Pharmacology & Therapeutics 2

Question 1

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

Answer 1

G-protein coupled to IP3 and DAG second messengers

Question 2

What second messengers are M2 and M4 receptors coupled to?

Answer 2

G-protein coupled to cAMP second messengers

Question 3

What type of ion channel are nicotinic receptors?

Answer 3

Lingand-gated

Question 4

How many sub units do nicotinic receptors have?

Answer 4

5

α, β, γ, δ, ε

Question 5

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

Answer 5

The subunit combination

Question 6

What are the muscarinic effect on the eye?

Answer 6

• 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)

Question 7

What leads to glaucoma?

Answer 7

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

Question 8

How is glaucoma treated?

Answer 8

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.

Question 9

What are the muscaranic effects on the heart?

Answer 9

• 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

Question 10

What are the muscarinic effects on the vasculature?

Answer 10

• 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

Question 11

What are the overall muscarinic effects on the cardiovascular system?

Answer 11

• 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

Question 12

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

Answer 12

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

Question 13

What are the muscarinic effects on the exocrine glands?

Answer 13

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

Question 14

What are the two classes of cholinomimetic drug?

Answer 14

Directly acting

Indirectly acting

Question 15

Why is acetylcholine of no therapeutic use?

Answer 15

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

Question 16

What type of directly acting cholinomimetic drug is aceytlcholine?

Answer 16

Choline ester

Question 17

What are the different directly acting cholinomimetic drugs?

Answer 17

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

Question 18

What type of activity does nicotine stimulate?

Answer 18

Sympathetic and parasympathetic activity.

It stimulates all autonomic ganglia

Question 19

What type of cholinomimetic drug is pilocarpine?

Answer 19

• Alkaloid

- Non-selective muscarinic agonist with good lipid solubility

Question 20

What is the half life of pilocarpine?

Answer 20

3-4 hours

Question 21

What is pilocarpine used as treatment for?

Answer 21

Glaucoma?

Question 22

What are the side effects of pilocarpine?

Answer 22

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

Question 23

What type of cholinomimetic drug is bethanechol?

Answer 23

Choline ester

Question 24

What makes bethanechol less resistant to degradation that acetylcholine?

Answer 24

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

Question 25

What is the half life of bethanechol?

Answer 25

3-4 hours

Question 26

What is the use of bethanechol?

Answer 26

• Assist bladder emptying

- Enhance gastric motility

Question 27

What are the side effects of bethanechol?

Answer 27

• Sweating
• Impaired vision
• Nausea
• Bradycardia
• Hypotension
• Respiratory difficulty

Question 28

What are the actions of indirectly acting cholinomimetic drugs?

Answer 28

• 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

Question 29

Give examples of reversibly anticholinesterases

Answer 29

• Physostigmine
• Neostigmine
• Donepezil (‘aricept’)

Question 30

Give examples of irreversible anticholesterases

Answer 30

• Exothiopate
• Dyflos
• Sarin

Question 31

What does cholinesterase metabolise acetylcholine to?

Answer 31

Choline and acetate

Question 32

What are the effects of anticholinesterases?

Answer 32

• 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.

Question 33

What are the two types of cholinesterases?

Answer 33

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

Question 34

Where are acetylcholinesterases found?

Answer 34

All cholinergic synapses (peripheral and central)

Question 35

How fast is the action of acetylcholinesterases?

Answer 35

Very rapid

Hydrolysis occurs at over 10,000 reactions per second

Question 36

Where is butryrylcholinesterase found?

Answer 36

In plasma and most tissues but NOT cholinergic synapses

Question 37

Describe the specificity of butyrylcholinesterase

Answer 37

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

Question 38

What is the principle reason for low plasma acetylcholine?

Answer 38

The action of butyrylcholinesterase

Question 39

How do reversible anticholinesterase drugs work?

Answer 39

• 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

Question 40

Where does physostigmine primarily act?

Answer 40

Postganglionic parasympathetic synapse

Question 41

What is the half life of physostigmine?

Answer 41

30 mins

Question 42

What is physostigmine used for?

Answer 42

• Treatment of glaucoma aiding intraocular fluid drainage

- Treats atropine poisoning, particularly in children

Question 43

How do irreversible anticholinesterase drugs work?

Answer 43

• 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)

Question 44

Which irreversible anticholinesterase drug is in clinical use?

Answer 44

Ecothiopate

- others commonly used as insecticides and nerve gas

Question 45

What does ecothiopate inhibit?

Answer 45

Potent inhibitor of acetylcholinesterase

Question 46

What is ecothiopate used in the treatment of?

Answer 46

Glaucoma

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

Question 47

What are the systemic side effects of ecothipate?

