxation.

217
Q

What is Rho? What does it do within a cell? (In terms of contraction)

A

Rho is a GTP binding protein.

It inhibits MLC phophatase causing a shift towards contraction

218
Q

What two mechanisms lead to calcium sensitisation?

A

The activation of Rho, or the activation of PKC by NO.

Both lead to MLC phosphatase inhibition and increase or maintain contraction.

219
Q

Give an example of a locally induced change in the chemical composition of the extracellular fluid surrounding a smooth muscle cell that could have an effect on the smooth muscles contractile activity?

A

Histamine from mast cells.

Thromboxane from platelets.

220
Q

What vasodilators can the endothelial cells release in the artery wall?

A

NO, PG12 and EDNF.

221
Q

Release of vasodilators from the endothelium can be caused by?

A

Increase in EC calcium by agonists (adrenaline,bradykinin)

Mechanical forces (blood flow, pressure)

222
Q

What is the role played by PGI2 in endothelium dependant relaxation?

A

PGI2 activates IP receptor on SMC. the IP receptor is coupled to adenylate cyclase. This generates cAMP. Camp activates protein kinase A which regulates MLC kinase (this phosphorylates MLC causing contraction)

223
Q

When is the EDHF response typically observed?

What does it involve?

A

When other relaxing factors are inhibited.

Involves endothelium calcium activated potassium channels and gap junctions.

224
Q
How do nitrate drugs work?
How do molsidomine drugs work?
How do alpha blockers work?
How do ACE inhibitors work?
How do potassium channel activators work?
How does hydrazine work?
A

How do nitrate drugs work?act as NO donors
How does molsidomine work? Metabolised in the liver to form unstable drug that releases NO
How do alpha blockers work? Eg prazosin removes basal sympathetic contraction to cause relaxation
How do ACE inhibitors work? Eg captopril reduces angiotensin 2 levels and removes its constrictor action on VSM in resistance arteries causing passive relaxation
How do potassium channel activators work? Eg minoxidil causes VSM hyperpolarisation which closes VDCC leading to relaxation
How does hydrazine work? Interferes with IP3 mediated release of intracellular calcium.

225
Q

How is arterial blood pressure calculated?

A

Peripheral resistance x cardiac output

226
Q

What is starlings law?

A

Stroke volume is dependant on venous return/filling pressure

227
Q

Why is high blood pressure harmful?

A

It is a risk factor for CHD and stroke as it puts strain on blood vessels
Can cause endothelial cell damage leading to atherosclerosis
Can cause kidney damage and failure
Can cause left ventricular hypertrophic which is increased cardiac mass leads to reduced cardiac output

228
Q

Name some risk factors for cardiovascular diseases?

A
Smoking
High salt intake
Lack of exercise
Obesity
Alcohol
Dyslipidaemias
Diabetes
Genetic
Gender
Age
229
Q

What are the two types of hypertension?

A

Essential (primary) hypertension which means there is no apparent cause

Secondary hypertension which means hypertension is secondary to another disease such as adrenal gland disorders, kidney diseases and drugs.

230
Q

What are the different stages of hypertension?

At what stage is treatment initiated in?

A

Stage one 140/90
Stage two 160/100
Stage three 180/110

Stage 2 and 3 have treatment and stage 1 but only if there is organ damage, established cardiovascular disease, renal disease, diabetes or a 10 year CV risk equivalent to over 20%

231
Q

What are the treatment goals for blood pressure in the under 80s and over 80s?

A

Under 80 is 140/90

Over 80 is 150/90

232
Q
Where do each of these drugs act?
Alpha 2 adrenoceptors agonists-
Imidazole receptor agonists-
Sympathetic ganglion blockers-
Andrenergic neuron blockers-
Beta adrenoceptor antagonists-
Beta 2 adrenoceptor agonists-
Alpha 1 adrenoceptor antagonists-
ACE inhibitors-
AT1 receptor inhibitors-
Direct acting vasodilators-
Calcium channel blockers-
Potassium channel openers-
Alpha 1 adrenoceptor blockers-
Dopamine D1 receptor agonists-
Diuretics-
ACE inhibitors-
AT1 receptor inhibitors-
Beta adrenoceptor antagonists-
Dopamine D1 receptor agonist-
Renin inhibitors (alkskiren)
A

THE SYMPATHETIC NERVOUS SYSTEM
Alpha 2 adrenoceptors agonists- brain
Imidazole receptor agonists- brain
Sympathetic ganglion blockers-
Andrenergic neuron blockers-
Beta adrenoceptor antagonists-heart, kidney
Beta 2 adrenoceptor agonists-blood vessels
Alpha 1 adrenoceptor antagonists- blood vessels

BLOOD VESSELS
ACE inhibitors-
AT1 receptor inhibitors-
Direct acting vasodilators-
Calcium channel blockers-
Potassium channel openers-
Alpha 1 adrenoceptor blockers-
Dopamine D1 receptor agonists-
KIDNEY
Diuretics-
ACE inhibitors-
AT1 receptor inhibitors-
Beta adrenoceptor antagonists-
Dopamine D1 receptor agonist-
Renin inhibitors (alkskiren)
233
Q

What type of drug are clonidine and alpha methyldopa?

