Pharmacology & Therapeutics 2 Flashcards

1
Q

What second messengers are M1, M3 and M5 receptors coupled to?

A

G-protein coupled to IP3 and DAG second messengers

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2
Q

What second messengers are M2 and M4 receptors coupled to?

A

G-protein coupled to cAMP second messengers

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3
Q

What type of ion channel are nicotinic receptors?

A

Lingand-gated

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4
Q

How many sub units do nicotinic receptors have?

A

5

α, β, γ, δ, ε

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5
Q

What do the ligand binding properties of a nicotinic receptor depend on?

A

The subunit combination

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6
Q

What are the muscarinic effect on the eye?

A
  • Contraction of the ciliary muscle: accommodation for near vision
  • Contraction of the sphincter pupillae: Constricts pupil (miosis) and improves drainage of intraocular fluid
  • Lacrimation (tears)
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7
Q

What leads to glaucoma?

A

Increased intraocular pressure is produced by a decreased drainage of aqueous humour via the canals of Schlemm, anterior to the iris

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8
Q

How is glaucoma treated?

A

Stimulating the smooth muscle using a muscarinic agent which causes contraction of the sphincter pupillae which opens the pathway for drainage. This reduced the pressure.

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9
Q

What are the muscaranic effects on the heart?

A
  • Ach effects on M2 acetylcholine receptors in the atria and nodes decrease cAMP. This leads to decreased Ca++ entry and increased K+ reflux.
  • Cardiac output and heart rate decrease.
    Negative ionotrophic and chronotrophic effect
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10
Q

What are the muscarinic effects on the vasculature?

A
  • Most blood vessels do not have parasympathetic innervation, but instead M3 acetylcholine receptors on vascular endothelial cell
  • Acetylcholine acts on vascular endothelial cells to stimulate NO release. This induced smooth muscle relaxation.
  • Total peripheral resistance is reduced
  • Therefore muscarinic agonists can be used as a possible treatment for hypertension
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11
Q

What are the overall muscarinic effects on the cardiovascular system?

A
  • Decreased heart rate (bradycardia)
  • Decreased cardiac output (due to decreased atrial contraction)
  • Vasodilation (stimulation of NO production)
  • All of these combined can lead to a sharp drop in blood pressure
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12
Q

What are the muscarinic effects on non-vascular smooth muscle?

A

Smooth muscle that does have parasympathetic innervation tends to respond in the opposite way to vascular muscle- meaning it contracts.

e. g.
- Lung: Bronchoconstriction
- Gut: Increased peristalsis (motility)
- Bladder: Increased bladder emptying

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13
Q

What are the muscarinic effects on the exocrine glands?

A
  • Salivation
  • Increased bronchial secretions
  • Increased gastro-intestinal secretions (including gastric HCl production)
  • Increased sweating (SNS-mediated)
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14
Q

What are the two classes of cholinomimetic drug?

A

Directly acting

Indirectly acting

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15
Q

Why is acetylcholine of no therapeutic use?

A

It does not differentiate between nicotinic and muscarinic receptors and it is is rapidly degraded

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16
Q

What type of directly acting cholinomimetic drug is aceytlcholine?

A

Choline ester

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17
Q

What are the different directly acting cholinomimetic drugs?

A

1) Acetylcholine
2) Nictone
3) Muscarine
4) Pilocarpine
5) Bethanechol

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18
Q

What type of activity does nicotine stimulate?

A

Sympathetic and parasympathetic activity.

It stimulates all autonomic ganglia

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19
Q

What type of cholinomimetic drug is pilocarpine?

A
  • Alkaloid

- Non-selective muscarinic agonist with good lipid solubility

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20
Q

What is the half life of pilocarpine?

A

3-4 hours

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21
Q

What is pilocarpine used as treatment for?

A

Glaucoma?

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22
Q

What are the side effects of pilocarpine?

A
  • Blurred vision
  • Sweating
  • Gastro-intestinal disturbance and pain
  • Hypotension
  • Respiratory distress
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23
Q

What type of cholinomimetic drug is bethanechol?

A

Choline ester

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24
Q

What makes bethanechol less resistant to degradation that acetylcholine?

A

Has a similar structure to acetylcholine but has an addition of a methyl group
- Is an M3 acetylcholine receptor agonist

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25
Q

What is the half life of bethanechol?

A

3-4 hours

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26
Q

What is the use of bethanechol?

A
  • Assist bladder emptying

- Enhance gastric motility

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27
Q

What are the side effects of bethanechol?

A
  • Sweating
  • Impaired vision
  • Nausea
  • Bradycardia
  • Hypotension
  • Respiratory difficulty
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28
Q

What are the actions of indirectly acting cholinomimetic drugs?

A
  • Increase the effect of normal parasympathetic nerve stimulation by inhibiting the action of acetylcholinesterase therefore preventing the breakdown of acetylcholine.
  • Have the potential to increase the cholinergic activity of all cholinergic synapses
  • Anticholinesterases
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29
Q

Give examples of reversibly anticholinesterases

A
  • Physostigmine
  • Neostigmine
  • Donepezil (‘aricept’)
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30
Q

Give examples of irreversible anticholesterases

A
  • Exothiopate
  • Dyflos
  • Sarin
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31
Q

What does cholinesterase metabolise acetylcholine to?

A

Choline and acetate

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32
Q

What are the effects of anticholinesterases?

A
  • Enhanced muscarinic activity (at low dose)
  • Further enhancement of muscarinic activity with increased transmission at all autonomic ganglia (at moderate dose)
  • Can be toxic at a high dose. Showing a depolarising block at all autonomic ganglia.
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33
Q

What are the two types of cholinesterases?

A
  • Acetylcholinesterase (true or specific cholinesterase- highly selective for acetylcholine)
  • Butyrylcholinesterase (pseudocholinesterase)
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34
Q

Where are acetylcholinesterases found?

A

All cholinergic synapses (peripheral and central)

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35
Q

How fast is the action of acetylcholinesterases?

A

Very rapid

Hydrolysis occurs at over 10,000 reactions per second

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36
Q

Where is butryrylcholinesterase found?

A

In plasma and most tissues but NOT cholinergic synapses

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37
Q

Describe the specificity of butyrylcholinesterase

A

Broad substrate specificity
Hydrolysis other esters e.g. suxamethonium
- Shows genetic variation

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38
Q

What is the principle reason for low plasma acetylcholine?

A

The action of butyrylcholinesterase

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39
Q

How do reversible anticholinesterase drugs work?

A
  • Compete with acetylcholine for active site on the cholinesterase enzyme
  • Donates a carbamyl group to the enzyme which blocks the active site. This prevents acetylcholine from binding
  • The carbamyl group is removed by slow hydrolysis (mins)
  • This increases the the duration of type that acetylcholine acts in the synapse
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40
Q

Where does physostigmine primarily act?

A

Postganglionic parasympathetic synapse

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41
Q

What is the half life of physostigmine?

A

30 mins

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42
Q

What is physostigmine used for?

A
  • Treatment of glaucoma aiding intraocular fluid drainage

- Treats atropine poisoning, particularly in children

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43
Q

How do irreversible anticholinesterase drugs work?

A
  • Rapidly react with the enzyme active site, leaving a large blocking group
  • This is stable and resistant to hydrolysis, recovery may require the production of new enzymes (days/weeks)
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44
Q

Which irreversible anticholinesterase drug is in clinical use?

A

Ecothiopate

- others commonly used as insecticides and nerve gas

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45
Q

What does ecothiopate inhibit?

A

Potent inhibitor of acetylcholinesterase

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46
Q

What is ecothiopate used in the treatment of?

A

Glaucoma

- Acts to increase intraocular fluid drainage with a prolonged duration of action

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47
Q

What are the systemic side effects of ecothipate?

A
  • Sweating
  • Blurred vision
  • GI pain
  • Bradycardia
  • Hypotension
  • Respiratory difficulty
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48
Q

What type of anticholinesterases can cross the blood brain barrier?

A

Non-polar

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49
Q

What are the outcomes if anticholinesterases cross the blood-brain barrier?

A

Low doses: Excitation with the possibility of convulsions

High doses: Unconsciousness, respiratory depression, death

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50
Q

What anticholinesterase drugs are used as a treatment for Alzheimer’s?

A

Donepezil
Tacrine
- Potentiation of central cholinergic transmission relieves the symptoms but does not affect degeneration
- Ach is important in leaning and memory

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51
Q

What can accidental exposure to organophosphates used in insecticides result in?

A

Severe toxicity

- Increased muscarinic activity, CNS excitation and a depolarising neuromuscular block

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52
Q

What is used to treat organophosphate poisoning?

A
  • IV atropine
  • Artificial respiration
  • IV Pralidoxime
  • The phosphorylated enzymes age within a few hours
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53
Q

What are the differences between agonists and antagonists with regards to affinity and efficacy?

A

Agonists show affinity and efficacy (binding & response)
Antagonists show affinity (binding & no response)

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54
Q

What are the two groups of cholinoreceptors?

A

Nicotinic

Muscarinic

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55
Q

Why can a drug interfering with nicotinic cholinoreceptors have the ability to intefere with the whole of the autonomic nervous system?

A

Nicotinic receptors are present at all autonomic ganglia

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56
Q

Give examples of nicotinic receptor antagonists

A

Hexamethhonium: 1st antihypertensive
Trimetaphan: hypotension during surgery (short acting)

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57
Q

What are clinically useful nicotinic receptor antagonists called?

A

Ganglion blocking drugs

  • They block the ion channel which preents ions from moving through the channel pore
  • These drugs interfere with both parasympathetic and sympathetic action with widespread effects
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58
Q

What does the term ‘use-dependent block’ refer to?

A

The fact that nicotinic receptor antagonists work most effectively when the ion channels are open. The more agonist that is present at the receptor, the more opportunity there is for the antagonist to block the channel. Therefore, the more useful and effective these drugs can be

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59
Q

What is the effect when a nicotinic cholinoreceptor is administered to sympathetically dominated tissues?

A

Sympathetic effects are lost.

  • Shows hypotensive effects.
  • Blood pressure falls because sympathetically driven responses to reduce blood pressure are lost
  • Examples of sympathetically dominated tissues include the kidneys and blood vessels
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60
Q

What effect does the muscarinic receptor antagonist atropine have on the CNS

A

Normal dose: little effect

Toxic dose: mild restlessness -> agitation (less M1 selective)

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61
Q

What effect does the muscarinic recepotr antagonist hyoscine have on the CNS?

A

Normal dose: Sedation, amnesia

Toxic dose: CNS depression or paradoxical CNS excitation (associated with pain)

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62
Q

How is the muscarinic receptor antagonist tropicamide use clinically?

A
  • Acts on receptors within the iris of the eye to cause pupil dilation
  • Used in eye exams to examine the retina
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63
Q

Why are muscarinic receptor antagonists good for anaesthetic premedication?

A
  • They cause the airways to dilate (useful when administering a gas mask)
  • Dry the throat a bit, reducing the risk of aspiration.
  • Reduce secretions in the lungs and mouth (inhaling secretions -> pneumonia)
  • Removes parasympathetic effects of slowing heart rate and reducing contractility. Anaesthetic already reduced rate and contractility.
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64
Q

What are the clinical uses of the muscarinic receptor antagonist Hyoscine?

A
  • Hyoscine patch for motion sickness
  • Muscarinic receptors important in relaying information from inner ear to vomiting centres
  • Muscarinic receptor antagonist reduce flow of information, reducing nausea
  • Controls eye movements to maintain vision whilst in motion
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65
Q

How are muscarinic receptor antagonists used in treating Parkinson’s disease?

A
  • Not first line treatment
  • Nigrostial dopamine neurons in the brain are lost in Parkinson’s disease. They are important for fine control and movement.
  • Muscarinic receptors have a negative effect on dopamine signalling from these neurons
  • Antagonists take out the M4 receptors, losing the inhibitory effect. The last few dopamine neurons can fire at a maximum rate.
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66
Q

Which muscarinic receptor antagonist is used in treating asthma and COPD

A

Ipratropium Bromide

- Removes the effect of bronchoconstriction

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67
Q

How can muscarinic receptor antagonist be used in irritable bowel syndrome?

A
  • Removing parasympathetic effects within the gut reduced smooth muscle contraction, gut motility and gut secretion.
  • This relieves some of the symptoms of irritable bowel syndrome.
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68
Q

What are the unwanted side effects of muscarinic receptor antagonists/

A
  • Hot as hell (decreased sweating interferes with thermoregulation)
  • Dry as a bone (reduced secretions everywhere )
  • Blind as a bat (due to effects on accomodation ability of ciliary muscle- cyclopegia)
  • Mad as a hatter (high doe effect CNS agitation, restlessness, confusion, etc)
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69
Q

How is poisoining from muscarinic receptor antagonists treated?

A
  • With anti-cholinesterase such as Physostigmine
  • Massive amount of atropine overloads the system and the Ach receptors become blocked.
  • Anti-cholinesterase prevents ACh breakdown in the synapse, so AcH levels out-compete Atropine, slowly clearing Atropine from the body
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70
Q

What is the mechanism of Botulinum Toxin?

A
  • It interferes with exocytosis (ACh release from nerve terminals)
  • Binds to SNARE complex, which would usually allow vesicles to fuse with the membrane and release ACh
  • Botulinum toxin prevents this so the vesicles remain in the nerve.
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71
Q

What is the clinical use of Botulinum Toxin?

A

Botox

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72
Q

What types of adrenoreceptors does adrenaline show more selectivity for?

A

b1 = b2 > a1 = a2

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73
Q

What types of adrenoreceptors does noradrenaline show more selectivity for?

A

a1 = a2 > b1 = b2

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74
Q

Give examples of directly acting SNS agonists

A
  • Adrenaline (non-selective)
  • Phenylephrine (a1)
  • Clonidine (a2)
  • Dobutamine (b1)
  • Salbutamol (b2)
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75
Q

What are the uses of adrenaline?

A

1) Allergic reaction and anaphylactic shock (IV) Reverses potentially life-threatening hypotension and bronchoconstriction
2) COPD. Relieves breathing difficulties.
3) Acute management of heart block
4) In spinal anaesthesia (IV)
5) To prolong duration of local anaesthetics (local administration)
6) To treat glaucoma (eye drops)

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76
Q

What are the unwanted actions of adrenaline?

A

1) Secretions- reduced and thickened mucous
2) CNS- minimal
3) CVS
- tachycardia, palpitations, arrhythmias
- cold extremities, hypertension
- overdose- cerebral haemorrhage, pulmonary oedema
4) GIT- minimal
5) Skeletal muscle- tremor

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77
Q

Which adrenoreceptors is phenylephrine more selective for?

A

Selective for a1 receptors

a1»a2»>b1/b2

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78
Q

What is phenylephrine resistant to?

A

Resistant to COMT but not MAO

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79
Q

What is phenylephrine chemically related to?

A

Adrenaline

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80
Q

What are the clinical uses of phenylephrine?

A
  • Vasoconstriction
  • Mydriatic
  • Nasal decongestant
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81
Q

Where does phenylephrine have unwanted actions?

A

Cardiovascular system

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82
Q

Which adrenoreceptors is clonidine selective for?

A

a2 receptors

a2»a1»>b1/2

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83
Q

What are the clinical uses of clonidine?

A

1) Treatment of hypertension and migraine
2) Reduces sympathetic tone
- a2 adrenoreceptor mediated presynaptic inhibition of NA release
- Central action in brainstem within baroreceptor pathway to reduce sympathetic outflow

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84
Q

What adrenoreceptors is isoprenaline selective for?

A

B1 and B2 receptors

ß1=ß2»»α1/2

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85
Q

Isoprenaline is chemically similar to adrenaline. How does it differ?

A

Isoprenaline is less susceptibile to uptake 1 and MAO breakdown

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86
Q

What is the plasma half life of isoprenaline?

A

2 hours

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87
Q

What are the clinical uses of isoprenaline?