Answer 47

• Sweating
• Blurred vision
• GI pain
• Bradycardia
• Hypotension
• Respiratory difficulty

Question 48

What type of anticholinesterases can cross the blood brain barrier?

Answer 48

Non-polar

Question 49

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

Answer 49

Low doses: Excitation with the possibility of convulsions

High doses: Unconsciousness, respiratory depression, death

Question 50

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

Answer 50

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

Question 51

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

Answer 51

Severe toxicity

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

Question 52

What is used to treat organophosphate poisoning?

Answer 52

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

Question 53

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

Answer 53

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

Question 54

What are the two groups of cholinoreceptors?

Answer 54

Nicotinic

Muscarinic

Question 55

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

Answer 55

Nicotinic receptors are present at all autonomic ganglia

Question 56

Give examples of nicotinic receptor antagonists

Answer 56

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

Question 57

What are clinically useful nicotinic receptor antagonists called?

Answer 57

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

Question 58

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

Answer 58

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

Question 59

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

Answer 59

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

Question 60

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

Answer 60

Normal dose: little effect

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

Question 61

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

Answer 61

Normal dose: Sedation, amnesia

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

Question 62

How is the muscarinic receptor antagonist tropicamide use clinically?

Answer 62

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

Question 63

Why are muscarinic receptor antagonists good for anaesthetic premedication?

Answer 63

• 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.

Question 64

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

Answer 64

• 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

Question 65

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

Answer 65

• 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.

Question 66

Which muscarinic receptor antagonist is used in treating asthma and COPD

Answer 66

Ipratropium Bromide

- Removes the effect of bronchoconstriction

Question 67

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

Answer 67

• 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.

Question 68

What are the unwanted side effects of muscarinic receptor antagonists/

Answer 68

• 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)

Question 69

How is poisoining from muscarinic receptor antagonists treated?

Answer 69

• 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

Question 70

What is the mechanism of Botulinum Toxin?

Answer 70

• 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.

Question 71

What is the clinical use of Botulinum Toxin?

Answer 71

Botox

Question 72

What types of adrenoreceptors does adrenaline show more selectivity for?

Answer 72

b1 = b2 > a1 = a2

Question 73

What types of adrenoreceptors does noradrenaline show more selectivity for?

Answer 73

a1 = a2 > b1 = b2

Question 74

Give examples of directly acting SNS agonists

Answer 74

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

Question 75

What are the uses of adrenaline?

Answer 75

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)

Question 76

What are the unwanted actions of adrenaline?

Answer 76

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

Question 77

Which adrenoreceptors is phenylephrine more selective for?

Answer 77

Selective for a1 receptors

a1»a2»>b1/b2

Question 78

What is phenylephrine resistant to?

Answer 78

Resistant to COMT but not MAO

Question 79

What is phenylephrine chemically related to?

Answer 79

Adrenaline

Question 80

What are the clinical uses of phenylephrine?

Answer 80

• Vasoconstriction
• Mydriatic
• Nasal decongestant

Question 81

Where does phenylephrine have unwanted actions?

Answer 81

Cardiovascular system

Question 82

Which adrenoreceptors is clonidine selective for?

Answer 82

a2 receptors

a2»a1»>b1/2

Question 83

What are the clinical uses of clonidine?

Answer 83

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

Question 84

What adrenoreceptors is isoprenaline selective for?

Answer 84

B1 and B2 receptors

ß1=ß2»»α1/2

Question 85

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

Answer 85

Isoprenaline is less susceptibile to uptake 1 and MAO breakdown

Question 86

What is the plasma half life of isoprenaline?

Answer 86

2 hours

Question 87

What are the clinical uses of isoprenaline?

Answer 87

• Cardiogenic shock
• Acute heart failure
• Myocardial infarction

Question 88

Why must isoprenaline be used with caution?

Answer 88

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

Question 89

What adrenoreceptors are Dobutamine selective for?

Answer 89

Beta-1 receptors

β1»β2»>α1/2

Question 90

What are the clinical uses of dobutamine?

Answer 90

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

Question 91

What is the plasma half life of dobutamine?

Answer 91

2 minutes

It is rapidly metabolised by COMT

Question 92

What adrenoreceptor is salbutomol selective for?

Answer 92

Beta-2 receptors

b2»b1»>a1/2

Question 93

What is salbutamol (ventolin)?

Answer 93

A synthetic catecholamine derivative with relative resistance to MAO and COMT

Question 94

What are the clinical uses of salbutamol?

Answer 94

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

Question 95

What are the side effects of salbutamol?

Answer 95

Reflex tachycardia
Tremor
Blood sugar dysregulation

Question 96

Give examples of indirectly acting SNS agonists

Answer 96

• Cocaine (uptake 1 inhibitor)

- Tyramine

Question 97

What are the actions of cocaine on the CNS?