What are they used to treat?

A

They are alpha 2 adrenoceptor agonists acting centrally on the sympathetic nervous system

Clonidine is used to treat insomnia

Methyldopa is used in pregnancy

234
Q

What type of drug is moxonidine?

What is it used to treat?

A

It is an imidazoline I1 receptor agonist in the sympathetic nervous system.

Used to treat mild to moderate essential hypertension used when thiazides, beta blockers or calcium channel blockers are not working or contraindicated. Not to be used with thiazides as they enhance each others effect.

235
Q

What do clonidine, alpha methyldopa and moxonidine do in the body? (Mechanism of action)

A

Reduction in the activity of vasomotor centre in the brain leading to decrease in sympathetic activity-useful effect, and increase in parasympathetic outflow- bad for the heart.

236
Q

What type of drug is trimetaphan? What receptor does it act on? What is its mechanism of action? Is it used much?
What are the side effects?

A

It is a ganglion blocking drug.

It is a nicotinic acetylcholine receptor competitive.

It causes a general blockade of parasympathetic and sympathetic ganglia.

It is obsolete except in some highly specialised surgical procedures.

Causes postural hypotension and inability to focus eyes (cycloplegia)

237
Q

What type of drug is reserpine? What is its mechanism? What are its clinical uses?
What is its contraindications? What are its side effects? Is it used?

A

It is a adrenergic neurone blocking drug.
It is taken up by uptake1 and irreversibly inhibits monoamine pump on synaptic vesicles stored noradrenaline.
Used with diuretics

Not to be used with MAO inhibitors
Side effects of hypotension and worsening asthma, also bradycardia.

Not used in the UK but is used in some developing countries.

238
Q

What type of drug is guanethidine?
What is its mechanism of action?
What is its clinical uses?
What are its main side effects?

A

It is an adrenergic neurone blocking drug
it is taken up by uptake 1
It competes with noradrenaline at the vesicular monoamine pump, reducing stored noradrenaline. It blocks noradrenaline release.

Used in severe hypertension

Side effect of postural hypotension ( blood doesnt reach brain fast enough as blood vessels relaxed.

239
Q

What type of drugs are prazosin, doxazosin and urapidil?
What is their mechanism of action?
What are their other benefits?
What are there clinical uses?
Side effects?
What do they cause less of than other drugs for the same condition?

A

Alpha 1 adrenoceptor antagonists

Blocks of post synaptic alpha 1 adrenoceptors on arterial resistance vessels.
Dilates venous capacitance vessels leading to decreased Venus return so decreased preload
Little reflex tachycardia.

Other benefit of reducing LDL/VLDL
Clinical uses in patients where other drugs intolerant or ineffective or in patients with benign prostate hyperplasia.

Side effects of postural hypotension, dizziness and fatigue.

Cause less sedation dry mouth and male impotenance

240
Q
What types of drug are 
Atenolol-
Metoprolol-
Propranolol-
Pindolol-
Labetalol-
Carvedilol-
Nebivolol-

What are the selective for?
What is the mechanism of actions?

A

They are all beta adrenoceptor antagonists. Ie beta blockers.

Atenolol- beta 1
Metoprolol- beta 1
Propranolol- beta 1 and 2
Pindolol- beta 1 selective also partial beta agonist when sympathetic activity is low meaning less bradycardia.
Labetalol- beta 1 and alpha 1
Carvedilol- beta 1 and alpha 1
Nebivolol- beta 1 selective can also stimulate NO release in vascular endothelium. Meaning less fatigue, bradycardia and impotenance.

Reduction of heart rate and contractility
Blockade of juxtaglomerular beta adrenoceptors leading to decreased renin secretion.

241
Q

What are the main side effects of beta blockers?

A

They cause bronchoconstriction meaning they are contraindicated in asthma.

Increase risk of hypoglycaemia and decrease of hypoglycaemia awareness.

242
Q

Give an example of thiazides

Give an example of loop diuretics

Give an example of potassium sparing diuretics

When are each other these drugs used?

A

Thiazides- bendrofluazide, chlorothiazide
First line treatment in elderly and African-Caribbean people

Loop diuretics- furosemide, bumetanide
In non responsive to thiazides
In patients with renal insufficiency

Potassium sparing diuretics- amiloride, triamterene, spironolactone.
With thiazides if hypokalemia develops.

243
Q

What system do captopril and enalapril effect?

What type of of drug are they?

What do they do?

What drug are they usually combined with?

What is the main side effect?

What are they contraindicated in?

A

The renin angiotensin aldosterone system.
They are ace inhibitors
They reduce peripheral resistance with little effect on heart rate or cardiac output
Reduce sodium retention due to decreased aldosterone

Beneficial use with diuretics

Main side effect is a cough due to prolonged half life of bradykinin

Contraindicated in pregnancy due to veto toxicity, and with NSAIDs due to renal failure.