A
  • Cardiogenic shock
  • Acute heart failure
  • Myocardial infarction
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88
Q

Why must isoprenaline be used with caution?

A

B2-stimulation in vascular smooth muscle in skeletal muscle results in a fall in venous blood pressure. This triggers a reflex tachycardia via the stimulation of baroreceptors

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89
Q

What adrenoreceptors are Dobutamine selective for?

A

Beta-1 receptors

β1»β2»>α1/2

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90
Q

What are the clinical uses of dobutamine?

A
  • Cardiogenic shock
  • Lacks isoprenaline’s reflex tachycardia
  • Administered by IV infusion
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91
Q

What is the plasma half life of dobutamine?

A

2 minutes

It is rapidly metabolised by COMT

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92
Q

What adrenoreceptor is salbutomol selective for?

A

Beta-2 receptors

b2»b1»>a1/2

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93
Q

What is salbutamol (ventolin)?

A

A synthetic catecholamine derivative with relative resistance to MAO and COMT

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94
Q

What are the clinical uses of salbutamol?

A

1) Treatment of asthma
- Beta-2 relaxation of bronchial smooth muscle
- Inhibition of release of bronchoconstrictor substances from mast cells
2) Treatment of threatened premature labour
- Beta 2- relaxation of uterine smooth muscle

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95
Q

What are the side effects of salbutamol?

A

Reflex tachycardia
Tremor
Blood sugar dysregulation

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96
Q

Give examples of indirectly acting SNS agonists

A
  • Cocaine (uptake 1 inhibitor)

- Tyramine

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97
Q

What are the actions of cocaine on the CNS?

A

Low doses:
- Euphoria, excitement, increased motor activity
High doses:
- Activation of chemoreceptor trigger zone, CNS depression, respiratory failure, convulsions and death

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98
Q

What are the actions of cocaine on the CVS?

A

Low doses:
- Tachycardia, vasoconstriction, raised blood pressure
High doses:
- Ventricular fibrillation and cardiac arrest

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99
Q

What is the clinical use of cocaine?

A
  • Local anaesthetic in ophthalmology (rare); do not co-administer with adrenaline
  • Well absorbed from all sites; readily crosses blood-brain barrier- unlike adrenaline or noradrenaline
  • Degraded by plasma esterases and hepatic enzymes; plasma half life approximately 30 minutes excreted in urine
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100
Q

What is tyramine?

A

A dietary amino acid
(cheese, red, wine and soy sauce)
- Acts as a ‘false’ transmitter
- It is not a problem when normal mechanisms for degradation of monoamines are in operation

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101
Q

How does tyramine operate?

A

1) Has soem weak agnostic activity in its own right at post synaptic adrenoreceptors
2) Competes with catecholamines for uptake 1- it is taken up into adrenergic nerve terminals
3) Displaces no-adrenaline from intracellular storage vesicles into cytosol
4) Nor-adrenaline and tyramine compete for sites on MAO
5) Cytoplasmic nor-adrenaline leaks through the neuronal membrane to act at postsynaptic adrenorececptors
- Not usually a problem due to first pass metabolism and short half life so does not enter the CNS

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102
Q

Why does tyramine cause problems when MOAs are inhibited?

A

Ingestion of foods may cause a hypertensive crisis

‘cheese reaction’

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103
Q

What are the types of adrenoreceptors?

A

a1- Vasoconstriction, relaxation of GIT
a2- Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions
B1- Increased cardiac rate and force, relaxation of GIT, renin release from kidney
B2- Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
B3- Lipolysis

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104
Q

What are the different types of adrenoreceptor antagonists?

A
  • Non- selective: (a1+ b1) Labetalol
  • a1 + a2: Phentolamine
  • a1: Prazosin
    B1 + B2: Propanolol
    B1: Atenolol
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105
Q

What are the clinical uses of SNS antagonists and false transmitters?

A
  • Hypertension
  • Cardiac arrhythmias
  • Angina
  • Glaucoma
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106
Q

What is hypertension defined as?

A

Sustained diastolic arterial pressure greater than 90 mmH

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107
Q

What are the main elements that contribute to hypertension?

A
  • Blood volume
  • Cardiac output
  • Peripheral vascular tone
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108
Q

What are the tissue targets for antihypertensives?

A
  • Sympathetic nerves that release the vasoconstrictor noradrenaline
  • The kidney: blood volume/vasoconstriction
  • The heart
  • Arterioles: determine peripheral resistance
  • CNS: determined blood pressure set point and regulates some systems that are involved in blood pressure control and ANS
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109
Q

How can B-blockers be classified?

A

Whether they are non-selective (propranolol), cardioselective (atenolol) or whether they have some additional a1 atagonist activity

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110
Q

How do B-adrenoceptor antagonists work?

A

Competitive antagonism of b1 adrenoreceptors

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111
Q

What is the mode of action of b-adrenoceptor antagonists?

A
  • Reduced sympathetic tone in the CNS
  • Acts on the heart (B1) to reduce heart rate and cardiac output. This effect disappears in chronic treatment
  • Acts on the kidney (B1) to reduce renin production. A common long term feature in their anti-hypertensive action is a reduction in peripheral resistance.
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112
Q

What are the pre-synaptic effects of B-adrenoceptor antagonists?

A

Presynaptic beta receptors have a positive effect on the synthesis and release of noradrenaline.
B1 antagonists cause a blockade on this presynaptic facilitation.
This may contribute to the antihypertensive effect.

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113
Q

What are the unwanted effects of B-adrenoceptor antagonists?

A
  • Bronchoconstriction: Has little importance in the absence of airway disease. In asthmatic patients, this can be dramatic and life-threatening. Has clinical important in patients with obstructive lung disease e.g. bronchitis
  • Cardiac failure: patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output. Removal of this by blocking B receptors will produce a degree of cardiac failure.
  • Hypoglycaemia (sweating, palpitations, tremor)
  • Fatigue: Due to reduced cardiac output and reduced muscle perfusion
  • Cold extremities: Loss of B-receptor mediated vasodilation in cutaneous vessels
  • Bad dreams
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114
Q

Why are the unwanted effects of hypoglycaemia more dangerous with the use of non-selective B-antagonists?

A
  • The use of B antagonists mask the symptoms of hypoglycaemia
  • Use of non-selective B antagonists are more dangerous in such patients since they will also block the B2 receptors driven breakdown of glycogen.
  • B1-selective agents may have advantages since glucose release from the liver is controlled by B2-receptors.
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115
Q

What type of Beta-blocker in propranolol?

A

B1+B2- non-selective

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116
Q

What are the effects of of propranolol in a subject at rest?

A
  • Causes very little change in heart rate, cardiac output or arterial pressure. However, it reduces the effect of exercise or stress on these variables
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117
Q

Why does propranolol produce all the typical adverse effects?

A

It is non-selective

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118
Q

How is the selectivity of atenolol described?

A

It is a B1 selective drug

Cardioselective

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119
Q

What are the effects of atenolol?

A
  • As it is B1 selective, it mainly antagonises the effects of noradrenaline on the heart but will affect any tissue with B1 receptors such as the kidney
  • Has less effect on airways than non-selective drugs but is still not safe with asthmatic patients
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120
Q

What type of adrenoceptor antagonist is labetalol?

A

Dual acting B1 and A1 antagonist.

Has a ratio of B1 to A1 of 4:1

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121
Q

What are the effects of labetalol?

A
  • The drug lowers blood pressure via a reduction in peripheral resistance
  • Like B-blockers, labetolol induces a change in heart rate or cardiac output. This effect wanes with chronic use
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122
Q

Why do non-selective alpha-adrenoceceptor antagonists cause a rapid fall in arterial pressure?

A
  • Cause a rapid fall in arterial pressure as alpha receptors are the main mediators of peripheral resistance
  • Due to subcutaneous vasodilation which causes increased blood flow through cutaneous and splanchnic vascular beds. Has only slight effects on vascular smooth muscle
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123
Q

What are the side effects of non-selective alpha-adrenoceptor antagonists?

A

Postural hypotension induced reflex tachycardia.

B-receptors show a reflex response due to the fall in arterial pressure

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124
Q

What type of antagonist is phentolamine?

A

Non-selective alpha-antagonist

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125
Q

What are the effects of phentolamine?

A
  • Causes vasodilation and a fill in blood pressure due to blockade of alpa-1 receptors
  • However, concomitant blockade of alpha-1 receptors tends to increased noradrenaline release. This enhances the reflex tachycardia that occurs with any blood pressure lowering agent.
  • Increased GIT motility, diarrhoea is a common problem
  • It is no longer clinically used
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126
Q

What type of antagonist is prazosin?

A

Alpha -1 antagonist

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127
Q

What are the effects of prazosin?

A
  • Vasodilation and a fall in arterial pressure
  • Less tachycardia than non-selective antagonists since they do not increase noradrenaline release form nerve terminals (no alpha-2 actions)
  • Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels
  • Dramatic hypotensive effect
  • Does not affect cardiac function appreciably, although postural hypotension is troublesome
  • Differs from other anti-hypertensives as alpha-1 antagonists cause a modest decrease in LDL and an increase in HDL cholesterol
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128
Q

What is methyldopa and what is it used for?

A

Is a false transmitter

Used as an antihypertensive agent

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129
Q

How does methyldopa work?

A
  • Taken up by noradrenergic neurons

- Decarboxylated and hydroxylated to form the false transmitter, alpha-methyl noradrenaline

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130
Q

Why does methyldopa accumulate in larger quantities than noradrenaline?

A

It is not deaminated within the neuron by Mono Amine Oxidase (MAO) and therefore tends to accumulate in larger quantities than noradrenaline, and displaces noradrenaline from synaptic vesicles

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131
Q

What is the mechanism of action of methyldopa?

A
  • The false transmitter is release in the same way as noradrenaline
  • Differs in two important respects in its action on adrenoceptors
    1) Less active than noradrenaline on a1- receptors, less effective in causing vasoconstriction
    2) More active on presynaptic (a2) receptors, auto-inhibitory feedback mechanism operates more strongly, reduces transmitter release below normal levels
  • Also some CNS effects, stimulates vasopressor centre in the brainstem to inhibit sympathetic outflow
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132
Q

What are the benefits of methyldopa?

A
  • Renal and CNS blood flow is well maintained, widely used in hypertensive patients with renal insufficiency or cerebrovascular disease
  • Recommended in hypertensive pregnant women, has no adverse effects on the foetus despite crossing the blood-placenta barrier
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133
Q

What are the adverse effects of methyldopa?

A
  • Dry mouth
  • Sedation
  • Orthostatic hypotension
  • Male sexual dysfunction
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134
Q

What is the main cause of arrhythmias?

A

Myocardial ischaemia

  • There is an increase in sympathetic tone after myocardial infarction.
  • An increase in sympathetic drive to the heart via B1 can precipitate or aggravate arrhythmias
  • AV conductance depends critically on sympathetic activity, and the refractory period of the AV node is increased by B-adrenoceptor antagonists, intefering with AV conduction in atrial tachycardias and to slow ventricular rate
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135
Q

Which B-antagonist acts as a antiarrhythmics?

A

Propanolol- a non selective B-antagonist. Also classed as a class II antiarrhythmic- mainly due to beta-1 antagonism

  • Reduces the mortality of patients with myocardial infarction
  • Particularly successful in arrhythmias that occur during exercise or mental stress
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136
Q

What is angina?

A

Pain that occurs when the oxygen supply to the myocardium is insufficient for its needs
It is brought on by exertion or excitement

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137
Q

Where is pain distributed in angina?

A

Chest, arm, neck

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138
Q

What is stable angina?

A

Pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels. E.g. atheroma

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139
Q

What is unstable angina?

A

Pain with less and less exertion, culminating with pain at rest.
Platelet-fibrin thrombus associated with a ruptures atheromatous plaque, but without complete occlusion of the vessel.
There is a risk of infarction

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140
Q

What is variable angina?

A

Occurs at rest, caused by coronary artery spasm.

It is associated with atheromatous disease.

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141
Q

What is used to treat angina?

A

B-adrenoceptor antagonists in order to reduce myocardial oxygen

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142
Q

How do B-adrenoceptor antagonists treat angina?

A
  • Reduce myocardial oxygen on demand
  • Decrease heart rte
  • Decrease systolic blood pressure
  • Decrease cardiac contractile activity
  • At low doses, B1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle
  • Reduce the oxygen demand whilst maintaining the same degree of effort
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143
Q

What are the adverse effects of B-adrenoceptor antagonists being used to treat angina?

A
  • ## Fatigue, dizziness, sexual dysfunction, bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility.
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144
Q

In which cases should B-adrenoceptor antagonists not be used to treat angina?

A

In patients with bradycardia, bronchospasm, hypotension, AV block or sever congestive heart failure

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145
Q

Where is aqueous humour produced and what course does it take to drain into the canal of Schlemm?

A
  • Produced by blood vessels in ciliary body via the actions of carbonic anhydrase
  • Flows into posterior chamber, through the pupil anterior chamber
  • Drains into trabecular network and into veins and canal of Schlemm
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146
Q

What is the production of aqueous humour indirectly related to?

A

Blood pressure and blood flow in the ciliary body

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147
Q

What non selective beta-antagonists are used to treat glaucoma?

A
  • Carteolol hydrochloride, levobunolol hydrochloride, timolol maleate
  • Reduce the rate of aqueous humor formation by blocking the receptors on the the ciliary body
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148
Q

What selective beta antagonists are used to treat glaucoma?

A

B1 antagonist betaxolol hydrochloride

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149
Q

What are some other uses of Beta-antagonists?

A
  • Anxiety states: to control somatic symtpoms associated with sympathetic over reactivity, such as palpitations and tremor
  • Migraine prophylaxis
  • Benign essential tremor
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150
Q

What is a neuromuscular junction?

A

The synapse of the axon terminal of a motor neuron with a motor end plate, the highly excitable region of muscle fibre plasma membrane which is responsible for the initiation of action potentials across the muscles surface which causes the muscle to contract

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151
Q

Which neurotransmitter is involved in neurotransmission at the neuromuscular junction?

A

Acetylcholine

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152
Q

What is the nicotinic acetyl-choline receptor made up of?

A
  • 5 sub units
  • All arranged symmetrically around a central pore
  • Each subunit comprises 4 transmembrane domains with both the N and C terminus located extracellularly
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153
Q

What drugs affect CNS processes of the musculoskeletal system?

A

Spasmolytics

eg. Diazepam and Baclofen

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154
Q

What drugs affect the conduction of nerve action potential in the motor neurone?

A

Local anaestetics

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155
Q

What drugs affects acetylcholine release?

A

Ca++ entry blockers

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156
Q

What drug affects choline reuptake?

A

Hemicholinium

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157
Q

What drugs affect propagation of action potentials along muscle fibres?

A

Spasmolytics

eg. Dantrolene

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158
Q

What are neuromuscular blocking drugs?

A

Act at the final site at which drugs can act- the neuromuscular junction.
They prevent depolarisation of the motor-end plate and post-synaptic action potential initiation
They act post-synaptically

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159
Q

What are the types of neuromuscular blocking drugs?

A

1) Non-depolarising- competitive antagonists eg. Tubocarine and atracurium
2) Depolarising- agonists eg. suxamethonium (succinylcholine)

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160
Q

What are the affects of neuromuscular blocking drugs?

A
  • Do NOT affect consciousness or pain sensation

- DO affect respiratory muscles therefore respiration must always be assisted until the drug is inactive or antagonised

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161
Q

What is the mode of action of Tubocarine?

A
  • Non-depolarising neuromuscular blocking drug
  • Competitive nicotinic Ach receptor antagonist
  • A 70-80% block is necessary to achieve the desired effects
  • Produces a graded block, in which there are different proportions of fibres blocked
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162
Q

What are the pharmacokinetics of tubocarine?