Answer 97

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

Question 98

What are the actions of cocaine on the CVS?

Answer 98

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

Question 99

What is the clinical use of cocaine?

Answer 99

• 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

Question 100

What is tyramine?

Answer 100

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

Question 101

How does tyramine operate?

Answer 101

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

Question 102

Why does tyramine cause problems when MOAs are inhibited?

Answer 102

Ingestion of foods may cause a hypertensive crisis

‘cheese reaction’

Question 103

What are the types of adrenoreceptors?

Answer 103

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

Question 104

What are the different types of adrenoreceptor antagonists?

Answer 104

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

Question 105

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

Answer 105

• Hypertension
• Cardiac arrhythmias
• Angina
• Glaucoma

Question 106

What is hypertension defined as?

Answer 106

Sustained diastolic arterial pressure greater than 90 mmH

Question 107

What are the main elements that contribute to hypertension?

Answer 107

• Blood volume
• Cardiac output
• Peripheral vascular tone

Question 108

What are the tissue targets for antihypertensives?

Answer 108

• 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

Question 109

How can B-blockers be classified?

Answer 109

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

Question 110

How do B-adrenoceptor antagonists work?

Answer 110

Competitive antagonism of b1 adrenoreceptors

Question 111

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

Answer 111

• 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.

Question 112

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

Answer 112

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.

Question 113

What are the unwanted effects of B-adrenoceptor antagonists?

Answer 113

• 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

Question 114

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

Answer 114

• 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.

Question 115

What type of Beta-blocker in propranolol?

Answer 115

B1+B2- non-selective

Question 116

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

Answer 116

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

Question 117

Why does propranolol produce all the typical adverse effects?

Answer 117

It is non-selective

Question 118

How is the selectivity of atenolol described?

Answer 118

It is a B1 selective drug

Cardioselective

Question 119

What are the effects of atenolol?

Answer 119

• 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

Question 120

What type of adrenoceptor antagonist is labetalol?

Answer 120

Dual acting B1 and A1 antagonist.

Has a ratio of B1 to A1 of 4:1

Question 121

What are the effects of labetalol?

Answer 121

• 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

Question 122

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

Answer 122

• 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

Question 123

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

Answer 123

Postural hypotension induced reflex tachycardia.

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

Question 124

What type of antagonist is phentolamine?

Answer 124

Non-selective alpha-antagonist

Question 125

What are the effects of phentolamine?

Answer 125

• 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

Question 126

What type of antagonist is prazosin?

Answer 126

Alpha -1 antagonist

Question 127

What are the effects of prazosin?

Answer 127

• 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

Question 128

What is methyldopa and what is it used for?

Answer 128

Is a false transmitter

Used as an antihypertensive agent

Question 129

How does methyldopa work?

Answer 129

• Taken up by noradrenergic neurons

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

Question 130

Why does methyldopa accumulate in larger quantities than noradrenaline?

Answer 130

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

Question 131

What is the mechanism of action of methyldopa?

Answer 131

• 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

Question 132

What are the benefits of methyldopa?

Answer 132

• 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

Question 133

What are the adverse effects of methyldopa?

Answer 133

• Dry mouth
• Sedation
• Orthostatic hypotension
• Male sexual dysfunction

Question 134

What is the main cause of arrhythmias?

Answer 134

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

Question 135

Which B-antagonist acts as a antiarrhythmics?

Answer 135

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

Question 136

What is angina?

Answer 136

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

Question 137

Where is pain distributed in angina?

Answer 137

Chest, arm, neck

Question 138

What is stable angina?

Answer 138

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

Question 139

What is unstable angina?

Answer 139

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

Question 140

What is variable angina?

Answer 140

Occurs at rest, caused by coronary artery spasm.

It is associated with atheromatous disease.

Question 141

What is used to treat angina?

Answer 141

B-adrenoceptor antagonists in order to reduce myocardial oxygen

Question 142

How do B-adrenoceptor antagonists treat angina?

Answer 142

• 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

Question 143

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

Answer 143

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

Question 144

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

Answer 144

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

Question 145

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

Answer 145

• 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

Question 146

What is the production of aqueous humour indirectly related to?

Answer 146

Blood pressure and blood flow in the ciliary body

Question 147

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

Answer 147

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

Question 148

What selective beta antagonists are used to treat glaucoma?

Answer 148

B1 antagonist betaxolol hydrochloride

Question 149

What are some other uses of Beta-antagonists?

Answer 149

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

Question 150

What is a neuromuscular junction?

Answer 150

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

Question 151

Which neurotransmitter is involved in neurotransmission at the neuromuscular junction?

Answer 151

Acetylcholine

Question 152

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

Answer 152

• 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

Question 153

What drugs affect CNS processes of the musculoskeletal system?