244
Q

What type of drug is losartan?
What is in contraindicated in?
Why is it preferred to ACE inhibitors?

A

Angiotensin receptor AT1 antagonist

No effect on bradykinin levels meaning no cough

Contraindicated in pregnancy.

245
Q

What type of drug is alkskiren?

What does it do?
What does it treat?

What are the main side effects?

A

It is a renin inhibitor

It inhibits renin activity by binding to it and preventing conversion of angiotensinogen to angiotensin 1.
Treats primary essential hypertension

Side effects of head and neck angioedema
Hypotension
Hyperaemia

246
Q

What are the three classes of L-VDCC blockers?

What tissue are they selective to? Give examples of each type.

What are the clinical uses?

What are the side effects?

A
  1. 1,4 dihydropyridines- nifedipine and amlodipine. Selective to vascular tissue
  2. Phenylalkylamines- verapamil. Selective to cardiac tissue.
  3. Benzodiazepines- diltiazem. Intermediate tissue selectivity.

The most effective are class 1. They are first line antihypertensive treatment in elderly and African/Caribbean patients.

Side effects of postural hypotension, flushes, tremors.
Can’t use nifedipine after acute myocardial infarction as it increases mortality.
AV. Block and negative inotropic effects.

247
Q

What are the third generation of dihydropyridine calcium channel blockers?

What do they do?

A

Benidipine, manidipine, nilvdipine, efonidipine.

Long lasting
Improve renal function
Block L type and T type calcium channels in the vasculature.

None available in the UK yet.

248
Q

How do potassium channel activators work?

A
Potassium channel opens
Membrane hyperpolarisation
L-VDCCs close
Vasorelaxation
Decrease in peripheral resistance.
249
Q

What are minoxidil and diazoxide drug types?
What is the mechanism?
What is the clinical use?
Side effects?

A

Potassium channel activators

Activates ATP Sensitive potassium channels in vascular smooth muscle cell membrane.

Used in severe hypertension and if renal failure.
With diuretics and beta blockers

Side effects of reflex tachycardia and fluid retention
Stimulates facial hair growth.

250
Q

What type of drug is hydralazine?

What is its mechanism?

What is it used in?

Side effects?

A

Direct acting vasodilators, third line drug.

Uncertain mechanism. May increase cGMP

Used in mild to moderate hypertension
Used in hypertensive emergencies
In pregnancy
With beta blockers and thiazides diuretics

Side effects of reflex tachycardia and fluid retention
Can cause lupus like syndrome.

251
Q

What type of drug is fenoldopam?

What are its clinical uses?

A

Dopamine D1 receptor agonist.

Short acting vasodilator, increases renal perfusion, enhances natriuresis.

Used in high risk surgery, kidney transplants, in hospital control of severe hypertension.

252
Q

What is atherosclerosis?

What is is a major cause of? X2

A

is a disease of the intima (epithelial cells in living artieries) of large and medium sized arteries resulting in the formation of atheromatous lesions or plaques.

It is a major cause of myocardial infarction
And stroke.

253
Q

What are the modifiable risk factors of atherosclerosis?

A

Hypertension, diabetes can treat these

High fat diet, obesity, lack of exercise, smoking, alcohol can change life style

Increased cholesterol (hypercholesterolaemia) can treat with lipid lowering drugs.

254
Q

What is hypercholesterolaemia a form of?

When there is increased cholesterol and triglycerides what is it called?

When hypercholesterolaemia has genetic causes what is it called?

A

What is hypercholesterolaemia a form of? Hyperlipidaemias

When there is increased cholesterol and triglycerides what is it called? Combined hyperlipidaemia

When hypercholesterolaemia has genetic causes what is it called? Familial hypercholesterolaemia

255
Q

What are normal plasma cholesterol levels?

A

Lower than 5.2 mmol/L

256
Q

Which is good and which is bad cholesterol?

A

Low denisity lipoprotein is bad

High density lipoprotein is goodish.

257
Q

What is the guideline of total cholesterol? What is the guideline for LDL cholesterol?

A

Under 4.0

Under 2.0

258
Q

How are LDL and HDL cholesterol transported?

What makes LDL bad and HDL good?

A

Transported in the blood.

LDL has a consistent structure. The phospholipids make it soluble.

HDL pick up triglycerides extruded from the cell and take them away.

259
Q

How is cholesterol synthesised?

A

It is continually synthesised by the endogenous pathway. It is synthesises in the liver from hepatocytes. ACoA converted to MVA which is converted to a cholesterol prescursor VLDL. These contain triglycerides and esterased cholesterol.

260
Q

What does endothelial dysfunction result in?

A

Reduced production of prostacyclin (PIP2 and PGI2)

Reduced production of nitric oxide

261
Q

How are prostaglandins synthesised?

What can block the enzymes involved?