A
  • Administered intravenously (highly charged)
  • Duration of action = Between 40 and 60 minutes
  • Not metabolised
  • Excreted 70% in urine and 30% in bile. Therefore, care must be taken if the patient has their renal or hepatic function impaired.
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163
Q

What are the effects of tubocarine?

A
  • Flaccid paralysis
  • First the extrinsic eye muscles are affected. The patients will experience double vision
  • Second, the small muscles of the face, limbs and pharynx are affected
  • Lastly, the respiratory muscles are effected
  • Recovery occurs in the reverse order
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164
Q

What are the clinical uses of tubocarine?

A
  • Relaxation of skeletal muscles during surgical operations so that less anaesthetic is required
  • Permits artificial ventilation
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165
Q

How can the actions of tubocarine be reversed?

A

Anticholinesterases such as Neostigmine, co-administered with Atropine

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166
Q

What are the unwanted effects of tubocarine?

A
  • Ganglion block & histamine release from mast cells
  • Ganglion block > decreased peripheral resistance > hypotension and reflex tachycardia
  • Histamine release > bronchospasm, excessive bronchial salivary secretions
  • Apnoea also caused by histamine release
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167
Q

What is Atracarium?

A

Antagonist of Ach at the post-synaptic site at the neuromuscular junction.
Non-depolarising blocker like Tubocarine but the effects have a shorter duration

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168
Q

What is suxamethonium (succinulcholine)?

A
  • Depolarising neuromsucular blcoker
  • Structure is related to acetylcholine and is a post synaptic nAChR agonist
  • Causes excitation for a long period of time, action potentials can no longer be produced as the cell cannot repolarise.
  • Degraded by Butyrylcholinesterase
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169
Q

What are the main effects of the sympathetic nervous system on the heart?

A
  • Increased force of contraction (positive ionotropic effect)
  • Increased heart rate (positive chronotropic effect)
  • Increased automaticity
  • Reploarisation and restoration of function following generalised cardiac depolarisation
  • Reduced cardiac efficiency (i.e. cardiac oxygen consumption is increased more than cardiac work)
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170
Q

What are the effects of the sympathetic nervous system on the heart mainly due to?

A
  • The activation of Beta-1 adrenoceptors
  • Activation stimulates adenyl cyclase resulting in production of cyclic AMP from ATP. This acts as an intracellular messenger which increases intracellular Ca++ and stimulates Na-K ATPase in cardiac myocytes
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171
Q

What are the effects of activation of the parasympathetic system on the heart?

A
  • Cardiac slowing
  • Reduced automaticity
  • Inhibition of AV conduction
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172
Q

What do the drugs used to treat the symptoms of angina aim to improve?

A

The balance between supply and demand for oxygen

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173
Q

Give an example of an organic nitrate

A

Glyceryl trinitrate

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174
Q

How do organic nitrates act?

A
  • Act mainly as venodilators, reducing venous return and cardiac work via the Frank Starling relationship
  • They release nitric oxide
  • Nitrates ay also have weak anti-platelet actions and cause coronary arterial vasodilation.
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175
Q

Which potassium channel opener is used in angina?

A

Nicorandil

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176
Q

How do potassium channel openers work in anginda?

A
  • Open KATP channels and also act as nitric oxide donors.

- These agents cause venodilation and arterial dilation.

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177
Q

What are the adverse effects of nitrates?

A

Hypotension

Headache

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178
Q

What are the two classes of calcium antagonists?

A

1) Rate slowing (cardiac and smooth muscle actions)
- Phenylalkylamines (eg. Verapamil)
- Benzothirazepine (e.g. Diltizaem)
2) Non-rate slowing (smooth muscle actions-more potent)
- Dihyropyridines (e.g. amlodipine)
- No effect on the heart. Profound vasodilation can lead to reflex tachycardia

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179
Q

How do calcium antagonists act to reduce cardiac workload?

A

They bind to and inhibit the opening of L-type calcium channels
They cause arterial vasodilation.

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180
Q

Why does verapamil have negative chronotropic and ionotropic actions?

A

Reduce Ca++ entry into cardiac myocytes

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181
Q

What are the side effects of verapamil?

A

Heart block
Heart failure
Constipation

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182
Q

What are the side effects of calcium antagonists?

A

Flushing
Headaches
Hypotension
Ankle swelling

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183
Q

What are the limitations of the Vaughan Williams classification?

A

It is widely cites but not helpful in predicting the effects of a particular anti-dysrhythmic agent and a number of useful agents cannot be classified by this system

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184
Q

What are the determinants of myocardial oxygen supply?

A

Coronary blood flow

Arterial 02 content

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185
Q

What are the determinants of myocardial oxygen demand?

A

Heart rate
Preload
Afterload
Contractility

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186
Q

What decreases with vasodilation?

A

Afterload

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187
Q

What decreases with venodilation?

A

Preload

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188
Q

What is the Vaughan-Williams classification of arrhythmic drugs?

A

I- Sodium channel blockade
II- Beta adrenergic blockade
III- Prolongation of repolarisation
IV- Calcium channel blockade

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189
Q

Give examples of antidysrhythmic agents

A

Adenosine
Verapamil
Amiodarone
Digoxin and cardiac glycosides

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190
Q

What is adenosine?

A
  • Endogenous mediator
  • Produced by metabolism of ATP
  • Acts on A1 receptors to hyperpolarise cardiac tissue and slow conduction through the AV node
  • Used intravenously to terminate superventricular tachyarrhythmias (SVT)
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191
Q

Why is adenosine safer than verapamil?

A

Its actions are short lived- 20 to 30 seconds

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192
Q

What are the uses of verapamil?

A
  • Reduction of ventricular responsiveness to atrial arrhythmias
  • Prevents recurrence of paroxysmal SVT
  • Reduced ventricular rate in patients with atrial fibrillation provided they do not have Wolff-Parkinson-White or similar abnormal conduction pathwyas
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193
Q

What is the mechanism of action for verapamil?

A

Depresses automaticity of SA node and subsequent AV node conduction

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194
Q

What are the uses of amiodarone?

A
  • Superventricular and ventricular tachyarrhythmias- often due to reentry
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195
Q

What is the mechanism of action for amiodarone?

A
  • Complex action probably involving multiple ion channel block
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196
Q

What are the adverse effects of amiodarone?

A
  • Accumulates in the body (half life= 10-100 days)
  • Has a number of effects which include:
  • Photosensitive skin rashes
  • Hypo/hyper -thyroidism
  • Pulmonary fibrosis
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197
Q

How do digoxin and cardiac glycosides work?

A

Act as inhibitors of the Na-K ATPase (Na/K) pump

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198
Q

What are the cardiac effects of digoxin?

A
  • Cardiac slowing and reduced rate of conduction through the AV node (largely as a result of central vagal stimulation)
  • Increased force of contraction
  • Disturbances of rhythm especially:
    • Block of AV conduction
    • Increased ectopic pacemaker activity
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199
Q

What are the uses of digoxin and cardiac glycosides?

A
  • Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output
  • Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and the ventricular rate will fall.
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200
Q

What are the adverse effects of digoxin and cardiac glycosides?

A
  • Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
  • Hypokalaemia lowers the threshold for digoxin toxicity
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201
Q

What are cardiac ionotropes?

A

Agents that increase the force of cardiac contraction and are used to treat heart failure in some situations (eg. after cardiac surgery or in cardiogenic or septic shock)

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202
Q

What is Dobutamine?

A

Beta1 Adrenoceptor agonist that stimulates cardiac contraction without a major effect on heart rate

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203
Q

How do inhibitors of phosphodiesterase have ionotropic effects?

A

Inhibit the breakdown of cyclic AMP in cardiac myocytes

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204
Q

Give an example of an inhibitor of phosphodiesterase

A

Milrinone

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205
Q

What are the uses of ACE inhibitors?

A
  • Hypertension
  • Heart failure
  • Post-myocardial infarction
  • Diabetic nephropathy
  • Progressive renal insufficiency
  • Patients at high risk of cardiovascular disease
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206
Q

What are the adverse affects of ACE inhibitors and angiotensin receptor blockers

A
  • Cough (ACEI)
  • Hypotension (both)
  • Urticaria/ Angioedema (ACEI- rare)
  • Hyperkalaemia
  • Fetal injury (both)
  • Renal failure in patients with renal artery stenosis (both)
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207
Q

What mediates most of the affects of angiotensin II?

A

AT1 receptor

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208
Q

What is spironolactone an antagonist of?

A

The mineralcorticoid- aldosterone

It inhibits the sodium retaining effects of aldosterone

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209
Q

What is spironolactone useful for?

A

Heart failure

Resistant cases of hypertension

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210
Q

What are the unwanted effects of spironolactone?

A
  • Can cause hyperkalaemia due to its aldosterone antagonism

- Steroid like effects such as gynaecomastia, menstrual disorders and testicular atrophy

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211
Q

Give an example of an ACE inhibitor

A

Enalapril

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212
Q

What are the types of calcium channel blockers?

A

Dihydropyridines:
- More selective for blood vessels
- Nicardipine- does not cause any negative ionotropy
- Also licensed for prophylaxis of angina
Non-DHPs (rate limiting):
- Verapamil- large negative ionotropic effect

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213
Q

What are the uses of beta-adrenoreceptor blockers?

A
Angina 
Post myocardial infarction 
Cardiac dysrhythmias 
Chronic heart failure 
Hypertension 
Thyrotoxicosis 
Glaucoma 
Anxiety states 
Migraine prophylaxis 
Benign essential tremor
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214
Q

Why might beta blockers be an effective treatment for hypertension

A
  • Causes a decrease in heart rate and force of contraction. Therefore there is a decrease in cardiac output
  • The heart does not have to work as hard so there is a reduction in blood pressure
  • Renin and Angiotensin II release decreases
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215
Q

Why does Carvedilol have additional vasodilator properties to Atenolol?

A

Atenolol is B1- selective.
Carvedilol is a mixed B-alpha blocker.
The Alpha-1 gives additional vasodilator properties

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216
Q

What is hydralazine?

A

A direct vasodilator that acts mainly on arteries and arterioles

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217
Q

Under what circumstances would hydralazine cause a reflex tachycardia?

A

In the absence of a beta-blockade due to the drugs vasodilator effects

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218
Q

How does doxazosin act as an arterial vasodilator?

A

It is an alpha blocker (competitive antagonist of a1-adrenoceptors). Acts as an arterial vasodilator by inhibiting the vasoconstrictor effects of the sympathetic nervous system acting via a1-adrenoceptors on vascular smooth muscle

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219
Q

When is phenoxybenzamine used?

A
  • It is an irreversible non-selective alpha antagonist

- Provides a long-lasting alpha-blockade in pheochromocytoma (combined with a beta blocker)

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220
Q

Give examples of centrally acting antihypertensive agents

A

Clonidine
-methyldopa (a2-adrenoceptor agonists)
Moxonidine (imidazole agonist)
Reserpine (depletes neuronal noradrenaline)

  • These agents act by reducing sympathetic activity
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221
Q

What is guanethidine?

A

Adrenergic neuron blocker

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222
Q

What is trimethaphan?

A

Short acting ganglion blocker

- Is occasionally used in anaesthesia to lower blood pressure

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223
Q

What is sumitriptan and what does it do?

A

Agonist at 5HT1D receptors.

Causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission

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224
Q

What is sumitriptan used for?

A

Treats migraine attacks, contraindicated in patients with coronary disease

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225
Q

What are the side effects of sumitriptan?

A

Dizziness
Drowsiness
Asthenia
Fatigue

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226
Q

When can adrenaline be used?

A

Cardiac arrest

Anaphylactic shock

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227
Q

How is blood pressure calculated?

A

cardiac output x total peripheral resistance

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228
Q

How is hypertension defined?

A

Being consistently above 140/90 mmHg

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229
Q

What is hypertension a major risk factor if?

A

Stroke
Myocardial infarction
Chronic kidney disease

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230
Q

What is chronic heart failure?

A

Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue

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231
Q

What do patients with chronic heart failure typically receive?

A
  • Diuretic
  • ACE Inhibitor (ARB)
  • Beta blocker
  • +/- spironolactone
  • +/- digoxin
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232
Q

What is a narcotic?

A

A drug that produces morphine like effects

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233
Q

What causes the euphoric feeling obtained from drugs?

A
  • The mesolimbic system and pathways go up into the nucleus accumbens go up into the nucleus accumbens to release dopamine
  • The release dopamine into the nucleus accumbens causes the euphoric feeling- this is also the natural reward pathway?
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234
Q

Where do the mesolimbic system and pathways originate?

A

Ventral tegmental area

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235
Q

What are the different routes of administration for drugs of abuse?

A

1) Snorting (intra-nasal)- drug crosses the mucous membranes of nasal sinus, into the blood then systemic circulation back to the heart then up to the brain (slow absorption)
2) Eating (oral)- drug absorbed in GI tract, passes through liver then goes back into circulation (very slow absorption)
3) Smoking (inhalation)- drug transfers across small airways and into blood (rapid absorption and distribution)
4) Injection (intra-venous)- rapid absorption

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236
Q

How are drugs of abuse classified?

A

Nacrotics/painkillers- opiate like drugs e.g. heroin
Depressants- ‘downers’ e.g. alcohol, benzodiazepines (valium), bariturates
Stimulants- ‘uppers’ e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)
Miscellaneous- e.g. Cannabis, ecstacy (MDMA)

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237
Q

How many compound does herbal cannabis contain?

A

Over 400 compounds including over 60 cannabinoids

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238
Q

What is the most potent psychoactive agent in cannabis?

A

9-tetrahydrocannabinol

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239
Q

What are cannabinoids present in?

A
  • Marijiuana/CAnnabis: leaves and flowering tops of cannabis sativa plants
  • Hashish- resinous material of cannabis plant, leaves, flowers and seeds of the plants, and also in the resin secretion by the female plant
    Hash oil- plant extract (with organic solvents
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240
Q

How does oral ingestion of cannabinoids differ from it being smoked?

A

Blood concentration are 25-30% of those obtained by smoking the same dose- due to first pass metabolism.
Onset of action is delayed (0.5-2h) but duration is prolonged to slow absorption from the gut

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241
Q

What is a major metabolite of cannabinoids?

A

11-hydroxy-THC

- is a postent cannabinoid itself

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242
Q

Where are cannabinoids metabolised?

A

Liver

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243
Q

Where are cannabinoids excreted?

A

Urine (25%)
Gut (65%)
They are reabsorbed from the gut which further prolongs their actions

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244
Q

What are the neuronal cannabinoid receptors?

A

CB1

Present in hippocampus/cerebellum/cerebral cortex/basal ganglia

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245
Q

What are the cannabinoid receptors in immune cells?

A

CB2

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246
Q

What is the endogenous agonist of cannabinoids?

A

Anandamide- an arachidonic acid derivative

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247
Q

What are the psychological effects of cannabinoids?

A
  • Effects on perception: colours seem brighter, music is more vivid, emotions more poignant
  • Perceived time goes faster than clock time
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248
Q

How do cannabinoids affect cognition and psychomotor performance?

A

Slow reaction times, motor incoordination, defects in short term memory

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249
Q

What are the CVS effects of cannabinoids?

A
  • Tachycardia up to 160 beats/minute
  • Widespread vasodilation
  • Reddening of the conjunctivae- a characteristic sign of cannabis use
  • Postural hypotension and fainting may occur
  • Risk factor for severe mental illness
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250
Q

What is the purpose of the anterior cingulate cortex?

A

Involved with performance monitoring with behavioural adjustment in order to avoid losses

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251
Q

How does cannabis affect the anterior cingulate cortex?

A

Leads to hypo-activity

- This is associated with poor control

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252
Q

How does cannabis affect food intake?

A
  • Positive effect on orexigenic neurones in lateral hypothalamus
    1) Presynaptic inhibition of GABA increases MCH neuronal activity
    2) Increased orexin production
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253
Q

What are the peripheral effects of cannabis?

A
  • Immunosuppressant

- Tachycardia/vasodilation

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254
Q

What is Dronabinol used for?