Answer 153

Spasmolytics

eg. Diazepam and Baclofen

Question 154

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

Answer 154

Local anaestetics

Question 155

What drugs affects acetylcholine release?

Answer 155

Ca++ entry blockers

Question 156

What drug affects choline reuptake?

Answer 156

Hemicholinium

Question 157

What drugs affect propagation of action potentials along muscle fibres?

Answer 157

Spasmolytics

eg. Dantrolene

Question 158

What are neuromuscular blocking drugs?

Answer 158

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

Question 159

What are the types of neuromuscular blocking drugs?

Answer 159

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

Question 160

What are the affects of neuromuscular blocking drugs?

Answer 160

• Do NOT affect consciousness or pain sensation

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

Question 161

What is the mode of action of Tubocarine?

Answer 161

• 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

Question 162

What are the pharmacokinetics of tubocarine?

Answer 162

• 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.

Question 163

What are the effects of tubocarine?

Answer 163

• 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

Question 164

What are the clinical uses of tubocarine?

Answer 164

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

Question 165

How can the actions of tubocarine be reversed?

Answer 165

Anticholinesterases such as Neostigmine, co-administered with Atropine

Question 166

What are the unwanted effects of tubocarine?

Answer 166

• 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

Question 167

What is Atracarium?

Answer 167

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

Question 168

What is suxamethonium (succinulcholine)?

Answer 168

• 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

Question 169

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

Answer 169

• 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)

Question 170

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

Answer 170

• 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

Question 171

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

Answer 171

• Cardiac slowing
• Reduced automaticity
• Inhibition of AV conduction

Question 172

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

Answer 172

The balance between supply and demand for oxygen

Question 173

Give an example of an organic nitrate

Answer 173

Glyceryl trinitrate

Question 174

How do organic nitrates act?

Answer 174

• 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.

Question 175

Which potassium channel opener is used in angina?

Answer 175

Nicorandil

Question 176

How do potassium channel openers work in anginda?

Answer 176

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

- These agents cause venodilation and arterial dilation.

Question 177

What are the adverse effects of nitrates?

Answer 177

Hypotension

Headache

Question 178

What are the two classes of calcium antagonists?

Answer 178

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

Question 179

How do calcium antagonists act to reduce cardiac workload?

Answer 179

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

Question 180

Why does verapamil have negative chronotropic and ionotropic actions?

Answer 180

Reduce Ca++ entry into cardiac myocytes

Question 181

What are the side effects of verapamil?

Answer 181

Heart block
Heart failure
Constipation

Question 182

What are the side effects of calcium antagonists?

Answer 182

Flushing
Headaches
Hypotension
Ankle swelling

Question 183

What are the limitations of the Vaughan Williams classification?

Answer 183

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

Question 184

What are the determinants of myocardial oxygen supply?

Answer 184

Coronary blood flow

Arterial 02 content

Question 185

What are the determinants of myocardial oxygen demand?

Answer 185

Heart rate
Preload
Afterload
Contractility

Question 186

What decreases with vasodilation?

Answer 186

Afterload

Question 187

What decreases with venodilation?

Answer 187

Preload

Question 188

What is the Vaughan-Williams classification of arrhythmic drugs?

Answer 188

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

Question 189

Give examples of antidysrhythmic agents

Answer 189

Adenosine
Verapamil
Amiodarone
Digoxin and cardiac glycosides

Question 190

What is adenosine?

Answer 190

• 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)

Question 191

Why is adenosine safer than verapamil?

Answer 191

Its actions are short lived- 20 to 30 seconds

Question 192

What are the uses of verapamil?

Answer 192

• 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

Question 193

What is the mechanism of action for verapamil?

Answer 193

Depresses automaticity of SA node and subsequent AV node conduction

Question 194

What are the uses of amiodarone?

Answer 194

• Superventricular and ventricular tachyarrhythmias- often due to reentry

Question 195

What is the mechanism of action for amiodarone?

Answer 195

• Complex action probably involving multiple ion channel block

Question 196

What are the adverse effects of amiodarone?

Answer 196

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

Question 197

How do digoxin and cardiac glycosides work?

Answer 197

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

Question 198

What are the cardiac effects of digoxin?

Answer 198

• 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

Question 199

What are the uses of digoxin and cardiac glycosides?

Answer 199

• 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.

Question 200

What are the adverse effects of digoxin and cardiac glycosides?

Answer 200

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

Question 201

What are cardiac ionotropes?

Answer 201

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)

Question 202

What is Dobutamine?

Answer 202

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

Question 203

How do inhibitors of phosphodiesterase have ionotropic effects?

Answer 203

Inhibit the breakdown of cyclic AMP in cardiac myocytes

Question 204

Give an example of an inhibitor of phosphodiesterase

Answer 204

Milrinone

Question 205

What are the uses of ACE inhibitors?