A
Membrane phospholipids 
Converted by phospholipase A2
Arachidonic acid
Converted by COX-1 and COX-2
Cyclic endoperoxides
Prostaglandins 

NSAIDS and glucocorticoids block COX 1 and 2.
Lipocortin blocks phospholipase A2.

262
Q

What happens when platelets are activated?

What enhances this?
What prevents this?

A

They aggregate.
ADP enhances this
Prostacyclin and nitric oxide prevent this.

263
Q

How are atherosclerotic plaques formed?

A

Oxidation of LDL by free radicals, lipid peroxidation of LDL receptors on EC’s. macrophages migrate into intima and fatty streaks are formed.

The vessels try to repair themselves so cytokines are released and growth hormones by platelets, macrophages and ECs lead to proliferation of SMC’s; lipid accumulation and deposits calcification forms a fibrous cap over damaged area.

The plaque becomes unstable there is an increase in macrophages and a decrease in SMCs and matrix proteins destabilise plaque: platelets activation lead to release of blood clothing factors; blood clot formation.

SMC is smooth muscle content.

264
Q

How do simvastatin, lovostatin, pravastatin, atorvastatin work? ( mechanism of action)
What are the clinical uses and side effects?

What is the effect of grapefruit juice on statins?

A

Reversible competitive inhibition of 3-hydroxy-3-methylglutaryl (HMG)- CoA reductase. This is a key enzyme in the production of cholesterol.
There is a compensatory increased synthesis of LDL receptors and HMG-CoA reductase so cholesterol is taken back into hepatocytes from the blood.
Also decreased triglycerides and increased HDL.

Clinical uses: primary prevention of arterial disease with elevated serum cholesterol. Secondary prevention of MI and stroke with symptomatic atherosclerotic disease. Familial hypercholesterolaemia.

Side effects of hepatotoxicity (but rare) and skeletal muscle damage (rare)

Grapefruit juice inhibits station metabolism.

265
Q

What happens when statins inhibit RhoA?

A

This decreases calcium sensitisation as it blocks the interaction of Rho with GTP thus helping the blood vessel to be relaxed.

266
Q

What type of drug are clofibrate, fenofibrate and gemfibrozil?

How do they act?
What are the clinical uses?

A

They are fibrates.

They act via activation of peroxisomal proliferation activator receptor alpha.
This reduces production of ApoC3 in hepatocytes causing:
increase in lipoprotein lipase activity so decrease in serum triglycerides
Increase in apolipoproteins A1 and A11 causing increase in HDL
Stimulation of B oxidation of fatty acids

Used in various dyslipidemas
Used in diabetes type 2.

267
Q

What type of drug are colestyramine and cholestipol?
How do they act?
Clinical use?
Side effects?

A

Bile acid-binding resins

Bind bile in the gut so increase plasma cholesterol clearance via entero-hepatic circulation

Used clinically in combination with statins or in patients with liver disease where statins are not recommended.

Side effects include constipation and diarrhoea.

268
Q

What type of drugs are nicotinic acid and vitamin B?
How do they work?
What are their clinical uses?
What are the side effects?

A

Niacins.

They are prescursor to NAD, NADH, NADP and NADPH.

Bind to GPCR linked to Gi alpha subunit in adipose tissue and in epidermal cells
Inhibit lipolysis in adipose tissue leading to decrease in LDL
In epidermal cells increases prostaglandin D2 production-relaxes terminal blood vessels.

Used as hypercholesterolaemias and dyslipoproteinemias. Given orally with statins usually.

Side effects of facial flashes, diarrhoea,nausea and reduced appetite also increased glucose levels.

269
Q

How does ezetimibe work?

When is it prescribed?

A

Inhibits cholesterol absorption in small intestine
Binds to neimann pick C1 like 1 (NPC1L1), a plasma membrane transporter, in intestinal epithelial cells.

NPC1 is a recessive cholesterol storage disorder associated with severe and progressive neurodegeneration.

Modified in intestine and liver to more active form then inhibits transporter.

Generally prescribed as a last resort.

270
Q

What is myocardial ischaemia?

What is the main cause?

A

Reduced blood supply to the heart due to reduced coronary blood flow.

Main cause: atheromatous disease of coronary arteries.

271
Q
What is the cause of each of these?
Stable angina-
Variant (printzmetals angina)-
Unstable angina-
Acute myocardial infarction-
A

Stable angina- coronary atheroma (mismatch between oxygen demand and oxygen supply)
Variant (printzmetals angina)- coronary spasm
Unstable angina- transient platelet aggregation
Acute myocardial infarction- coronary blood clotting

272
Q

How does angina pectoris usually manifest itselfs? Ie what symptom

A

Often manifested as a characteristic pain in the upper chest and the left arm.

Imbalance between coronary blood supply and myocardial oxygen demand.

273
Q

What are the aims of therapeutical strategies for treatment of ischaemic heart disease.

A

Increase myocardial oxygen supply
Decrease myocardial oxygen demand by lowering peripheral resistance, decreasing preload and decreasing heart rate and force.