A

Treats nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results
- Also treats loss of appetite and weight loss in people who have AIDS

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255
Q

Which drugs target the cannabinoid system?

A
  • Dronabinol and Nabilone
  • Savitex
  • Rimonabant
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256
Q

What examples of disease show how the up-regulation of CB receptors can mitigate a disease?

A
  • In multiple sclerosis and schizophrenia, activating CB1 and CB2 receptors, has a beneficial effect as it stops the toxic necrosis of the neurons in the brain.
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257
Q

What are the different forms cocaine is available in?

A

IV, ORAL, INTRANASAL:

1) Paste- 80% cocaine (organic solvent)
2) Cocaine HCl- dissolve in acidic solution

INHALATION:

3) Crack- precipitate with alkaline solution e.g. baking soda
4) Freebase- dissolve in non-polar solvent (e.g. ammonia and ether)

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258
Q

Why is there slower absorption when cocaine is snorted as opposed to smoked?

A

It is absorbed through the mucous membranes that line the sinuses.
100-500ng/mL

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259
Q

What are the routes of administration of cocaine that have rapid absorption?

A
  • Smoking

- Cocaine HCl being injected IV

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260
Q

How is cocaine metabolised?

A

Cocaine metabolises primarily into ecgonine methyl ester and benzolyecgonine on first passage through the liver which are renally excreted.
These metabolites account for 75-90% of cocaine metabolism

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261
Q

What is the half life of cocaine?

A

90 minutes

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262
Q

What effects does cocaine have on the reward pathway?

A

Inhibit the reuptake of dopamine in the Nacc

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263
Q

How does cocaine have a local anaestetic effect?

A

Cocaine blocks sodium channels to prevent nerve conduction. (major therapeutic use of cocaine)
- Cocaine also binds to and inhibits monoamine transporter proteins. Influences the transport of neurotransmitters. Cocaine blocks the transporters e.g. for serotonin, dopamine and noradrenaline

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264
Q

How does cocaine induce euphoria?

A
  • Cocaine directly affects the mesolimbic neurons
  • Binds to dopamine transporter present on the terminals of dopaminergic neurons and prevents the re-uptake on dopamine.
  • If dopamine is prevented from being removed from the synapse in the nucleus accumbens, the effect is prolonged and this is how the euphoria is caused
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265
Q

How does cocaine affect the CNS?

A
  • Cocaine is a stimulant and enhances CNS effects

- An overdose can induce severe effects like irritability, hostility, anxiety and insomnia

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266
Q

What are the cardiovascular effects of cocaine?

A
  • Cocaine increases the production of endothelin-1 (powerful vasoconstrictor)
  • Decreases NO production (vasodilator
  • Increases platelet activation and sympathetic stimulation and an overall increase in heart rate.
  • This explains the link between cocaine use and sudden death
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267
Q

What is nicotine?

A

Plant derived alkaloid that is contained within tar droplets, which are very lipid soluble and pass down into the lungs and onto the bloodstream

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268
Q

What are the routes of administration of nicotine?

A

1) Nicotine spray (intranasal)- contains about 1mg of nicotine (20-50% gets into the bloodstream)
2) Nicotine gum- contains 2-4mg of nicotine (50-70% gets into the bloodstream)
3) Cigarettes- contain 9-17mg of nicotine (20% gets into the bloodstream
4) Nicotine patches- contain 15-22mg of nicotine which are applied over 24 hours (70% gets into the bloodstream transdermally)

269
Q

What is the pKa of nicotine?

A

7.9

Cigarette smoke is relatively acidic

270
Q

Why is most of nicotine in smoke absorbed in the lungs?

A
  • Cigarette smoke is relatively acidic
  • Most of nicotine in smoke is ionised therefore little is absorbed into the bloodstream via the mucous membranes of the mouth
  • Most is absorbed int eh lungs because the alveoli are so thin therefore it does not matter it is ionised
271
Q

What is the quickest route of administration for nicotine?

A

Cigarettes

272
Q

What is the purpose of nicotine spray, gum and the patch?

A
  • Remove the nicotine ‘spike’ which tends to encourage the individual to take another cigarette
  • A low level of nicotine is needed over a long period of time to wean people off cigarettes
273
Q

What is the half life of nicotine?

A

2 hours

274
Q

How is nicotine metabolised?

A
  • Broken down predominantly (70-80%) in the liver by cytochrome P2A6 into continine which is excreted in the urine.
  • The quick excretion explains why there is repetitive abuse of the drug
275
Q

How does nicotine act?

A
  • Acts on nicotinic acetylcholine receptors in the ANS of which there are 5 subunits
  • Binding causes Na+ channels to open which causes depolarisation and subsequent action potentials at all ganglia and the adrenal medulla
  • Nicotine binds to the nicotinic acetylcholine receptors on cell bodies of the dopaminergic neurons in the ventral tegmental area. This stimulates them, and activates them to release dopamine into the nucleus accumbens
276
Q

What subunits of the nicotinic acetylcholine receptors does nicotine bind to in order to produce its effects?

A

Alpha 4

Beta 2

277
Q

What are the main side affects of nicotine?

A

Cardiovascular:

  • Increased heart rate and stroke volume
  • Profound vasoconstriction (particularly in coronary arterioles and skin) vasodilation in skeletal muscle
  • Increased lipolysis
  • Increased platelet activity because of enhances thromboxane A2 and reduced nitric oxide
  • Heart therefore has to work harder, blood flow is reduced and increases risk that vessels supplying the heart will become blocked
278
Q

What are the metabolic effects of nicotine?

A
  • Increased metabolic rate

- Apetite suppressant

279
Q

Why might nicotine protect against Parkinson’s disease?

A

It increases brain cytochrome P450 which metabolises a lot of neurotoxins in the brain

280
Q

Why might nicotine protect against Alzheimer’s disease?

A

It decreases beta-amyloid toxicity and the build up of amyloid precursor proteins (APP) which are thought to be of pathological importance

281
Q

Why can caffeine theoretically induce euphoria?

A
  • Adenosine tends to decrease dopamine content within the synapse
  • Caffeine inhibits adenosine receptors thus reducing the suppression by adenosine. The amount of dopamine increases to produce euphoria
  • Most coffee has a low dose of caffeine and is taken orally therefore the effects are slow
282
Q

How does chocolate simulate euphoria?

A

Stimulates the reward system

283
Q

How much is 1 unit of alcohol?

A

8g ethanol

284
Q

What is alcohol?

A

Ethanol (C2H5OH)

285
Q

What are the recommended limits of alcohol?

A
Men= 21 units 
Women= 14 units
286
Q

What is the number of people in the UK with alcohol related problems?

A

40,000

287
Q

How is the absolute amount of alcohol calculated?

A

%ABV x0.78 (g/100ml)

ABV= Alcohol by volume

288
Q

How are units calculated?

A

% ABV x vol(ml) / 1000

289
Q

What is considered binge drinking?

A

More than 8 units in one sitting

290
Q

What are the effects of 20-40mg/ml of alcohol?

A
Minimal effects
(1/2 pint - 1 pint)
291
Q

What are the effects of up to 50mg/ml of alcohol?

A

Very little effects on motor skills

292
Q

What are the effects of up to 80mg/ml of alcohol?

A

Legal driving limit

x4 increased likelihood of car accident

293
Q

What are the effects of up to 150mg/ml of alcohol?

A

25x more likelihood of car accident

294
Q

What are the effects of 300mg/ml of alcohol?

A

Coma

295
Q

What are the effects of 400-500mg/ml of alcohol?

A

Death

296
Q

What is the route of administration for alcohol?

A
  • Mostly administered orally
  • Once administered, 20% is absorbed in the stomach and80% in the ileum
  • Therefore, speed of onset is directly related to gastric emptying. If stomach is full, alcohol sits in stomach and absorption is poor. Alcohol will then move into the stomach at a slower rate, alcohol in the blood is what has an effect
  • Drinking on an emptying stomach differs as drinking fluid stimulates gastric emptying. Alcohol will therefore pass straight through the small intestine and a large proportion of the dose will be absorbed into the bloodstream
297
Q

What % of ingested alcohol dose is metabolised in the body?

A

90%

- 10% is expired unchanged in the breath

298
Q

What % of alcohol is metabolised in the liver?

A

85%

299
Q

What are the two important enzymes in the liver needed for the metabolism of alcohol?

A

They both break alcohol down into acetaldehyde
75% done by- ALCOHOL DEHYDROGENASE
25% done by- MXED FUNCTION OXIDASE

300
Q

Why can a person’s tolerance/capacity for alcohol be increased?

A
  • A result of the Mixed Function Oxidase system
  • Regularly drinking alcohol will lead to the MFO enzyme being up-regulated leading to to the capacity for alcohol to be metabolised becoming greater
301
Q

Why is the rate of consumption of alcohol important?

A
  • Oral administration has to pass through first pass hepatic metabolism in order to enter the systemic circulation to produce its effects
  • If ones liver is better at metabolising the alcohol, less alcohol will reach the systemic circulation
  • Liver enzymes can become saturated which causes a greater increase in blood ethanol levels
302
Q

Why does alcohol have a greater effect on women?

A
  • 15% of alcohol is absorbed in the stomach where ADH acts to generate acetaldehyde
  • Women have 50% less ADH in their stomach therefore less able to metabolise the alcohol
  • Also, women have more fat than men meaning they have a smaller volume of body water. Alcohol is a water soluble compound therefore alcohol will be more concentrated in a woman
303
Q

How can low doses of alcohol show some CNS excitability?

A
  • Depends on personality of individual and the environment
  • Alcohol affects GABA pre- and post-synaptically. It facilitates chloride ion influx and therefore promotes the affects of GABA. It also has an inhibitory effect pre-synaptically via the generation of neuroactive steroid - Allopregnolone which has a stimulatory effect on releasing GABA
304
Q

In the CNS, what receptors can alcohol bind to in order to reduce function?

A
NMDA receptors (stimulatory) 
Reduces function and decreases the effects of excitatory neurotransmitters
305
Q

Why does down-regulating calcium channel activity show a depressant effect?

A

Neurotransmitter release is calcium dependent

306
Q

How does alcohol affect the corpus callosum?

A
  • Has a role in communication between the right and left hemisphere
  • Alcohol leads to a disconnect between rules/logic and impulse feelings
  • Become more impulsive
307
Q

How does alcohol affect the hypothalamus?

A
  • Regulating appetite, body temperature, emotional behaviour, pain and sensation
  • Alcohol leads to loss of regulation
  • Experience munchies, become emotional and feel no pain
308
Q

How does alcohol affect the reticular activating system

A
  • Regulates consciousness

- Alcohol leads to impaired consciousness at a very high dose

309
Q

How does alcohol affect the hippocampus?

A
  • Involved in memory formation

- Alcohol leads to loss of memory

310
Q

How does alcohol affect the cerebellum?

A
  • Movement and coordination

- Alcohol leads to stumbling

311
Q

How does alcohol affect the basal ganglia?

A
  • Perception of time

- Alcohol leads to a loss of sense of time

312
Q

How can the effects of alcohol on the cardiovascular system be explained?

A
  • Alcohol dampens down calcium channel activity
  • Cutaneous vasodilation (fascial flushing) is related to decreased calcium entry and increased vasodilating prostaglandins
313
Q

How does alcohol affect the endocrine system?

A
  • Alcohol increases diuresis (polydipsia), both by way of volume and direct effect on ADH
  • It reduces ADH secretion which stimulates diuresis. This is links to reduced potassium entry into the posterior pituitary
314
Q

What are the chronic effects of alcohol on the CNS

A
  • Cortical atrophy and an increased volume of cerebral matter&raquo_space; dementia
  • Cerebellar cortex degeneration&raquo_space; ataxia
  • Dementia and ataxia lead to WERNICKE-KORSAKOFF SYNDROME which is encephalopathy related to the 3rd ventricle and aqueduct
  • Eventually this leads to KORSAKOFF’S PSYCHOSIS which is related to the interference with memory, which is irreversible
315
Q

What are the chronic effects of alcohol on the liver?

A
  • Alcohol uses up all the NAD+ in the aldehyde dehydrogenase pathway
  • This affects every metabolic pathway which requires NAD+ and results in a shift away from gluconeogenesis and glycolysis towards ketogenesis, lipid production and fatty deposition. This leads to an increase of storage of fats as triaglycerol in the liver = FATTY LIVER
  • If fatty liver deposits occurs chronically, inflammatory changes will happen in the liver. There is generation of pro-inflammatory cytokines and free radicals which leads to inflammation of the liver and hepatitis.
  • Inflammation will trigger fibroblasts to start laying down connective tissue, so you start to lose active liver tissue and hepatocyte regeneration = CIRRHOSIS
316
Q

What are the beneficial effects of alcohol on the cardiovascular system?

A
  • There is reduced mortality from coronary artery disease, increases HDL levels, increased tPA and a reduction in platelet aggregation according to evidence
317
Q

How does alcohol pose an increased risk of stomach cancer?

A
  • In the GI tract, 15% of alcohol is metabolised to acetaldehyde.
  • Acetaldehyde results in damage to the gastric mucosa and is carcinogenic
318
Q

How could alcohol lead to a Cushing’s like syndrome?

A
  • Alcohol stimulates ACTH which leads to increased cortisol synthesis.
  • Also, it is linked with a decreased testosterone secretion leading to gynaecomastia
319
Q

What is the effect a hangover is thought of us?

A

Rebound excitation effect

- Symptoms peak as blood alcohol concentration reaches zero

320
Q

What are the symptoms of a hangover?

A
  • Nausea and vomiting (irritant to vagus to vomiting centre)
  • Headache (vasodilation)
  • Fatigue (sleep deprivation, rebound)
  • Restlessness and muscle tremors (rebound)
  • Polyuria and polydipsia (decreased ADH secretion)
321
Q

What are the effects of alcohol on foetal development?

A
  • Foetal alcohol syndrme (when mothers drink at least 4 units/day)
  • Abnormal facial development (and other anatomical abnormalities)
  • Growth retardation
  • Mental retardation
  • Caused by inhibition of cell division/migration
322
Q

Why is Disulfiram used as aversion therapy for alcoholics?

A
  • Inhibits acetaldehyde dehydrogenase acetaldehyde accumulation
  • High levels of acetaldehyde causes flushing, tachycardia, hyperventilation and panic/distress
  • Useful in discouraging recovering alcoholics from drinking (no effect without alcohol present)
323
Q

How long does tolerance take to build?

A

1-3 week with continuing ethanol administration

324
Q

How is physical withdrawal from alcohol characterised?

A
  • Tremor
  • Hallucinations
  • Convulsions
  • Behaviour disturbances
  • Nausea
  • Fever
325
Q

What are the constituents of blood?

A
Blood cells: 45%
99% erythrocytes  
Leukocytes 
Thrombocytes 
Blood plasma: 55% 
Water 90% 
Electrolytes
Proteins 
Lipoproteins 
  • Clotting factors
326
Q

What is haemostasis?

A
  • Essential physiological process

- Blood coagulation prevents excessive blood loss

327
Q

What is thrombosis?

A
  • Pathophysiological process
  • Blood coagulates within blood vessel which obstructs blood flow
  • Venous thromoses (red thrombi) have high fibrin components
  • Clot becomes life-threatening if it dislodges from the vessel and it embolises
328
Q

What is Athersclerosis?

A
  • Pathophysiological process
  • Thrombus forms within athersclerotic plaque
  • Plaque rupture- thrombus released into lumen (ischaemia)
  • Arterial thromboses (white thrombi)- high platelet components
329
Q

What is Virchow’s triad?

A

1) Rate of blood flow: if blood flow is slow/stagnating, there is no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
2) Consistency of blood: natural imbalance between procoagulation and anticoagulation factors e.g. Factor V Leiden
3) Blood vessel wall integrity: damaged endothelia leads to blood being exposed to procoagulation factors

330
Q

What is the process of coagulation according to the cell based theory?