Answer 205

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

Question 206

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

Answer 206

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

Question 207

What mediates most of the affects of angiotensin II?

Answer 207

AT1 receptor

Question 208

What is spironolactone an antagonist of?

Answer 208

The mineralcorticoid- aldosterone

It inhibits the sodium retaining effects of aldosterone

Question 209

What is spironolactone useful for?

Answer 209

Heart failure

Resistant cases of hypertension

Question 210

What are the unwanted effects of spironolactone?

Answer 210

• Can cause hyperkalaemia due to its aldosterone antagonism

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

Question 211

Give an example of an ACE inhibitor

Answer 211

Enalapril

Question 212

What are the types of calcium channel blockers?

Answer 212

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

Question 213

What are the uses of beta-adrenoreceptor blockers?

Answer 213

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

Question 214

Why might beta blockers be an effective treatment for hypertension

Answer 214

• 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

Question 215

Why does Carvedilol have additional vasodilator properties to Atenolol?

Answer 215

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

Question 216

What is hydralazine?

Answer 216

A direct vasodilator that acts mainly on arteries and arterioles

Question 217

Under what circumstances would hydralazine cause a reflex tachycardia?

Answer 217

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

Question 218

How does doxazosin act as an arterial vasodilator?

Answer 218

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

Question 219

When is phenoxybenzamine used?

Answer 219

• It is an irreversible non-selective alpha antagonist

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

Question 220

Give examples of centrally acting antihypertensive agents

Answer 220

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

• These agents act by reducing sympathetic activity

Question 221

What is guanethidine?

Answer 221

Adrenergic neuron blocker

Question 222

What is trimethaphan?

Answer 222

Short acting ganglion blocker

- Is occasionally used in anaesthesia to lower blood pressure

Question 223

What is sumitriptan and what does it do?

Answer 223

Agonist at 5HT1D receptors.

Causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission

Question 224

What is sumitriptan used for?

Answer 224

Treats migraine attacks, contraindicated in patients with coronary disease

Question 225

What are the side effects of sumitriptan?

Answer 225

Dizziness
Drowsiness
Asthenia
Fatigue

Question 226

When can adrenaline be used?

Answer 226

Cardiac arrest

Anaphylactic shock

Question 227

How is blood pressure calculated?

Answer 227

cardiac output x total peripheral resistance

Question 228

How is hypertension defined?

Answer 228

Being consistently above 140/90 mmHg

Question 229

What is hypertension a major risk factor if?

Answer 229

Stroke
Myocardial infarction
Chronic kidney disease

Question 230

What is chronic heart failure?

Answer 230

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

Question 231

What do patients with chronic heart failure typically receive?

Answer 231

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

Question 232

What is a narcotic?

Answer 232

A drug that produces morphine like effects

Question 233

What causes the euphoric feeling obtained from drugs?

Answer 233

• 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?

Question 234

Where do the mesolimbic system and pathways originate?

Answer 234

Ventral tegmental area

Question 235

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

Answer 235

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

Question 236

How are drugs of abuse classified?

Answer 236

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)

Question 237

How many compound does herbal cannabis contain?

Answer 237

Over 400 compounds including over 60 cannabinoids

Question 238

What is the most potent psychoactive agent in cannabis?

Answer 238

9-tetrahydrocannabinol

Question 239

What are cannabinoids present in?

Answer 239

• 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

Question 240

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

Answer 240

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

Question 241

What is a major metabolite of cannabinoids?

Answer 241

11-hydroxy-THC

- is a postent cannabinoid itself

Question 242

Where are cannabinoids metabolised?

Answer 242

Liver

Question 243

Where are cannabinoids excreted?

Answer 243

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

Question 244

What are the neuronal cannabinoid receptors?

Answer 244

CB1

Present in hippocampus/cerebellum/cerebral cortex/basal ganglia

Question 245

What are the cannabinoid receptors in immune cells?

Answer 245

CB2

Question 246

What is the endogenous agonist of cannabinoids?

Answer 246

Anandamide- an arachidonic acid derivative

Question 247

What are the psychological effects of cannabinoids?

Answer 247

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

Question 248

How do cannabinoids affect cognition and psychomotor performance?

Answer 248

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

Question 249

What are the CVS effects of cannabinoids?

Answer 249

• 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

Question 250

What is the purpose of the anterior cingulate cortex?

Answer 250

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

Question 251

How does cannabis affect the anterior cingulate cortex?

Answer 251

Leads to hypo-activity

- This is associated with poor control

Question 252

How does cannabis affect food intake?

Answer 252

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

Question 253

What are the peripheral effects of cannabis?

Answer 253

• Immunosuppressant

- Tachycardia/vasodilation

Question 254

What is Dronabinol used for?