Decrease platelet aggregation

Correction of lipid abnormalities and reverse atherosclerosis

Repercussion of occluded vessels with thromolitic agents

Surgical interventions- angioplasty/coronary stent or coronary bypass.

274
Q

What are the steps of treating angina pectoris?

A
Nitrate vasodilators
Beta lockers
Ivabradine
Calcium channel blockers
Potassium channel openers
Statins
Aspirin
ACE inhibitors
Surgery
275
Q

In variant printzmetals angina what is the main aim? What drugs do this?

A

To dilate coronary arteries.

Treated with nitrate vasodilators and calcium channel blockers and if not responsive to these then alpha adrenoceptor antagonists. Bets blockers are not recommended.

276
Q

What drug type are nitroglycerin, isosorbide dinitrate and sodium nitroprusside?

What is the main issue associated with this type of drug?

How do they work?

A

They are nitrate vasodilators which are nitric oxide donors.

Problems is tolerance develops after prolonged treatment so treatment planned to have drug free periods during the day

They have greater vasodilation effect on veins compared to arteries
Reduced cardiac preload means reduced cardiac oxygen demand.

277
Q

Why is prolonged dilation of a healthy artery next to obstructed or diseased one useful?

A

Because blood can be diverted from the ischaemic area.

278
Q

How are beta blockers used to treat angina? Method of action.

A

They block cardiac beta 1 adrenoceptors which

Decrease force and heart rate leading to reduced cardiac oxygen demand

Decreased heart rate also leads to increased diastolic time which means increased coronary flow so increased cardiac oxygen supply.

279
Q

How do nitrates treat angina? Mechanism.

A

Nitrates cause increase in nitric oxide which leads to

Venodilation causing decreased preload so decreased oxygen demand. Also arteriodilation which causes decreased after load meaning decreased oxygen demand.

Dilation of large and medium coronary arteries leading to increases oxygen supply.

280
Q

How does ivabradine work?
What is it used in?

What are the side effects?

A

It inhibits pacemaker If current in the SA node. Reduces heart rate

Used in management of stable angina in patients with normal sinus rhythm when beta blockers are contraindicated.

Side effects are visual: blurred vision and photopsia, bradycardia, AV block and arrhythmia’s.

281
Q

How do calcium channel blockers treat angina?

A

They block vascular L-type calcium channels.

This causes peripheral arterio and veno dilation which causes decreased preload and after load and so decreased cardiac oxygen demand.

This also causes dilation of coronary arteries so increase in coronary flow so increase in cardiac oxygen supply.

282
Q

In stable angina how are calcium channel blockers used as treatment? What are they combined with?

Same with in variant angina?

A

Stable
Used alone or in combination with nitrates or beta blockers.
Dihydropyridine and beta blockers can be used in patients with CHF.

Varient
Usually in combination with nitrates
Nifedipine can be used alone

283
Q

What are the side effects of nifedipine?

What drugs cause less of these side effects? Why?

What are the side effects of diltiazem and verapamil?

A

Causes veno dilation peripheral oedema.
Is rapidly acting so causes reflex tachycardia.

These effects are less with more slowly acting nicardipine and amlodipine.

Diltiazem causes bradycardia
Verapamil causes constipation
They both cause hypotension and heart failure.

284
Q

What type of drug is nicorandil?
How does it work?
What is its major effects?

What is a side effect of the drug?

A

Potassium channel opener.

This activates vascular potassium channels and releases nitric oxide which increases cGMP

Major effect via decrease of cardiac preload due to venodilation.

285
Q

What does ranolazine treat?
How?
Side effects?

A

Treats chronic unstable angina.

Selectively blocks cardiac slow inactivating persistent sodium channels which activity is increased by hypoxia. This leads to cellular sodium overload so cellular calcium overload so cell death.

286
Q

What is the main aim of therapy of unstable angina?

What drugs are used to do this?

A

To reduce progression to acute MI.

Antiplatelets
Anticoagulants 
Lipid lowering drugs
Nitrate vasodilators
Beta blockers
Ace inhibitors
Coronary revascularisation
287
Q

What is acute myocardial infarction?

A

Irreversible occlusion of coronary artery leads to
Maintained ischaemia leads to
Myocardial cell death.

288
Q
All these drugs are antiplatelets but what type of drug are they?
Aspirin
Clopidogrel
Dipyridamole
Abciximab
Eptifibatide
Tirofiban
A
Aspirin COX-1 inhibitor
Clopidogrel- ADP receptor antagonists
Dipyridamole- phosphodiesterase inhibitor
Abciximab- GP2b/3a receptor antagonists
Eptifibatide- same
Tirofiban- same
289
Q

What is low dose aspirin used to treat?

What are the side effects?

A

Primary prevention of MI in people with increased risk of CVD.
Prevention of secondary MI

Side effects of gastrointestinal bleeding, brain haemorrhage.

290
Q

What is clopidogrels mechanism?
Clinical uses?
Side effects?