A

1) Initiation
2) Amplification
3) Propagation

331
Q

What does the initiation stage of coagulation involve?

A

This phase involves the smalls scale production of thrombin mediated by tissue factor bearing cells.

  • TF bearing cells activate factors X and V forming the prothrombinase complex
  • The prothrombinase complex activates factor II (prothrombin) which creates factors IIa (thrombin)
332
Q

What type of cell does the initiation step of coagulation occur in?

A

The step is localised to cells that express tissue factor which are normally found outside the vasculature

333
Q

What needs to occur for the coagulation process to proceed to the amplification phase?

A

When the tissue factor bearing cells come into contract with

1) platelets which are only present within blood vessels and
2) the factor VIII/von Willebrand factor complex, which is only released when the vascular endothelium is damaged

334
Q

What does the amplification phase of the coagulation process involve?

A

Sets the stage for subsequent large-scale thrombin production and involves thrombin-mediated activation of factors V, VIII, IX on the surface of platelets

  • Thrombin activates platelets.
  • The activated platelet then changes shape and becomes sticky and attaches to other platelets
335
Q

Where does the propagation phase of the coagulation process occur?

A

Predominantly on the surface of the platelets that have been recruited to the site of injury.

336
Q

What does the propagation phase of the coagulation process involve?

A

Large scale production of thrombin on the surface of activated platelets resulting in the formation of fibrin strands, which are key constituents of a blood clot

  • Activated platelets lead to large-scale thrombin production
  • Factor IIa binds to fibrinogen and converts to fibrin strands
337
Q

How does antithrombin affect the initiation phase of the coagulation process?

A

It inactivates factor IIa and factor Xa

338
Q

Which anticoagulant inhibits factor IIa?

A

Dabigatran

339
Q

Which anticoagulant inhibits factor Xa

A

Rivaroxaban

340
Q

What are the actions of low molecular weight heparins?

A

They are partially digested heparin lacking the thrombin region and mainly effective at inhibiting fXa.
The pharmacokinetics are more reproducible and longer half-life therefore only s.c injection 1-2 times a day
- Activates antithrombin

341
Q

What are examples of low-molecular weight heparins?

A

Dalteparin

Enoxaparin

342
Q

How do heparin’s act?

A

Acts by exerting a conformational change on antithrombin making the enzyme significantly more potent, thus inhibiting thrombin and fXa.
Has a short half life (1 hr) and must be given at regular intervals by continuous infusion

343
Q

What is warfarin?

A

Vitamin K antagonist

344
Q

How does warfarin act?

A
  • Vitamin K is essential for the formation of thrombinase, fVII, fIX and fX
  • Coumarin is a naturally occurring compound that inhibits coagulation by preventing the reduction of vitamin K.
345
Q

When are anticoagulants used?

A
  • Deep vein thrombosis and pulmonary embolism
  • Thrombosis during surgery
  • Atrial fibrillation- prophylaxis of stroke
346
Q

Give examples of anticoagulants that are indirect thrombin inhibitors

A
  • Heparin
  • Low molecular weight heparins
  • Fondaparinux
  • Rivaroxaban
347
Q

Give examples of anticoagulants that are direct thrombin inhibitors

A
  • Bivalurudin

- Dabigatran

348
Q

What steps lead to platelet activation?

A
  • Thrombin: binds to protease-activated receptor (PAR) on platelet receptor
  • PAR activation leads to a ride in intracellular Ca++
  • Ca++ rise leads to exocytosis of adenosine diphosphate (ADP) from dense granules
349
Q

How do ADP receptors contribute to platelet activation?

A

ADP activates P2Y12 receptors which leads to platelet activation/aggregation

350
Q

How does cyclo-oxygenase (COX) contributeto platelet activation?

A
  • Protease-activated receptor activation liberates arachidonic acid
  • COX generates thromboxane A2 from arachidonic acid
351
Q

How do glycoprotein IIb/IIIa receptors contribute to platelet activation?

A
  • Thromboxane A2 activation leads to the expression of Glycoprotein IIb/IIa integrin receptor on platelet surface
  • GPIIb/IIa is involved in platelet aggregation
352
Q

What is the action of Clopidogrel (oral)?

A

Prevents platelet activation/aggregation

- Is an ADP (P2Y12) receptor antagonist

353
Q

What is the action of Aspirin (oral)?

A
  • Inhibits the production of TXA2
  • It is an irreversible COX-1 inhibitor
  • High doses are no more effective but there are more side effects
354
Q

What is the action of Abciximab (IV, SC)?

A
  • Prevent platelet aggregation

- Limited use and only by specialists

355
Q

Give examples of GP IIb/IIIa receptor antagonists

A
  • Abciximab
  • Tirofiban
  • Eptifibtatide
356
Q

What is the mechanism of thrombolytics?

A
  • Convert plasminogen to plasmin

- Plasmin- protease degrades fibrin

357
Q

What is Alteplase?

A
  • A thrombolytic
  • Given IV
  • Recombinant activator (rt-PA)
358
Q

What is streptokinase?

A
  • Plasminogen activator

- Is administered IV as soon as possible following a myocardial infarction to dissolve the clots

359
Q

Why will the body develop immunity to streptokinase?

A

It is a bacterial product

360
Q

What is Reteplase?

A
  • Recombinant tisssue PA analogue
  • Non-glycosylates form of human tPA administered by IV injection
  • Used to treat acute MI
361
Q

What is Tenecteplase?

A
  • Recombinant tissue PA analogue
  • Genetically engineered variant of alteplase with three mutations designed to increase plasma half life, potency and reduce PA inhibitor action
362
Q

When are thrombolytics used?

A

Arterial and venous thrombosis

  • Stroke- first line treatment
  • ST elevated MI
363
Q

When are antiplatelets used?

A

Arterial thrombosis

  • Acute coronary syndromes- myocardial infarction
  • Atrial fibrillation- prophylaxis of stroke
364
Q

What are deep vein thromboses causes by?

A
  • Reduction in the rate of blood flow

- Damage to the endothelium

365
Q

What is used to manage a deep vein thrombus?

A

Anticoagulants

366
Q

What is an NSTEMI?

A
  • Non-ST elevated myocardial infarction
  • ‘White’ thrombus -> partially occluded coronary artery
  • Caused by: Damage to endothelium, atheroma formation, platelet aggregation
367
Q

What is used to manage acute coronary syndromes (stroke)

A

Anti platelets
- Need to prevent further arterial occlusion
- Reduce lipid accumulation and platelet aggregation
Thombolytics
- Prevent death and dissolve thrombus

368
Q

What is used to treat aortic aneurism?

A

Anti-platelets

369
Q

What is used to treat pulmonary embolism?

A

Anticoagulants/thrombolytics

370
Q

What is the purpose of the exogenous metabolic pathway?

A

It is concerned with the transport and utilisation of dietary fats

371
Q

Where is dietary fat broken down?

A

Gastrointestinal tract

372
Q

What is dietary fat broken down into?

A

Cholesterol
Fatty acids
Mono- and- and di-glycerides
- Together with bile acids these molecules form water soluble micelles that carry the lipid to absorptive sites in the duodenum

373
Q

What proportion of triglyceride and cholesterol is absorbed?

A

Triglyceride- 100%

Cholesterol- 50%

374
Q

In the exogenous metabolic pathway, what enters the bloodstream following absorption in the duodenum?

A

Chylomicrons are formed which enter the bloodstream via intestinal lymphatics and the thoracic duct

375
Q

In the exogenous metabolic pathway, what happens to the chylomicrons once it enters the plasma?

A
  • Rapid changes take place in the chylomicron
  • It is hydrolysed by the enzyme lipoprotein lipase releasing the triglyceride core, free fatty acids and mono and diglycerides for energy production or storage
376
Q

What happens to the residual chylomicrons after it enters the plasma in the exogenous metabolic pathway?

A
  • Undergoes further dilipidation which results in the formation of chylomicron remnants.
  • The remnants are taken up by tissues
377
Q

What happens to chylomicron remnants in the liver?

A
  • Undergo lysomal degradation.
  • They are either used for a variety of purposes including remanufacture into new lipoproteins, production of cell membranes
  • Or can be excreted as bile salts
378
Q

What os the endogenous metabolic pathway concerned with?

A

The breakdown of chylomicron remnants

379
Q

What do chylomicrons do?

A

Transport triglyceride from the gut to the liver?

380
Q

What does VLDL do?

A

Transport triglyceride from the liver to the rest of the body

381
Q

What happens to VLDL in the blood stream?

A
  • Triglyceride with cholesterol, cholesterol ester and other lipoprotein particles are transported in VLDL in the bloodstream
  • Here, VLDL undergoes delipidation with the enzyme lipoprotein lipase (the endogenous pathway of lipid metabolism)
382
Q

Which enzymes are involved in the lipolysis of VLDL particles?

A

Large VLDL particles: Lipoprotein lipase

Small VLDL and IDL particles: Hepatic lipase

383
Q

What provides a route for the excretion of cholesterol and bile acids?

A

Enterohepatic circulation

384
Q

What type of LDL particles are the most atherogenic?

A

Small and dense particles
- They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells which is the initial stage in the pathogenesis of atherosclerotic plaques

385
Q

Why is cholesterol eliminated intact?

A

It cannot be broken down within the body

- It is taken out of the tissues and transported back to the liver via HDL

386
Q

How is endothelial dysfunction in atherosclerosis characterised?

A

By a series of early changes that precede lesion formation.
- The changes include greater permeability of the endothelium, up-regulation of leucocyte and endothelium adhesion molecules and migration of leucocytes into the artery wall

387
Q

What is the earliest recognisable lesion of atherosclerosis?

A
  • The ‘fatty streak’
  • Caused by the aggregation of lipid-rich foam cells, derives from macrophages and T lymphocytes within the intima, the inner most part of the artery wall.
388
Q

How does a mature atherosclerotic plaque develop?

A

Migration of vascular smooth muscle cells to the intima and the laying down of collagen fibres which results in the formation of a protective fibrous cap over the lipid core

389
Q

Why is the fibrous cap a crucial component of the mature atherosclerotic plaque ?

A

It separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors

390
Q

What characterises a stable atherosclerotic plaque?

A

A necrotic lipid core covered by a thick VSM-rich fibroud cap

391
Q

What factors might influence the vulnerability of an atherosclerotic plaque and therefore increase its tendency to erode or rupture?

A
  • Hypertension
  • High turbulent blood flow
  • Increased number of inflammatory cells
  • Lipid rich core
  • Thin fibrous cap with few smooth muscle cells or collagen fibres
392
Q

If plaque formation hardens the arteries, how can this pose problems?

A
  • Weakening and thinning of vessel wall

- Leads to aneurysm and possibly haemorrhage

393
Q

At what sites do fibrous plaques usually occur?

A
  • Sites of thinning
  • Associates with regions where there is greater influx and activation of macrophages, accompanies by the release of metalloproteinases that are involved with the breakdown of collagen
394
Q

How are vulnerable plaques characterised?

A
  • Thin fibrous cap
  • Core rich is lipid and macrophages
  • Less evidence of smooth muscle proliferation
395
Q

By what % does CHD risk increase with a 10% increase in LDL cholesterol?

A

20%

396
Q

What factors modify the association between LDL cholesterol and the risk of CHD events?

A
  • Low HDL cholesterol
  • Smoking
  • Hypertension
  • Diabetes
397
Q

How does HDL cholesterol affect atherosclerosis and CHD?

A
  • Has a protective effect
  • The lower the HDL cholesterol level, the high the risk of atherosclerosis and CHD
  • HDLs tend to be low when triglycerides are high
398
Q

What can lower HDL cholesterol?

A
  • Smoking
  • Obesity
  • Physical inactivity
399
Q

What are normal triglyceride levels?

A
400
Q

What triglyceride levels are considered too high?

A

> 100mg/dl

401
Q

What are the clinical manifestations of atheosclerosis?

A
  • Coronary heart disease
  • Angina pectoris, myocardial infarction, sudden cardiac death
  • Cerebrovascular disease
  • Transient ischaemic attacks, stroke
  • Peripheeral vacular disease
  • Intermittent claudication, gangrene
402
Q

What are the stages of the pathogenesis of atherosclerotic plaques?

A

1) Endothelial damage
2) Protective response results in production of cellular adhesion molecules
3) Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells
4) Migrate through arterial wall to subendothelial space
5) Macrophages take up oxidised LDL-cholesterol
6) Lipid rich foam cells
7) Fatty streak and plaque

403
Q

What effect does a 10% reduction in total cholesterol have on

1) CHD mortality
2) Total mortality ?

A

1) 15% reduction in CHD mortality

2) 11% reduction in total mortality

404
Q

What is the mechanism of action for statins?

A
  • Body obtains cholesterol and triglyceride by either synthesising them in the liver or from the diet or storage sites in adipose tissue
  • The cholesterol synthesis pathway involves biochemical pathways and feedback mechanisms in the liver
  • Statins inhibit HMG-CoA reductase
  • In response, hepatocytes upregulate and increase the number of LDL receptors which increases the binding and removal of LDL cholesterol and LDL precursors from the plasma
  • Consequently, HDL levels increase
405
Q

What is the function of HMG-CoA reductase?

A

The enzyme involved in the rate-limiting step in the formation of cholesterol, which is usually responsible for two-thirds of the body’s cholesterol

406
Q

What causes the main adverse effects of statins?

A

Due to their non-selective effects on the body

407
Q

What are the effects of statins on lipids?

A
  • Rule of 6

- Doubling the dose only results in a 6% reduction in LDL

408
Q

How do bile acid sequestrants work?

A

They bind to bile acids and prevent reabsorption

409
Q

What is the effect of bile acid sequestrants?

A
  • Effect on the liver is to increase synthesis and excretion of the cholesterol from the liver
  • Does not have a significant effect on triglycerides
410
Q

What are the problems with bile acid sequestrants?

A
  • Compliance can be a problem
  • Patients may object to the taste and textute
  • Common adverse events are gastrointestinal bloating, nausea and constipation
411
Q

How is nicotinic acid used as a drug therapy?

A
  • B complex vitamin used in therapy at very high doses

- Number of effects on HDL, LDL, triglycerides as well as clotting

412
Q

What are the cons of using nicotinic acid as a drug therapy?

A
  • Adverse effects include flushing, skin problems, GI disease, liver toxicity, hyperglycaemia and hyperuricaemia
  • Is expensive and dosing is difficult
413
Q

What are fibrates?

A

Effective triglyceride-lowering drugs.

- Effective for patients with type III hyperliprotinaemia

414
Q

What is the main mechanism of action for fibrates?

A

Activation of PPAR alpha receptors
- Act on receptors in the liver and adipose tissue, resulting in a decreased level of plasma fatty acids and triglycerides

415
Q

What are PPAR alpha receptors?

A

Perioxisome proliferator activated receptors

416
Q

Why are fibrates not usually used?

A

Due to their effects on inflammatory responses, thrombosis, etc

417
Q

What is the mechanism of action for Ezetimibe?

A
  • Absorbed then activated as glucuronide in the liver
  • It is then secreted into the bile into the GIT where it blocks cholesterol absorption (85% is endogenous)
  • Studies show it reduces LDL significantly
418
Q

What are the benefits of inhibiting cholesterol ester transfer protein?

A

The protein causes the loss of cholesterol from HDL to LDL.

- Example of this drug is torcetrapib

419
Q

Why does torcetrapib show an increase in mortality?

A

It is associated with increased blood pressure through an increased aldosterone synthesis

420
Q

What are the analgesic uses of Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)

A
  • Relief of mild to moderate pain
  • Toothache, headache, backache
  • Postoperative pain (opiate sparing)
  • Dysmenorrhea (menstrual pain)
421
Q

What are the antipyretic uses of NSAIDs?

A
  • Reduction of fever

- Influenza

422
Q

What are the anti-inflammatory uses of NSAIDs?