Answer 254

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

Question 255

Which drugs target the cannabinoid system?

Answer 255

• Dronabinol and Nabilone
• Savitex
• Rimonabant

Question 256

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

Answer 256

• 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.

Question 257

What are the different forms cocaine is available in?

Answer 257

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)

Question 258

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

Answer 258

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

Question 259

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

Answer 259

• Smoking

- Cocaine HCl being injected IV

Question 260

How is cocaine metabolised?

Answer 260

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

Question 261

What is the half life of cocaine?

Answer 261

90 minutes

Question 262

What effects does cocaine have on the reward pathway?

Answer 262

Inhibit the reuptake of dopamine in the Nacc

Question 263

How does cocaine have a local anaestetic effect?

Answer 263

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

Question 264

How does cocaine induce euphoria?

Answer 264

• 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

Question 265

How does cocaine affect the CNS?

Answer 265

• Cocaine is a stimulant and enhances CNS effects

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

Question 266

What are the cardiovascular effects of cocaine?

Answer 266

• 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

Question 267

What is nicotine?

Answer 267

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

Question 268

What are the routes of administration of nicotine?

Answer 268

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)

Question 269

What is the pKa of nicotine?

Answer 269

7.9

Cigarette smoke is relatively acidic

Question 270

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

Answer 270

• 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

Question 271

What is the quickest route of administration for nicotine?

Answer 271

Cigarettes

Question 272

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

Answer 272

• 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

Question 273

What is the half life of nicotine?

Answer 273

2 hours

Question 274

How is nicotine metabolised?

Answer 274

• 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

Question 275

How does nicotine act?

Answer 275

• 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

Question 276

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

Answer 276

Alpha 4

Beta 2

Question 277

What are the main side affects of nicotine?

Answer 277

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

Question 278

What are the metabolic effects of nicotine?

Answer 278

• Increased metabolic rate

- Apetite suppressant

Question 279

Why might nicotine protect against Parkinson’s disease?

Answer 279

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

Question 280

Why might nicotine protect against Alzheimer’s disease?

Answer 280

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

Question 281

Why can caffeine theoretically induce euphoria?

Answer 281

• 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

Question 282

How does chocolate simulate euphoria?

Answer 282

Stimulates the reward system

Question 283

How much is 1 unit of alcohol?

Answer 283

8g ethanol

Question 284

What is alcohol?

Answer 284

Ethanol (C2H5OH)

Question 285

What are the recommended limits of alcohol?

Answer 285

Men= 21 units 
Women= 14 units

Question 286

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

Answer 286

40,000

Question 287

How is the absolute amount of alcohol calculated?

Answer 287

%ABV x0.78 (g/100ml)

ABV= Alcohol by volume

Question 288

How are units calculated?

Answer 288

% ABV x vol(ml) / 1000

Question 289

What is considered binge drinking?

Answer 289

More than 8 units in one sitting

Question 290

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

Answer 290

Minimal effects
(1/2 pint - 1 pint)

Question 291

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

Answer 291

Very little effects on motor skills

Question 292

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

Answer 292

Legal driving limit

x4 increased likelihood of car accident

Question 293

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

Answer 293

25x more likelihood of car accident

Question 294

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

Answer 294

Coma

Question 295

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

Answer 295

Death

Question 296

What is the route of administration for alcohol?

Answer 296

• 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

Question 297

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

Answer 297

90%

- 10% is expired unchanged in the breath

Question 298

What % of alcohol is metabolised in the liver?

Answer 298

85%

Question 299

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

Answer 299

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

Question 300

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

Answer 300

• 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

Question 301

Why is the rate of consumption of alcohol important?

Answer 301

• 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

Question 302

Why does alcohol have a greater effect on women?

Answer 302

• 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

Question 303

How can low doses of alcohol show some CNS excitability?

Answer 303

• 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

Question 304

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

Answer 304

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

Question 305

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

Answer 305

Neurotransmitter release is calcium dependent

Question 306

How does alcohol affect the corpus callosum?

Answer 306

• 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

Question 307

How does alcohol affect the hypothalamus?

Answer 307

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

Question 308

How does alcohol affect the reticular activating system

Answer 308

• Regulates consciousness

- Alcohol leads to impaired consciousness at a very high dose

Question 309

How does alcohol affect the hippocampus?

Answer 309

• Involved in memory formation

- Alcohol leads to loss of memory

Question 310

How does alcohol affect the cerebellum?

Answer 310

• Movement and coordination

- Alcohol leads to stumbling

Question 311

How does alcohol affect the basal ganglia?

Answer 311

• Perception of time

- Alcohol leads to a loss of sense of time

Question 312

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

Answer 312

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

Question 313

How does alcohol affect the endocrine system?