A

Irreversibly blocks Gi coupled P2Y12 receptors (activation of receptors causes inhibition of adenylate cyclase and decrease of cAMP.

Used with aspirin for 12 months after an A.M.I or used instead of aspirin

Side effects of haemorrhage.

291
Q

How does dipyridamole work?

A

Inhibits phosphodiesterase so increases cAMP and cGMP leading to inhibition of platelet activation and aggregation
also inhibits adenosine uptake so there is increased adenosine causing vasodilation.

292
Q

What type of drugs are abciximab, eptifibatide and tirofiban?
How are they administered?
How long do the effects last?

A

They are antiplatelets

Only tirofiban can be given orally the others are injections.

The effects last for up to 48 hours die to strong binding with receptors

293
Q

What factor do heparin, enoxaparin and Fondaparinux and rivaroxaban interact with?
What type of drugs are they?

A

Interact with factor Xa. They are anticoagulants

294
Q

What type of drugs are hirudin, lepirudin, dabigatran and warfarin?

A

Direct thrombin inihibitors, anticoagulants.

295
Q

What inactive precursor are factor XIIa XIa Xa and IIa formed from?
What type of molecule are they?
What inhibits them?

What is factor XIII involved in?

A

What inactive precursor are factor XIIa XIa Xa and IIa formed from? Zymogens
What type of molecule are they? Serine proteases
What inhibits them? Antithrombin III

What is factor XIII involved in? This is a transglutaminase and involved in the stabilisation of fibrin.

296
Q

What is a LMWH?

A

A low molecular weight heparin which is less than 8KDa.

297
Q

What does heparin have specificity to?

A

Xa over thrombin because inhibition of Xa doesn’t require binding of heparin to both ATIII and protease, whereas IIa does so there is not enough length for LMWH.

298
Q

What is heparin produced by?

A

Basophils and mast cells. Naturally occurring anticoagulants .

299
Q

What is the mechanism of action of heparin and LMWHs?

What are they side effects of these drugs?

A

Binds to antithrombin III (ATIII) and enhanced its binding activity to serine proteases.

Bleeding
Immune thrombocytopenia (low platelet levels)
Osteoporosis
Hypersensitivity

300
Q

What is the mechanism of rivaroxaban?
What are the drugs properties?
What are its uses?

A

Selective direct factor Xa inhibitor

oral anticoagulants
Long lasting action
No effect on thrombin
No effect on platelets

Used in atrial fibrillation to prevent stroke
Treatment and prevention of deep vein thrombosis
Prevention of pulmonary embolism

301
Q

What type of drugs are hirudin and lepirudin and dabigatran?

What are their properties?

A

Direct thrombin inhibitors (bind to thrombin active site.)

Oral anticoagulant
Long lasting action
Atrial fibrillationss
Replaced warfarin in some patients

302
Q
What type of drug is warfarin?
How is it metabolised?
Where is it found?
What are its side effects? 
What is its mechanism of actions?
A

What type of drug is warfarin? Oral anticoagulant
How is it metabolised? By cytochrome p450
Where is it found? In plasma mostly bound to albumin
What are its side effects? Haemorrhage.
What is its mechanism of action? Inhibits vitamin K reductase do preventing carboxylation of zymogens on glutamate resides which is important for their binding to phospholipids and activation.

303
Q

WhAt group of people are more resistant to warfarin?
What group are more sensitive?
What group has a 10% variation in dosing?

A

WhAt group of people are more resistant to warfarin? African Americans
What group are more sensitive? Asian americans
What group has a 10% variation in dosing? Caucasian people.

304
Q

What type of drug are alteplase and reteplase?
What is their mechanism?
What does this do?

A
Fibrinolytic agents
Recombinant tPA
prevent conversion of plasminogen to plasmin
Used to prevent bleeding. 
Like tranexamic acid.
305
Q

What is the treatment for acute MI?

A

Oxygen
Aspirin
Nitrates sublingual
Morphine sulphate

306
Q

What is the long term treatment for MI?

A
Beta blockers
Aspirin
ACE inhibitors
Aldosterone receptor antagonists
Statins
Warfarin
Control risk factors ie do regular exericse reduce alcohol and quit smoking.
307
Q

What is stroke?
What is the cause?
What are the symptoms?

A

A clinical syndrome consisting of rapidly developing clinical signs of focal disturbances of cerebral function lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin

Causes are ischaemia or haemorrhage

Symptoms include numbness, weakness or paralysis, slurred speech, blurred vision, loss of monocular vision, confusion, severe headache.

308
Q

What is the acute treatment of stroke?

A
Hospitalisation and brain imaging
Alteplase
Aspirin
Heparin and warfarin
Oxygen if oxygen saturation is less than 95%
309
Q

What is the long term treatment of stroke?

A
Aspirin
Warfarin
Cholesterol reduction
Blood pressure control
Reduce risk factors so change lifestyle
310
Q

What is deep vein thrombosis?
What are the causes?
The symptoms?
The treatment?