A
  • Rheumatoid arthiritis
  • Osteoarthiritis
  • Other forms of musculo-skeletal inflammation
  • Soft tissue injuries (strains and sprains)
  • Gout
423
Q

How many deaths are NSAIDs responsible for?

A

2000 deaths annually

424
Q

What are most emergency admissions as a result of NSAIDs due to?

A

GI ulceration

425
Q

What are prostanoids?

A

A specific family of inflammatory lipid mediators.

  • They are derived from arachidonic acid and include prostaglandins, prostacyclins and thromboxanes
  • Widely distributed
  • Cannot be stored
  • Released immediately when synthesised
426
Q

What is the mechanism of actions for NSAIDs

A

They inhibit prostanoids.

  • Inhibit the COX enzyme
  • COX is the rate-limiting step for the production of all prostanoids
  • COX converts arachidonic acid to prostaglandin H2
427
Q

How many prostanoid receptors are there?

A

10 known
DP2, DP2, EP1, EP2, EP3, EP4, FP, IP1, IP2, TP
- All are G protein coupled but also have effects independent of G proteins

428
Q

What are the analgesic actions of NSAIDS on Prostaglandin E2?

A
  • Lowers pain threshold
  • Stimulation of PG receptors on nerve endings sensitises nociceptors to chemical and thermal stimuli which cause pain. This therefore blocks the perception of PGE2.
  • Raising the threshold of nociceptors reduces the perception of pain
429
Q

What are thee unwanted actions of PGE2?

A
  • Increased pain perception
  • Thermoregulation
  • Acute inflammatory response
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
430
Q

What are the pyrogenic actions of NSAIDs on Prostaglandin E2?

A
  • PGE2 stimulates hypothalmic neurons which initiates a rise in body temperature.
  • Blocking its production can prevent the increase in body temperature
431
Q

What affect does a COX-2 inhibitor have on pain?

A

Prevents or reduces duration of prolonged pain

432
Q

What are the effects of NSAIDs on Prostaglandin E2?

A

Analgesic
Pyrogenic
Anti-inflammatory

433
Q

What effects does PGE2 have on immune and inflammatory pathways?

A
  • Enhances Th1 cell differentiation and also Th17 expansion.

- Contribute to inflammation

434
Q

What are the desirable actions of PHE2 and other prostanoids?

A
  • Gastroprotection
  • Regulation of renal blood flow
  • Bronchodilation
  • Vasoregulation
435
Q

What is the role of PGE2 in gastric cycoprotection?

A
  • PGE’s downregulate gastric acid secretion and stimulate the release of mucous and bicarbonate onto the stomach surface
  • This protects the stomach lining.
436
Q

How can the role of PGE2 in gastric cytoprotection explain the unwanted effects of NSAIDS

A

Prolonged use of NSAIDs may result in increase HCl production and a reduction/loss of protective mucous and bicarbonate.
Therefore there is an increased risk of gastric ulceration

437
Q

Why can NSAIDs cause renal toxicity?

A
  • PGE2 increases renal blood flow
    Therefore with use of NSAIDs there will be
  • Constriction of afferent renal arteriole
  • Reduction in renal artery flow
  • Reduced glomerular filtration rate
438
Q

Why should NSAIDs not be taken by asthmatic patients?

A
  • Most cyclo-oxygenase products cause bronchodilation
  • Inhibition of cyclooxygenase favours production of leukotrienes which are bronchoconstrictors
  • Some patients with asthma experience an exacerbation of symptoms on taking NSAIDs
439
Q

Why can NSAIDs have serious unwanted cardiovascular effects?

A
  • Prostanoids are vasoregulators
  • NSAIDs may cause myocardial infarction, stroke
  • NSAIDs cause a small rise in blood pressure, sodium retention, vasoconstriction
  • This can reduce the effectiveness of antihypertensives
440
Q

How do the NSAIDS- Ibuprofen and Indomethacin affect cyco-oxygenase?

A
  • Typical non- selective NSAIDs
  • Inhibit cyclo-oxygenase reversible
  • Inhibit both COX-1 and COX-2
  • Have anti-inflammatory analgesic and anti-pyretic actions
441
Q

Which NSAID selectively inhibits COX-2?

A

Celecoxin

442
Q

What are the pros and cons of COX-2 inhibitors?

A
  • Have a good GIT safety profile
  • Are well tolerated (but not recommended) for patients with asthma
  • BUT have significant unwanted CVS effects, possibly more than non-selective NSAIDs
443
Q

What strategies are available other than COX-2 selective NSAIDs for limiting GI side effects?

A
  • Topical application
  • Minimise NSAID use in patients with history of GI ulceration
  • Treat H pylori if present
  • If NSAID essential, administer with omeprazole or other proton pump inhibitor
  • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. Alcohol consumption, anticoagulant or glucocorticoid steroid use
444
Q

What cyclooxygenase is the NSAID- Aspirin selective for?

A

COX- 1

445
Q

What are the effects of aspirin?

A
  • Binds irreversibly to COX-1
  • Has anti-inflammatory, analgesic and anti-pyretic actions
  • Reduces platelet aggregatin
446
Q

What are the effects of prostanoids on platelet aggregation?

A

1) Thromboxane A2 is produced by platelets.
It stimulates platelet aggregation
2) Prostacyclin is produced by endothelial cells. It inhibits platelet aggregation

447
Q

What is the effect of aspirin on Thromboxane and Prostacyclin?

A

Inhibits both as
Thromboxane A2 is made by COX-1
Prostacyclin synthesis is by COX-1 and COX-2

448
Q

Why does aspirin stop all synthesis of thromboxane but not of prostacyclin.

A

Platelets have no nucleus therefore can not synthesise more enzyme
Endothelial cells are able to synthesise new COX enzymes

449
Q

What are the anti-platelet actions of aspirin due to?

A
  • Very high degree of COX-1 inhibition which effectively suppresses thromboxane production by platelets.
  • Covalent binding which permanently inhibits COX-1
  • Relatively low capacity to inhibit COX-2
  • Need low dose to allow endothelial resynthesis of COX-2
450
Q

What is inhibition of prostacyclin proportional to?

A

Inhibition of COX-2

451
Q

What are the major side effects of aspirin seen at therapeutic doses?

A
  • Gastric irritation and ulceration
  • Bronchospasm in sensitive asthmatic
  • Prolonged bleeding times
  • Nephrotoxicity
452
Q

Why are side effects more likely with aspirin than other NSAIDs?

A

Aspirin inhibits COX covalently rather than its selectively for COX-1

453
Q

Why is Paracetamol not a NSAID?

A
  • Despite the fact it is a good analgesic for mild-to-moderate pain and has anti-pyretic action
  • Has NO anti-inflammatory effect
454
Q

Why can a paracetamol overdose cause irreversible liver failure?

A

If glutathione is depleted, the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death

455
Q

What is the antidote for paracetamol poisoning?

A
  • Add compound with -SH groups
  • Usually intravenous Acetylcysteine
  • Occasionally oral methionine
  • Acetyl cysteine used in cases of attempted suicide
  • If not administered early enough, liver failure may be unpreventable
456
Q

What are diuretics?

A

Drugs that act on the renal tubule to promote the excretion of Na+, Cl-, H20 .
This increases the osmolarity of the tubular fluid which decreases the osmotic gradient across the epithelia.
Leads to diureses

457
Q

What is the target organ for all subtypes of diuretics?

A

The kidney

458
Q

How does passive transport occur in the proximal convoluted tubule?

A
  • Sodium and water freely diffuse across the apical membrane into the tubule cells along their concentration gradient
  • This concentration gradient is maintained by the Na/K ATPase on the basal membrane, which transports sodium from the cell into the interstitium and eventually into the blood
  • Sodium ions exert and osmotic pressure which drives water movement into the interstitium. The oncotic pressure of plasma proteins within renal capillaries exert a pull driving water transport
459
Q

What do the large gap junction between PCT cells allow?

A

Paracellular movement of sodium, chloride, bicarbonate, water and some drugs to diffuse along their concentration gradients

460
Q

How does active transport occur in the proximal convoluted tubule?

A
  • NA/H exchanger protein on apical membrane allows sodium to be reabsorbed into the PCT cell in exchange for H+ ions. The Na+ binds to this transporter and is also able to bind to glucose or amino acids. This allows the reabsorption of glucose and amino acids to occur.
461
Q

What is needed for the Na/H exchanger to function?

A

A supply of H+ ions within the cytoplasm of the PCT cell

- Maintained by carbonic anhydrase enzyme

462
Q

What are the two subtypes of carbonic anhydrase enzyme?

A
  • In the cytoplasm of the PCT cell. Carbonic anyhydrase combines water and carbon dioxide to generate H+ and HC03- ions.
  • In the tubule lumen, the enzym used H+ that are secreted into the lumen and combines them with luminal HCO3- to form water and carbon dioxide
463
Q

After passing through the proximal convoluted tubule, how much filtrate passes on to the loop of Henle?

A

30%

464
Q

How do the ascending and descending limbs of the loop of Henle differ?

A

Descending= completely permeable to water. Lumen fluid is roughly isotonic. Interstitial fluid is hypertonic. Water freely diffuses across the cell into the interstititium
Ascending= Impermeable to water and possesses various transmembrane carrier proteins
Apical membrane= Na+/K+/2xCl- co-transporter
Basal= Na+/K+ co-transporter and K+/Cl- co-transporter.
Most of ions are absorbed into interstitium.
Interstitium more hypertonix
Luminal fluid more hypotonic

465
Q

How do the descending and ascending limbs explain the countercurrent effect?

A
  • The descending limb is permeable to water. Therefore the more concentrated medullar interstitium draws water from the permeable descending limb.
    Fluid in descending limb increases in osmolarity
  • The ascending limb is ipermeable to water therefore Na+ leaves the ascending limb and enters medullar interitium. Fluid in ascending limb decreases in osmolarity
  • More fluid enters and forces fluid descending to ascending limb. This fluid has increased in osmolarity due to increase Na+ concentration in the medulla
466
Q

Is the DCT permeable to water?

A

No

467
Q

What carrier proteins are present on the DCT?

A
  • Sodium channel and Na+/Cl- co-transport protein on apical membrane. Concentration gradient which drives this is maintained by Na+/K+ exchanger and Cl/K co-transporter on the basal membrane.
  • Aquaporin molecule inserted on either side of cell in the later distal tubule which regulate water movement from lumen to interstitium.
468
Q

What control are aquaporin molecules under?

A

Vasopressin

469
Q

What influence is the distal tubule under?

A

Aldosterone

470
Q

What movement occurs in the collecting duct?

A
  • Similar to later distal tubule
  • Free movement of potassium (interstitium to lumen) and chloride (lumen to interstitium).
  • Last site of remaining water reabsorption to prevent excess water from being excreted
471
Q

What are the main 5 classes diuretics?

A

1) Osmotic diuretics e.g. mannitol
2) Carbonic anhydrase inhibitors e.g. acetazolamide
3) Loop diuretics e.g. frusemide
4) Thiazides e.g. bendrofluazine
5) Potassium sparing diuretics e.g. amiloride, spironolactone

472
Q

Where do the 5 main diuretics principally act

A

1) Osmotic diuretics- entire kidney tubule
2) Carbonic anhydrase inhibitors - PCT
3) Loop diuretics - ascending loop of Henle
4) Thiazides - early DCT
5) Potassium sparing diuretics - late DCT and collecting duct

473
Q

What is the target of osmotic diuretics?

A
  • No protein target

- Increase the osmolarity of the kidney filtrate, resulting in less water reabsorption and thus more water excretion

474
Q

How does mannitol work?

A
  • Pharmacologically inert substance which is freely filtered into the lumen but then poorly reabsorbed.
  • Decreases water reabsorption where the nephron is freely permeable to water including the PCT, DCT and Collecting duct
475
Q

What are the clinical uses of osmotic diurectics?

A
  • Not generally used for kidney-related issues
  • Prevention of acute renal failure
  • Decreasing intra-cranial pressure
476
Q

How do carbonic anhydrase inhibitors work?

A
  • Carbonic anhydrase generate bicarbonate within the PCT cells
  • The inhibitors increase bicarbonate and sodium loss, therefore water loss. Increased tubular fluid osmolarity also decreases water reabsorption in the collecting duct
  • Relatively weak diuretics
477
Q

Which diuretics are the most potent?

A

Loop diuretics

478
Q

How does frusemide work?

A
  • Acts on ascending limb of the loop of Henle. Blocks the Na+/Cl-/K+ co-transporter meaning that more ions are passed on the DCT and collecting duct
  • Reduced osmolarity of medullary interstitium therefore less water is reabsorbed
  • Increased delivery to the distal tubule increases the amount of potassium that is lost
479
Q

How much more of filtrate can be lost due to loop diuretics?

A

15-30%

480
Q

What are the clinical uses of Loop diuretics?

A

Oedema- heart failure, pulmonary, renal, cerebral

e.g. acute left ventricular failure

481
Q

What are the unwanted effects of Loop diuretics?

A

Hypovalaemia and hypotension
K+ loss
Metabolic alkalosis

482
Q

How does bendrofluazine work?

A
  • Block Na+/Cl- co-transport protein in the early DCT
  • Results in increased osmalarity of the tubule with a corresponding decrease in water reabsorption in the collecting duct
  • Increased delivery of Na+ results in an increase K+ loss, as well as increase Mg2+ and Ca2+ reabsorption
483
Q

What are the clinical uses of thiazide diuretics?

A
  • Cardiac failure
  • Hypertension (initially decrease blood volume and long term leads to vasodilation)
  • Idiopathic hypercalcuria (Stone formation)
  • Nephrogenic diabetes insipidus (paradoxical)
484
Q

What are the unwanted effects of Thiazide diuretics?

A

K+ loss
Metabolic alkalosis
Diabetes mellitus- inhibits insulin secretion

485
Q

What are the different classes of K+ sparing drugs?

A

1) Aldosterone receptor antagonists e.g. spironolactone

2) Inhibitors of aldosterone-sensitive Na+ channels e.g. amiloride

486
Q

How do potassium sparing diuretics act?

A
  • Inhibit Na+ reabsorption in the late DCT, therfore inhibits the concomitant K+ secretion.
  • Results in increased tubular fluid osmolarity and increased water loss with an increased H+ retention. This increases uric acid loss
  • Result in small increase in urine volume with small Na+ loss
  • Not very useful alone but taken in conjunction with other diuretics
487
Q

What is the clinical use of amiloride?

A

To be used with K+ losing diuretics

488
Q

What are the clinical uses of spironolactone?

A

Hypertension/heart failure

Hyperaldosteronism

489
Q

What are the unwanted effects of potassium sparing diuretics?

A

Hyperkalaemia and metabolic acidoses

Spironolactone- gynaecomastia, menstrual disorder, testicular atrophy

490
Q

What are the two major forms of inflammatory bowel disease?

A
Ulcerative colitis (UC) 
Crohn's disease (CD 
- Both are autoimmune disease
491
Q

What are the risk factors of IBD?

A
  • Genetic predisposition
  • Environmental factors (smoking, diet/obesity, gut microbiome)
  • Obesity is a risk factor for CD
492
Q

What can disruption of the immune surveillance of the gut lead to?

A

There is complex interplay between host and microbes.
Disruption to this leads to uncontrolled inflammation and physical damage to the epithelium and leakiness of tight junctions

493
Q

What are the differences between Crohn’s disease and Ulcerative Colitis as autoimmune diseases?

A
Crohn's disease= 
Th1-mediated 
- Florid T cell expansion 
Defective T cell apoptosis 
Ulcerative Colitis= 
Th2-mediated 
Limited clonal expansion 
Normal T cell apoptosis
494
Q

What gut layers are affected in CD and UC?

A
CD= All layers 
UC= Mucosa/submucosa
495
Q

What regions of the gut are affected in CD and UC?

A
CD= Any part of GI 
UC= Rectum, spreading proximally
496
Q

What are the inflamed areas in CD and UC?