Answer 313

• 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

Question 314

What are the chronic effects of alcohol on the CNS

Answer 314

• 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

Question 315

What are the chronic effects of alcohol on the liver?

Answer 315

• 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

Question 316

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

Answer 316

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

Question 317

How does alcohol pose an increased risk of stomach cancer?

Answer 317

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

Question 318

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

Answer 318

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

Question 319

What is the effect a hangover is thought of us?

Answer 319

Rebound excitation effect

- Symptoms peak as blood alcohol concentration reaches zero

Question 320

What are the symptoms of a hangover?

Answer 320

• 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)

Question 321

What are the effects of alcohol on foetal development?

Answer 321

• 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

Question 322

Why is Disulfiram used as aversion therapy for alcoholics?

Answer 322

• 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)

Question 323

How long does tolerance take to build?

Answer 323

1-3 week with continuing ethanol administration

Question 324

How is physical withdrawal from alcohol characterised?

Answer 324

• Tremor
• Hallucinations
• Convulsions
• Behaviour disturbances
• Nausea
• Fever

Question 325

What are the constituents of blood?

Answer 325

Blood cells: 45%
99% erythrocytes  
Leukocytes 
Thrombocytes 
Blood plasma: 55% 
Water 90% 
Electrolytes
Proteins 
Lipoproteins 

• Clotting factors

Question 326

What is haemostasis?

Answer 326

• Essential physiological process

- Blood coagulation prevents excessive blood loss

Question 327

What is thrombosis?

Answer 327

• 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

Question 328

What is Athersclerosis?

Answer 328

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

Question 329

What is Virchow’s triad?

Answer 329

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

Question 330

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

Answer 330

1) Initiation
2) Amplification
3) Propagation

Question 331

What does the initiation stage of coagulation involve?

Answer 331

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)

Question 332

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

Answer 332

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

Question 333

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

Answer 333

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

Question 334

What does the amplification phase of the coagulation process involve?

Answer 334

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

Question 335

Where does the propagation phase of the coagulation process occur?

Answer 335

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

Question 336

What does the propagation phase of the coagulation process involve?

Answer 336

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

Question 337

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

Answer 337

It inactivates factor IIa and factor Xa

Question 338

Which anticoagulant inhibits factor IIa?

Answer 338

Dabigatran

Question 339

Which anticoagulant inhibits factor Xa

Answer 339

Rivaroxaban

Question 340

What are the actions of low molecular weight heparins?

Answer 340

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

Question 341

What are examples of low-molecular weight heparins?

Answer 341

Dalteparin

Enoxaparin

Question 342

How do heparin’s act?

Answer 342

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

Question 343

What is warfarin?

Answer 343

Vitamin K antagonist

Question 344

How does warfarin act?

Answer 344

• 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.

Question 345

When are anticoagulants used?

Answer 345

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

Question 346

Give examples of anticoagulants that are indirect thrombin inhibitors

Answer 346

• Heparin
• Low molecular weight heparins
• Fondaparinux
• Rivaroxaban

Question 347

Give examples of anticoagulants that are direct thrombin inhibitors

Answer 347

• Bivalurudin

- Dabigatran

Question 348

What steps lead to platelet activation?

Answer 348

• 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

Question 349

How do ADP receptors contribute to platelet activation?

Answer 349

ADP activates P2Y12 receptors which leads to platelet activation/aggregation

Question 350

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

Answer 350

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

Question 351

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

Answer 351

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

Question 352

What is the action of Clopidogrel (oral)?

Answer 352

Prevents platelet activation/aggregation

- Is an ADP (P2Y12) receptor antagonist

Question 353

What is the action of Aspirin (oral)?

Answer 353

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

Question 354

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

Answer 354

• Prevent platelet aggregation

- Limited use and only by specialists

Question 355

Give examples of GP IIb/IIIa receptor antagonists

Answer 355

• Abciximab
• Tirofiban
• Eptifibtatide

Question 356

What is the mechanism of thrombolytics?

Answer 356

• Convert plasminogen to plasmin

- Plasmin- protease degrades fibrin

Question 357

What is Alteplase?

Answer 357

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

Question 358

What is streptokinase?

Answer 358

• Plasminogen activator

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

Question 359

Why will the body develop immunity to streptokinase?

Answer 359

It is a bacterial product

Question 360

What is Reteplase?

Answer 360

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

Question 361

What is Tenecteplase?

Answer 361

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

Question 362

When are thrombolytics used?

Answer 362

Arterial and venous thrombosis

• Stroke- first line treatment
• ST elevated MI

Question 363

When are antiplatelets used?

Answer 363

Arterial thrombosis

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

Question 364

What are deep vein thromboses causes by?

Answer 364

• Reduction in the rate of blood flow

- Damage to the endothelium

Question 365

What is used to manage a deep vein thrombus?