A

Formation of blood clots in the deep veins of the legs leading to pulmonary embolism.
Due to immobility and major surgery. Also travel related eg long flights.
Swelling pain and reddening may be symptoms
Treated with drugs.. Enoxaparin, Fondaparinux, heparin, warfarin, aspirin, rivaroxaban
Can treat with compression stockings
Also early mobilisation, hydration and foot elevation.

311
Q

What is heart failure?

A

The soup tuition when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.

312
Q

What symptoms may signify heart failure?

A

Breathing difficulties
SOB from walking stairs, trouble breathing when resting or lying down, waking up breathless at night, needing more than 2 pillows to sleep

Fatigue/exercise intolerance
Tiring easily,
Swelling of feet, ankles or legs oedema.
General feeling of fatigue

Coughing
Frequent coughing
Coughing that produces a mucus or pink blood tinged sputum
Dry, hacking cough when lying flat in bed.

313
Q

What Are the four classes of heart failure?

A

Class 1 mild: no limitation of physical activity. Ordinary physical activity does not cause undue fatigue.
Class 2 mild: slight limitation of physical activity. Comfortable at rest.
Class 3 moderate: markers limitation of physical activity. Comfortable at rest but less than ordinary activity causes fatigue.
Class 4 severe: unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest.

314
Q

What are risk factors and potential causes of heart failure?

A
Coronary heart disease
Myocardial infarction
Cardiac hypertrophy (enlargement of the heart)
Family history of cardiac hypertrophy
Chronic obstructive pulmonary disease
Damage to the heart valves history of heart murmur
Hypertension
Diabetes
315
Q

What is emphysema?

What is another name for it?

A

Loss of elasticity of the lung lining caused by destruction of structures feeding the alveoli.

Another name is COPD

316
Q

What are the categories heart failure can be put into?

Chronic vs ?
Low output vs ?
Systolic vs ?
Left sided vs ?
Forward vs?
A
Chronic vs ? Acute 
Low output vs ? High output
Systolic vs ? Diastolic 
Left sided vs ? Right sided
Forward vs? Backwards
317
Q

What is the treatment and potential causes for acute heart failure or cardiac arrest?

A

Treatment is CPR.

Causes of 
Pulmonary embolism
Acute MI
Drug overdose
Structural heart abnormalities
Arrhythmia's
Pericarditis
Airway obstruction eg chocking.
318
Q

What is high output heart failure due to?

What is low output heart failure secondary to?

A

High output due to hyperthyroidism, severe anaemia, low vitamin B (beriberi) arteriovenous fistulas

Low output secondary to IHD, hypertension, dilated cardiomyopathy, valve and pericardial diseases.

319
Q

What is systolic heart failure?

What is diastolic heart failure?

A

Systolic- inability to contract normally and expel sufficient blood caused by reduced inotropic response from CHD or post MI

Diastolic- inability to relax and fill normally can be caused by reduced capacity and impaired ventricular relaxation from hypertrophic cardiomyopathy or acute myocardial ischaemia.

In most cases both happen.

320
Q

What is left sided heart failure?
What is right sided heart failure?

Which is the most common?

A

Left sided - weakened LV function from CHD or post MI

Right sided- abnormal RV function from pulmonary hypertension or COPD

Most common is left sided from left ventricular systolic dysfunction ( Impaired contraction) and heart failure with preserved ejection fraction (impaired relaxation)

321
Q
What are the symptoms of these types of heart failure?
Left backwards?
Left forwards?
Right backwards?
Right forwards?

In general forward?
In general backwards?
Congestive symptoms?

A

Left backwards? Pulmonary congestion: breathing difficulties, cough, pulmonary oedema.

Left forwards? Poor systemic circulation: dizziness, confusion and cold extremities.

Right backwards? Fluid retention in peripheral capillaries: peripheral oedema, ascites, hepatomegaly.

Right forwards? Poor blood flow to the lungs.

In general forward? Normal ventricular filling, abnormal stroke volume
In general backwards? Abnormal ventricular filling, abnormal stroke volume
Congestive symptoms: abnormal ventricular filling, normal stroke volume.

322
Q

What are the drug metabolism implications of left forward heart failure? And right backwards?

A

Left forward- poor systemic blood flow causes reduced kidney function so reduced drug excretion

Right backwards- fluid retention so hepatic congestion so reduced drug metabolism.

323
Q

If myocardial damage leads to myocardial failure which decreases CO2 and blood pressure, what are the compensatory responses of…

Heart rate
Stroke volume
TPR afterload
Blood volume?

A

They all increase.

324
Q

What extrinsic neurohumoral mechanisms change to compensate for heart failure?

A

There is increased sympathetic nerve activity
Activation on the RAA
Arginine vasopressin (AVP) expression increases which increases water retention
Myocardial hypertrophy.

Frank starling effect.

325
Q

In a healthy 70kg man what is the stroke volume?
What is the left ventricular EDV?
What is therefore the ejection fraction?