A
CD= Patchy 
UC= Continuous
497
Q

What is the nature of abscesses in CD and UC?

A
CD= Common 
UC= Not common
498
Q

In CD and UC, is surgery curative?

A
CD= Not always curative 
UC= Curative
499
Q

What are the clinical features of IBD?

A
  • Weight loss
  • Abdominal pain
  • Anaemia, sweats, jaundice
  • Diarrhoea, blood, mucus
  • Skin rash,
  • Right iliac fossa mass/pain
  • Primary sclerosing cholagitis
  • Apthous ulcers
500
Q

What are the supportive therapies for IBD?

A
  • Fluid/electrolyte replacement
  • Blood transfusion/oral iron
  • Nutritional support (malnutrition is common)
501
Q

What treatments are available to treat the active disease and to prevent relapse of IBD?

A
  • Glucocorticoids e.g. prednisolone
  • Aminosalicylates e.g. Mesalazine
  • Immunosuppressives e.g. Azathioprine
502
Q

What are aminosalicylates?

A

Anti-inflammatory drugs with no immunosuppressive action

503
Q

Give 2 examples of aminosalicylates

A
  • Mesalazine or 5-aminosalicyclic acid (5-ASA)

- Olsalazine (2 linked 5-ASA molecules)

504
Q

Are aminosalicylates useful in UC and CD?

A
  • First line in inducing and maintaining remission in Ulcerative Colitis
  • Ineffective in Crohn’s Disease
505
Q

What is the mechanism of the anti-inflammatory action of aminosalicylates ?

A
  • Inhibition of IL-1, TNF-a, and platelet activating factor (PAF)
  • Decreased antibody secretion
  • Non-specific cytokine inhibition
  • Reduce cell migration (macrophages)
  • Localised inhibition of immune responses
506
Q

Where is Mesalazine absorbed?

A

Small bowel and colon

507
Q

Where is Olsalazine metabolised?

A

By colonic flora and absorbed in the colon

508
Q

What are glucocorticoids?

A

Powerful anti-inflammatory and immunosuppressive drugs

  • Derived from the hormone cortisol
  • Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors
509
Q

Give 3 examples of glucocorticoids?

A

Prednisolone
Fluticasone
Budesonide

510
Q

How are glucocorticoids used to treat IBD?

A

Ulcerative Colitis:
- Use in decline
- Used topically or IV if very severe
Crohn’s disease:
- GCs remain drugs of choice for inducing remission
- Likely to get side effects if used to maintain remission

511
Q

What are the strategies to minimise the unwanted effects of glucocorticoids?

A
  • Administer topically: fluid or foam enemas or suppositories
  • Use a low dose in combination with another drug
  • Use an oral or topically administered drug with high hepatic first pass metabolism e.g. Budesonide so little escapes into the systemic circulation
512
Q

What are the unwanted effects of glucocorticoids?

A
  • Osteoporosis
  • Increased risk of gastric ulceration
  • Suppression of HPA axis
  • Type II diabetes
  • Hypertension
  • Susceptibility to infection
  • Skin thinning, bruising and slow wound healing
  • Muscle wasting and buffalo hump
513
Q

What immunosuppressive agents have been tried for the treatment of IBD?

A

Azathiprine
Cyclosporine
Methrotrexate

514
Q

What is the use of Azathioprine?

A
  • It is immunosuppressive
  • Mainly used to maintain remission in Crohn’s disease
  • Steroid sparing
  • Useful for maintaining remission in some patients with Ulcerative Colitis
  • Slow onset as takes 3 to 4 months treatment for clinical benefit
515
Q

What is the mechanism of immunosuppression in Azathioprine?

A
  • Pro-drug activated in vivo by gut flora to: 6-mercaptopurine - Give mercaptopurine directly
  • Purin antagonist
  • Interferes with DNA synthesis and cell replication
516
Q

What do the immunosuppressive actions of Azathioprine cause it to impair?

A
  • Cell and antibody mediated immune responses
  • Lymphocyte proliferation
  • Mononuclear cell infiltration
  • Synthesis of antibodies
517
Q

What do the immunosuppressive actions of Azathioprine cause it to enhance?

A

T cell apoptosis

518
Q

What are the unwanted effects of Azathioprine?

A
  • Pancreatitis
  • Bone marrow suppression
  • Hepatotoxicity
  • Increased risk of lymphoma and skin cancer
519
Q

How can the microbiome be manipulation?

A

1) Nutrition based therapies
2) Faecal microbiota replacement therapies
3) Antibiotic treatment- Rifaximin

520
Q

How can Rifaximin treat IBD?

A
  • Interferes with bacterial transcription by binding RNA polymerase
  • Induces and sustains remission in moderatie CD
  • May be beneficial to UC
521
Q

What biological therapies are approved for use in IBD?

A
  • Anti-TNFa antibodies
  • Infliximab (IV)
  • Adalimumab (sc)
  • Other antibodies are effective but have more side effects
522
Q

What type of IBD is anti-tumour necrosis factor a used successfully in the treatment of?

A

Crohn’s disease

- Potentially curative

523
Q

What is the mechanism of action for Anti-TNFa?

A
  • Reduces activation of TNF a receptors in the gut
  • Production of other cytokines, infiltration and activation of leukocytes is reduced
  • Also binds to membrane associated TNFa
  • Induces cytolysis of cells expressing TNFa
  • Promotes apoptosis of activated T cells
524
Q

Give examples of anti-TNFalpha antibodies?

A

Infliximab

Adalimumab

525
Q

What are the pharmacokinetics of anti-TNFalpha antibodies?

A

Infliximab given IV

  • 9.5 day half life
  • Benefits last 30 days
  • Most patients relapse after 8-12 weeks therefore need repeat infusion every 8 weeks
526
Q

What are the adverse effects of anti-TNFalpha antibodies?

A
  • 4x-5x increase in incidence of tuberculosis and other infections
  • Risk of reactivating dormant TB
  • Increase risk of septicaemia
  • Worsening of heart failure
  • Increased risk of demyelinating disease
  • Increased risk of malignancy
  • Can be immunogenic
527
Q

What is an opiate?

A

An alkaloid derived from the poppy, Papaver somniferum

528
Q

Name 4 Opiates?

A

Morphine
Thebaine
Codeine
Papverine

529
Q

What about its structure is crucial to the analgesia of morphine?

A

The tertiary form of nitrogen

  • Permits receptor anchoring
  • Altering the structure is the target of antagonists so it cannot pass into the central nervous system
530
Q

Why is the hydroxyl group at position 3 an important feature of opiates?

A

It is required for binding.
Drug companies modify the side groups.
Codeine is formed by modifying morphine

531
Q

Why is the hydroxyl group at position 6 an important feature of opiates?

A

Oxidises the OH group and lipophilicity increases 10 fold

532
Q

Why are opioids likely to be ionises in the acidic stomach?

A

It is a weak base and therefore poorly absorbed from this site

533
Q

What happens to opioids in the small intestine?

A

Unionised and more readily absorbed

- First pass metabolism will decrease the bioavailability

534
Q

Why are most opioids largely ionised in the bloody?

A

Blood pH= 7.4

The

535
Q

Why is heroin more potent than morphine?

A

It is more lipid soluble

536
Q

How is morphine metabolised?

A

By the liver into morphine-6-glucurodine, which effects take action after about 30 minutes
- It is almost completely metabolised in the liver then picked up by the kidney and excreted in the urine

537
Q

What contributes to the pharmacological effects of morphine?

A

The active metabolite

Morphine-6-glucuronide

538
Q

Where is morphine-6-glucuronide liberated from morphine?

A

It ends up into the bile and secreted in the gut

539
Q

How is codeine metabolised?

A

In the liver by CYP2D6.
It is slow and converts codeine to morphine
- Codeine is a prodrug

540
Q

Why do some people not respond well to codeine?

A

Have a 2D6 polymorphism

541
Q

What is morphine metabolised by?

A

Uridine 5 Disphosphate glucoronosyltransferase

542
Q

How do opioids work?

A
  • Act via specific ‘opioid’ receptors’
  • These are endogenous receptors which are synthesised because of the endogenous opioid receptors produced including endorphins, enkaphalins and dynorphins/neoendorphins
543
Q

What opioid receptors do endorphins bind to and where are they found?

A

Mu (μ)
Delta (δ)
Thalamus, amygdala, nucleus accumbens, PAG

544
Q

What do endorphins affect?

A

Pain/mood/CVS

  • Associated with exercise
  • ‘High’ feeling
545
Q

What opioid receptors do enkephalins bind to and where are they found?

A

Delta (δ)

Nucleus accumbens, cerebral cortex, amygdala

546
Q

What do enkephalins affects?

A

Pain/mood/CVS

547
Q

What opioid receptors do dynorphins bind to and where are they found?

A

Kappa (κ)

Hypothalamus

548
Q

What do dynorphins affect?

A

Apetite

549
Q

What is the cellular mechanism of opioid?

A
  • Bind to their G-protein coupled receptors and decrease adenylate cyclase activity. This dampens down the capacity of the neurone to produce cAMP. Cellular signalling is thus decreased
  • At membrane levelm increase the capacity for K+ to leave (hyperpolarisation) and decrease capacity for Ca+ to enter the cell.
    Decreases the ability to excite the neurone and release transmitters. This is a depressant effect.
550
Q

What are the pharmacological actions of opioids?

A
  • Analgesia
  • Euphoria
  • Depression of cough centre (anti-tussive)
  • Depression of respiration (medulla)
  • Stimulation of chemoreceptor trigger zone (nausea/vomiting)
  • Pupillary constriction
  • GI effects
551
Q

How do opioids have analgesic action?

A
  • Have a profound effect within the dorsal horn
  • Suppress the relay of information from the periphery to the brain
  • There is a huge concentration of opioid receptors within the spinal cord
552
Q

How do opioids act as depressants?

A

Decrease the ability of information to be passed from sensory afferents to spinothalamic neurons which leads to decreased pain perception

553
Q

How do opioids increase pain tolerance?

A

They activate the PAG and by activating the NRPG.

This increases activation of the descending inhibitory pathway

554
Q

How do opioids produce euphoria?

A
  • Act on Mu receptors on the mesolimbic dopamine neurons arising in the ventral tegmental area and terminal in the nucleus accumbens
  • The dopamine released in the nucleus accumbens causes euphoria
  • GABA normally supresses this effect
  • Opiates suppress GABA by binding to μ receptors on the cell body
555
Q

How do opioids act as anti-tussive agents?

A
  • Acetylcholine and neurokinins are important in mediating the cough
  • Codeine inhibits the receptor activation within and cough centre and suppresses the release of ACh and NK within the upper airways
556
Q

How do opioids cause respiratory depression?

A
  • Act on central chemoreceptors which signal to the medulla to increase/decrease respiration which normally respond to arterial C02 pressure
  • Opioids desensitise the chemoreceptors which leads to loss of sensitivity to C02 and thus the ability of the medulla to control respiration
  • Main cause of death in overdose
557
Q

How do opioids cause nausea/vomiting?

A
  • Trigger zone is naturally oppressed but may be activating by signals from the stomach and intestines
  • Opioids cause you to lose this inhibition.
    Activate the trigger zone, relaying information to the medullary vomiting centre which results in the vomiting reflex
558
Q

How do opioids result in miosis (‘pin prick pupils)

A

Opioids cause stimulation of the occulomotor nerve, which signals via the ciliary ganglion resulting in pupillary constriction
- This is a diagnostic feature of heroin overdose

559
Q

What is the effect of opioids on the GI tract?

A
  • They are depressant drugs
  • Decrease gastric emptying
  • Decrease GI motility
  • Increase water absorption
  • All this results in constipation
560
Q

What do patients who experience an allergic response to opioids present with?

A

Pruritis (itching)
Urticaria (hives)
Hypotension (due to vasodilation)
- Due to G-protein receptor mediated activation of mast cells and release of histamine

561
Q

How may patients grow tolerant of opioids?

A
  • Taking opioids for a long time cause the tissues to response via an increased number of arrestins
  • These molecules cause receptor interalisation. Leads to less receptors and opioids will have less of a response and require a higher dose for the same effect
562
Q

What are the problems with prolonged treatment of opioids?

A

Tolerance

Dependence

563
Q

What may withdrawal from opioids in a patient who is dependent be associated with?

A
  • Psychological craving
  • Physical withdrawal
  • Resembles flu
564
Q

What will a patient suffering from an opiate overdose present with?

A
  • Coma
  • Respiratory depression
  • Pin point pupils
  • Hypotension
565
Q

What is the treatment for opioid overdose?

A

Naloxene

  • Opioid antagonist
  • IV
566
Q

What is an adverse drug event?

A

A preventable or unpredicted medication event, with harm to the patient

567
Q

How are adverse drug reaction described?

A

By:

  • Onset
  • Severity
  • Type
568
Q

How are acute, sub-acute and latent adverse drug reactions differentiated between?

A

Acute: Within 1 hour
Sub-acute: 1-24 hours
Latent: >2 days

569
Q

How is the severity of an adverse drug reaction distinguished?

A

Mild: requires no change in therapy
Moderate: requires change in therapy, additional treatment, hospitalisation
Severe: disabling or life- threatening

570
Q

What are the consequences of a severe adverse drug reaction?

A
  • Death
  • Life-threatening
  • Requires or prolongs hospitalisation
  • Causes disability
  • Causes congenital anomalies
  • Requires intervention to prevent permanent injury
571
Q

What is the pneumonic to remember classification of adverse drug reactions?

A
A= Augmented pharmacological effect 
B= bizarre 
C= Chronic 
D= Delayed 
E= End of treatment
572
Q

What is a Type A adverse drug reaction?

A
  • Extension of pharmacological effect
  • Usually predictable and dose dependent
  • Responsible for at least two-thirds of ADRs
573
Q

Give examples of Type A ADRs

A
  • Atenolol and heart block
  • Anticholinergics and dry mouth
  • NSAIDs and peptic ulcer
574
Q

What is a Type B ADR?

A
  • Idiosyncratic or immunological reaction
  • Includes allergy and ‘pseudoallergy’
  • Rare and unpredictable
575
Q

Give examples of Type B ADRs

A
  • Chloramphenicol and aplastic anaemia

- ACE inhibitors and angioedema

576
Q

What is a Type C ADR?

A
  • Associated with long-term use

- Involves dose accumulation

577
Q

Give examples of Type C ADRs

A
  • Methotrexate and liver fibrosis

- Antimalarials and ocular toxicity

578
Q

What is a Type D ADR?

A
  • Delayed effects (sometimes dose independent)
  • Carcinogenicity (e.g. immunosuppressants)
  • Teratogenicity (e.g. Thalidomide)
579
Q

What do Type E ADRs include?

A
  • Withdrawal reactions (opiates, benzodiazepines, corticosteroids)
  • Rebound reactions (clonidine, beta-blcokers, corticosteroids)
  • Adaptive reactions (Neuroleptics (major tranquilisers)
580
Q

What is a Type I allergic reaction?

A

Immedate, Anaphylactic

  • IgE mediated
  • E.g. anaphylaxis with penicillins
581
Q

What is a Type II allergic reaction?

A

Cytotoxic antibody

  • IgG, IgM mediated
  • E.g. methyldopa and haemolytic anaemia
582
Q

What is a Type III allergic reaction?

A

Serum sickness

  • IgG, IgM mediated
  • Forms antigen-antibody complexes
  • E.g. procainamide-induced lupus
583
Q

What is a Type IV allergic reaction?

A
Delayed hypersensitivity (T cell) 
e.g. contact dermatitis
584
Q

What are pseudoallergies?

A

Not immunologically determined, but pharmacologically determined ‘allergic’ responses

  • Aspirin/NSAIDs: bronchospasm
  • ACE inhibitors: cough/angioedema
585
Q

What are common causes of ADRs

A
  • Antibiotics
  • Antineoplastics
  • Anticoagulants
  • Cardiovascular drugs
  • Hypoglycemics
  • Antihypertensives
  • NSAID/Analgesics
  • CNS drugs
586
Q

How are ADRs detected?

A

1) Subjective report: patient complaint
2) Objective report
- direct observation of event
- Abnormal findings in physical examination, laboratory test and diagnostic procedure

587
Q

What is the process of reporting adverse drug reactions?

A

ADR suspecting
ADR confirmed
Frequency estimated
Prescribers informed

588
Q

Why is the incidence of drug-drug interactions difficult to determine?

A
  • Data for drug-related hospital admissions do not separate out drug interactions, focus of ADRs
  • Lack of availability of comprehensive databases
  • Difficulty in assessing OTC and herbal drug therapy use
  • Difficulty in determining contribution of drug interaction in complicated patients
589
Q

What are the three types of drug interactions?

A

1) Pharmacodynamic - related to the drug’s effects in the body
2) Pharmacokinetic- related to the bod’s effects on the drug
3) Pharmaceutical- drugs interacting outside the body

590
Q

What are pharmacodynamic drug interactions?

A

Additive, synergistic or antagonistic effects on the body which results from co-administration of two or more drugs

591
Q

Give examples of pharmacodynamic drug interactions

A
  • Synergistic actions of antibiotics
  • Overlapping toxicities- ethanol and benodiazepines
  • Antagonistic effect- anticholinergic mediations
592
Q

How can pharmacokinetic drug interactionss result?

A
  • Alteration in absorption
  • Protein binding effects
  • Changes in drug metabolism
  • Alteration in elimination
593
Q

What do alterations in absorption with regards to pharmacokinetic drug interactions include?

A

Chelation

  • Irreversible binding of drugs in the GI tract
  • Tetracyclines, quinolone antibiotics, ferrous sulfate, antacids, dairy products
594
Q

What do protein binding interactions with regards to pharmacokinetics drug interactions involve?

A
  • Competition between drugs for protein or tissue binding sites (increase in free (unbound) concentration may lead to enhanced pharmacological effect)
  • Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions
  • PB interactions are not usually clinically significant. Some are- warfarin
595
Q

What are the possible routes of drug metabolism and elimination?

A
  • Excretion unchanged by kidney
  • 1st phase metabolised by liver and excreted
  • 1st phase and 2nd phase metabolism with excretion by kidney
596
Q

What does phase I metabolism involve?

A

Oxidation
Reduction
Hydrolysis

597
Q

What does phase II metabolism involve?

A

Conjugation

  • Glucuronidation
  • Sulfation
  • Acetylation
598
Q

Why would drug metabolism continue if a drug is co-administered with a CYP450 inhibitor?

A
  • Few clinically used drugs are metabolised by a single predominant isozyme of P450, drugs are metabolised by more than one isozyme
  • Not all isozymes will be inhibited. Other isozymes can ‘pick up the slack’
599
Q

What are the most common isozymes of P450 involved in drug metabolism?

A

CYP3A4

CYP2D6

600
Q

Give examples of CYP450 inhibitors

A
  • Climetidine
  • Erythromycin and related antibiotics
  • Ketoconazole etc
  • Ciproflocaxin and related antibiotics
  • Ritonavir and other drugs
  • Fluoxetine and other SSRIs
  • Grapefruit juice
601
Q

Give examples of CYP450 inducers?

A
  • Rifampicin
  • Carbamazepine
  • St John’s wort
602
Q

Give an example of a good drug elimination interaction

A

Probenecid and penicillin

603
Q

Give an example of a bad drug elimination reaction

A

Lithium and thiazides

604
Q

Where to drug elimination interactions almost always take place?

A

Renal tubule

605
Q

What drug interactions are deliberate to produce a therapeutic benefit?

A
  • Levodopa & Carbidopa
  • ACE inhibitors & thiazides
  • Penicillins & Gentamicin
  • Salbutamol & Ipratropium
606
Q

What is nausea?

A

Subjective unpleasant sensation in throat and stomach, often precedes vomiting

607
Q

What is vomiting?

A

Forceful propulsion of stomach contents out of the mouth

608
Q

What are vomiting and nausea preceded by?

A
  • Salivation
  • Sweating
  • Increased heart rate
609
Q

What pathways are involved in vomiting?

A
  • Stomach, oesophagus and associated sphincters are relaxed; tension in gastric and oesophageal muscles trigger afferent nerve impulse
  • Contraction of upper small intestine, pyloric sphincter and pyloric region of stomach
  • Contents of upper jejunum, duodenum and pyloric region of stomach move into the body and fundus of stomach
  • Lower and upper oesophageal sphincters and oesophagus relax
  • Retching/vomiting may or may not occur
610
Q

How do acute, chronic and severe vomiting differ?

A

Acute: interferes with mental and physical activity
Chronic: very debilitating
Severe:
- Dehydration
- Loss of gastric hydrogen and chloride ions may lead to hypochloraemic metabolic alkalosis (raised blood pH)
- Contributes to reduction in renal bicarbonate excretion and an increase in bicarbonate reabsorption: accompanies by increased sodium reabsorption in exchange for potassium which leads to hypokalaemia

611
Q

What is promethazine?

A

A phenothiazine derivative

612
Q

What is the mode of action of promethazine?

A
  • Competitive antagonist at histaminergic (H1), cholinergic (muscarinic) and dopaminergic (D2) receptors
  • Order of potency of antagonistic activity H1>M>D2 receptors
  • Acts centrally (vestibular nucleus, CTZ, vomiting centre) to block activation of vomiting centre
613
Q

How is promethazine used as an anti-emetic?

A
  • Motion sickness: normally used prophylactically but some benefit may be gained when taken after onset of nausea and vomiting
  • Disorders of the labyrinth e.g. Meniere’s disease
  • Hyperemesis gravidarium
  • Pre- and post operatively
614
Q

What are the uses of promethazine other than as an anti-emetic?

A
  • Relief of allergic symptoms
  • Anaphylactic emergency
  • Night sedation; insomnia
615
Q

What are the unwanted effects of promethazine?

A
  • Dizziness
  • Tinnitus
  • Fatigue
  • Sedation
  • Excitation in excess
  • Convulsions
  • Antimuscarinic side-effects
616
Q

What dopamine receptor antagonists are used as anti-emetics?

A

Metoclopramide

Domperidone

617
Q

What is the mode of action of Metoclopramide?

A
  • Acts centrally, especially at CTZ
  • Prokinetic effects in the gastrointestinal tract:
  • Increases smooth muscle motility
  • Accelerated gastric emptying
  • Accelerates transit of intestinal contests
618
Q

What suppresses intestinal motility?

A

Enteric DA neurons which act on D2 receptors
- Antagonising the inhibitory effect of dopamine on myenteric motor neurons, dopamine receptor antagonists are effective as prokinetic agents

619
Q

What are the uses of metoclopramide/domperidone?

A

Treat nausea and vomiting associated with:

  • Uraemia (severe renal failrure)
  • Radiation sickness
  • Gastrointestinal disorders
  • Cancer chemotherapy (high doses) e.g. cisplatin
  • Parkinson’s disease treatments which stimulate dopaminergic transmission
  • Not effective against motion sickness
620
Q

What are the pharmacokinetic considerations of metoclopramide?

A
  • Administered orally, rapidly absorbed, extensive first pass metabolism. May be given IV
  • Crosses blood brain barrier
  • Crosses placenta
621
Q

Why should care be taken when metoclopramide is taken with digoxin?

A

Absorption and therefore effectiveness of digoxin may be reduced

622
Q

What are the unwanted effects of Metoclopramide in the CNS?

A
  • Drowsiness
  • Dizziness
  • Anxiety
  • Extrapyramidal reactions; children more susceptible than adults (Parkinsonian-like syndrome)
623
Q

What are the unwanted effects of Metoclopramide/Domperidone in the endocrine system?

A
  • Hyperprolactinaemia
  • Galactorrhoea
  • Disorders of menstruation
624
Q

What muscarinic receptor antagonist is used as an anti-emetic?

A

Hyoscine

625
Q

What is the mode of action of Hyoscine?

A

Order of antagonistic potency: Muscarinic>D2=H1 receptors

- Acts centrally, especially in vestibular nuclei, CTZ, vomiting centre to block the activation of the vomiting centre

626
Q

How is Hyoscine used as an anti-emetic?

A
  • Prevention of motion sickness
  • Has little effects one nausea/emesis is established
  • In operative pre-medication
627
Q

What are the unwanted effects of Hyoscine?

A

Typical anti-muscarinic side effects

  • Drowsiness
  • Dry mouth
  • Cycloplegia
  • Mydriasis
  • Constipation
628
Q

What is Ondansetron?

A

Serotonin receptor antagonist (5-HT3)

- used as an anti-emetic

629
Q

What is the mode of action of Ondanstron?

A

Acts to block transmission in visceral afferents and CTZ

630
Q

How is Ondansetron used as an anti-emetic?

A
  • Main use in preventing anticancer drug-induced vomiting especially cisplatin
  • Radiotherapy induced sickness
  • Post-operative nausea and vomiting
631
Q

What are the unwanted effects of ondansetron?

A
  • Headache
  • Sensation of flushing and warmth
  • Increased large bowel transit time (constipation)
632
Q

Wh is ondansetron used in combination with corticosteroids?

A
  • 5-HT2 receptor antagonists may be used for low emetogenic chemotherapy
  • Corticosteroids, such as dexamethasone may be used in combination with 5-HT3 receptor antagonists for high or moderately high emetogenic chemotherapy
  • Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids
633
Q

What types of drugs are used in the treatment of gastric and duodenal ulcers?

A

1) Antibitotics
2) Inhibitors of gastric acid secretion
3) Cytoprotective drugs
^ used in triple therapy
4) Antacids

634
Q

Where is the areas of damage in peptic ulcer disease?

A

Inner lining of the stomach (gastric ulcer) or upper part of the duodenum (duodenal ulcer)

635
Q

When is pain felt in a gastric ulcer?

A

At mealtimes, when gastric acid is secreted

636
Q

What are protective factors?

A

They lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes

1) Mucous from gastric mucosa creates gastrointestinal mucosal barrier
2) HCO3- ions trapped in mucous generate a pH of 6/7 at mucousal surface
3) Locally produced prostaglandins stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion

637
Q

What factors needed to convert food into chyme have the potential to damage the mucosal barrier?

A

1) Acid secretion from parietal cells of the oxyntic glands in the gastric mucosa
2) Pepsinogens from the chief cells which can erode the mucous layer

638
Q

What factors may cause damage to the mucosal gastrointestinal barrier

A
  • Increased acid and/or decreased bicarbonate production
  • Decreased thickness of mucosal layer
  • Increase in pepsin type I
    Decreased mucosal blood flow
  • Infections with Helicobacter pylori may play a role in pathogenesis of gastric cancer
639
Q

What are the risk factors for peptic ulcer?

A
  • Genetic predisposition
  • Stres
  • Diet, alcohol, smoking
640
Q

What are the aims of treatment for peptic ulcers?

A
  • Eliminate cause of mucosal damage

- Promote ulcer healing

641
Q

What is the purpose of antibiotics in treating peptic ulcers?

A

Eradicate H. pylori

642
Q

What is the purpose of inhibitors of gastric acid secretion in treating peptic ulcer?

A

Prevent gastric acid production

643
Q

What is the purpose of cytoprotective drugs in treating peptic ulcer?

A

Neutralise gastric acid

644
Q

What is the best practice in treating peptic ulcer disease?

A

Triple therapy

1) Antibiotics: a single antibiotic is not sufficiently effective due to development o resistance
2) Drugs which reduce gastric acid secretion
3) Drugs which promote healing

645
Q

What drugs inhibit gastric acid secretion?

A
  • Proton pump inhibitors
  • Histamine type 2 (H2) receptor antagonists
  • Anti-muscarinics
646
Q

What is omeprazole?

A

Proton pump inhibitor

647
Q

What is the mode of action of omeprazole?

A

Inhibits the basal and stimulated gastric acid secretion from the parietal by >90%

  • Irreversible inhibitors of the H+/K+ ATPase
  • It is inactive at neutral pH.
  • Is a weak base so it accumulates in the cannaculi of parietal cells. This concentrates its action there and prolongs its duration of action (2-3 days) and minimised its effect on ion pumps elsewhere in the body
648
Q

What are the uses of proton pump inhibitors?

A
  • Peptic ulcers which are resistant to H2 antagonists
  • Component of triple therapy
  • Gastrooesophageal reflux disease, oesophagitis
  • Prophylaxis of peptic ulcers in the intensive care setting, and among high risk patients prescribed aspirin, NSAIDs, antiplatelets and anticoagulants
649
Q

What are the unwanted effects of proton pump inhibitors?

A
Rare due to short term use 
Long term use associated with:
Enteric infections (Clostridium difficile) 
Community acquired pneumonia 
Hip fracture
650
Q

What are climetidine and ranitidine?

A

Histamine type 2 (H2) receptor antagonists

651
Q

What is the mode of action of H2 receptor antagonists?

A

Inhibits gastric acid secretion from the parietal by approx 60% and are less effective at healing ulcers than PPIs
- Competitive antagonism of H2 histamine receptors

652
Q

What are the unwanted effects of H2 receptor antagonists?

A

Rare - dizziness, headache
There are fewer side effects with Ranitine
- Relapses are likely after withdrawal of treatment

653
Q

What are cyto-protective drugs?

A

They enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer

654
Q

Give examples of cyto-protective drugs

A
  • Sucralfate
  • Bismuth chelate
  • Misoprostol
655
Q

What is Sucralfate?

A

A polymer containing aluminium hydroxide and sucrose octa-sulfate

656
Q

How does sucralfate act?

A
  • Acquires a strong negative charge in an acid environment
  • Binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like complexes, these coat and protect the ulcer, limit H+ diffusion and pepsin degradation of mucus
  • Increases PG, mucous and HCO3- and reduced the number of H.pylori
657
Q

What are the unwanted effects of sucralfate?

A

Most of the orally administered Sucralfate remains in the GIT which may cause constipation or reduced absorption of some other drugs (e.g. antibiotics and digoxin)

658
Q

When is bismuth chelate used?

A

Triple therapy

- Acts like sucalfate

659
Q

What is misoprostol?

A

A stable prostaglandin analogue

660
Q

How does misoprostol act?

A

Mimics the action of locally produced PG to maintain the gastroduodenal mucosal barrier

661
Q

What is the use of misoprostol?

A

May be co-prescribed with oral NSAIDs when used chronically

  • NSAIDs block the COX enzyme required for PG synthesis from arachidonic acid
  • Therefore there is a reduction in the natural factors that inhibit gastric acid secretion and stimulate mucoud and HCO3- production
662
Q

What are the unwanted effects of misoprostol?

A

Diarrhoea
Abdominal cramps
Uterine contractions

663
Q

What are antacids?

A

Mainly salts of Na+, Al3+ and Mg++

  • Sodium bicarbonate has rapid effects
  • Aluminium hydroxide and magnesium trisilicate have slower actions
664
Q

What is the mode of action of antacids?

A
  • Neutralise acid, raises gastric pH, reduces pepsin activity
  • May be effective in reducing duodenal ulcer recurrence rates
665
Q

What are antacids primarily used for?

A

Non-ulcer dyspepsia (OTC)

666
Q

What are the problems with triple therapy?

A
  • Compliance
  • Resistance to antibiotics (may be superseded by vaccination)
  • Adverse response to alcohol
667
Q

What is gastroesophageal reflux disease?

A

Stomach and duodenal contents reflux into the oesophagus
Occasional and uncomplicated GERD:
- Heart burn
- May treat by self medication with antacids and H2 antagonists
Chronically:
May progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma

668
Q

How is GERD treated?

A

PPIs (drug of choice)
H2 antagonists (less effective)
- Combine with drugs that increase gastric motility and emptying of the stomach e.g. Dopamine D2 receptor antagonist