A

70ml
120ml
so 70/120 or 0.58 which is 58%

326
Q

What are the potential biochemical mechanisms that could explain impaired contractility in heart failure?

A

Reduced rate of calcium binding by sacroplasmic recticulum

Decreases sodium calcium exchange

Decreased cytosolic levels of cyclic AMP

Reduced content of myofibrillar protein

Decreased activity of myofibrillar actomyosin and ATPase.

327
Q

After two years with heart failure how likely is a person to still be alive?

A

Only 50%

328
Q

What is the first line treatment of heart failure?

A

ACE inhibitor eg captopril, enalapril or lisinopril
Plus
Beta blocker eg cavedilol, bisoprolol of metoprolol
Plus
Diuretic

Potentially an angiotensin II receptor blocker (ARB) like valsartan or losartan if the ACE inhibitor is poorly tolerated.

329
Q

What is an alternative first line treatment of heart failure for African or Caribbean patients?

A

Hydralazine with nitrate vasodilators and diuretics.

330
Q

What is the second line treatment for moderate or severe heart failure?

A

Aldosterone receptor antagonists such as spironolactone and eplerenone
Cardiac glycosides such as digoxin

If there is angina as well

Calcium channel blockers such as amlodipine (avoiding more cardiac selective such as verapamil and diltiazem)

331
Q

What is the mechanism of action of angiotensin II inhibitors in CHF?

A

Prevent convention from angiotensin 1 to angiotensin 2 so stopping aldosterone production so reducing blood volume, stopping cell growth so reducing LV hypertrophy, and stopping vasoconstriction so causing vasodilation.

332
Q

What are the possible beneficial effects of using beta blockers to treat heart failure?

What drugs are used?

In combination with what drugs?

How are they introduced?

A
Increase density of beta1 receptors
Inhibit cardio toxicity of catecholamines so decrease heart rate and neurohumoral activation 
Antihypertensive and anti anginal
Anti arrhythmic
Antioxidant
Antiproliferative

Bisoprolol, cavedilol, metoprolol

Use in first line treatment with ACE inhibitors and diuretics
Introduce in a start low go slow manner.

333
Q

What cardiac inotropes are used in heart failure?

A

Digoxin a cardiac glycoside

Inamrinone a phosphodiesterase inhibitor

Levosimendan a cardiac sensitiser

Dobutamine a sympathomimetic beta 1 agonist.

334
Q

What does digoxin look like?

A

A hydroxyl group at the C3 position on the B ring. Includes a lactose and a triple repeating sugar called a glycoside.

335
Q

What type of drug are digitoxin and ouabain?

A

Cardiac glycosides

336
Q

Why does ouabain have to be injected?

A

It is not very liphphilic and has poor oral availability.

337
Q

What are the clinical uses of cardiac glycosides?

A

Negative chronological so used in patients with atrial fibrillation.

Positive inotropic so used in worsening and severe CHF.

338
Q

What is the positive inotropic mechanism of cardiac glycosides?

A

Block sodium potassium pimp by binding to extracellular potassium binding site
Compete with extracellular potassium for binding
Result in indirect activation of the reverse mode of sodium calcium exchanger
Leads to an increase in cytosolic calcium in cardiomyocytes so increased cardiac contractility.

339
Q

What is the therapeutic index of digoxin? how is this worked out?

A

Around 2

LD50/ED50

340
Q

What are the side effects of digoxin?
What can the toxicity be worsened by?
How might digoxin plasma levels be reduced?

A

What are the side effects of digoxin?
Gastric irritations and GI pain, nausea vomiting and anorexia and diarrhoea. Visual disturbances and headache, dizziness and fatigue. Neuromuscular weakness, arrhythmia’s and heart block.

What can the toxicity be worsened by?
Hypokalemia due to diuretics and aldosteronism, hyperkalemia due to spironolactone, hyperthyroidism, impaired kidney function (less excretion) drugs effecting renal excretion such as amiodarone.

How might digoxin plasma levels be reduced?
Cytotoxic agents/radiotherapy causing lining damage in the GI so less absorption and more exreation.
Chronic inflammatory bowel disease.

341
Q

How can digoxin toxicity be treated and prevented?

A

Low dose or withdrawal monitoring plasma levels

Oral K supplements if hypokalemia

Antiarrhythmic drugs such as lidocaine and phenytoin

Steroid binding resins like cholestipol and activated charcoal

Digoxin specific antibody fragments which increase drug clearance.

342
Q
What do phosphodiesterase inhibitors do? 
What are examples of them?
What is the use?
Effects?
Side effects?
A

What do phosphodiesterase inhibitors do? Prevent conversion of cAMP to AMP so so increase cAMP, PKA and force of contraction.
What are examples of them? Inamrinone, miltrinone, enximone.
What is the use?short term treat,met in acute decompensation of CHF.
Effects? Increase CO, reduce right atrial pressure, reduce TPR (total peripheral resistance)
Side effects? Nausea and vomiting, liver abnormalities, thrombocytopenia, lethal arrhythmia’s.