Answer 365

Anticoagulants

Question 366

What is an NSTEMI?

Answer 366

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

Question 367

What is used to manage acute coronary syndromes (stroke)

Answer 367

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

Question 368

What is used to treat aortic aneurism?

Answer 368

Anti-platelets

Question 369

What is used to treat pulmonary embolism?

Answer 369

Anticoagulants/thrombolytics

Question 370

What is the purpose of the exogenous metabolic pathway?

Answer 370

It is concerned with the transport and utilisation of dietary fats

Question 371

Where is dietary fat broken down?

Answer 371

Gastrointestinal tract

Question 372

What is dietary fat broken down into?

Answer 372

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

Question 373

What proportion of triglyceride and cholesterol is absorbed?

Answer 373

Triglyceride- 100%

Cholesterol- 50%

Question 374

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

Answer 374

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

Question 375

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

Answer 375

• 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

Question 376

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

Answer 376

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

Question 377

What happens to chylomicron remnants in the liver?

Answer 377

• 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

Question 378

What os the endogenous metabolic pathway concerned with?

Answer 378

The breakdown of chylomicron remnants

Question 379

What do chylomicrons do?

Answer 379

Transport triglyceride from the gut to the liver?

Question 380

What does VLDL do?

Answer 380

Transport triglyceride from the liver to the rest of the body

Question 381

What happens to VLDL in the blood stream?

Answer 381

• 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)

Question 382

Which enzymes are involved in the lipolysis of VLDL particles?

Answer 382

Large VLDL particles: Lipoprotein lipase

Small VLDL and IDL particles: Hepatic lipase

Question 383

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

Answer 383

Enterohepatic circulation

Question 384

What type of LDL particles are the most atherogenic?

Answer 384

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

Question 385

Why is cholesterol eliminated intact?

Answer 385

It cannot be broken down within the body

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

Question 386

How is endothelial dysfunction in atherosclerosis characterised?

Answer 386

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

Question 387

What is the earliest recognisable lesion of atherosclerosis?

Answer 387

• 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.

Question 388

How does a mature atherosclerotic plaque develop?

Answer 388

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

Question 389

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

Answer 389

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

Question 390

What characterises a stable atherosclerotic plaque?

Answer 390

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

Question 391

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

Answer 391

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

Question 392

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

Answer 392

• Weakening and thinning of vessel wall

- Leads to aneurysm and possibly haemorrhage

Question 393

At what sites do fibrous plaques usually occur?

Answer 393

• 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

Question 394

How are vulnerable plaques characterised?

Answer 394

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

Question 395

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

Answer 395

20%

Question 396

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

Answer 396

• Low HDL cholesterol
• Smoking
• Hypertension
• Diabetes

Question 397

How does HDL cholesterol affect atherosclerosis and CHD?

Answer 397

• 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

Question 398

What can lower HDL cholesterol?

Answer 398

• Smoking
• Obesity
• Physical inactivity

Question 399

What are normal triglyceride levels?

Question 400

What triglyceride levels are considered too high?

Answer 400

> 100mg/dl

Question 401

What are the clinical manifestations of atheosclerosis?

Answer 401

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

Question 402

What are the stages of the pathogenesis of atherosclerotic plaques?

Answer 402

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

Question 403

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

1) CHD mortality
2) Total mortality ?

Answer 403

1) 15% reduction in CHD mortality

2) 11% reduction in total mortality

Question 404

What is the mechanism of action for statins?

Answer 404

• 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

Question 405

What is the function of HMG-CoA reductase?

Answer 405

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

Question 406

What causes the main adverse effects of statins?

Answer 406

Due to their non-selective effects on the body

Question 407

What are the effects of statins on lipids?

Answer 407

• Rule of 6

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

Question 408

How do bile acid sequestrants work?

Answer 408

They bind to bile acids and prevent reabsorption

Question 409

What is the effect of bile acid sequestrants?

Answer 409

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

Question 410

What are the problems with bile acid sequestrants?

Answer 410

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

Question 411

How is nicotinic acid used as a drug therapy?

Answer 411

• B complex vitamin used in therapy at very high doses

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

Question 412

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

Answer 412

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

Question 413

What are fibrates?

Answer 413

Effective triglyceride-lowering drugs.

- Effective for patients with type III hyperliprotinaemia

Question 414

What is the main mechanism of action for fibrates?

Answer 414

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

Question 415

What are PPAR alpha receptors?

Answer 415

Perioxisome proliferator activated receptors

Question 416

Why are fibrates not usually used?

Answer 416

Due to their effects on inflammatory responses, thrombosis, etc

Question 417

What is the mechanism of action for Ezetimibe?

Answer 417

• 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

Question 418

What are the benefits of inhibiting cholesterol ester transfer protein?

Answer 418

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

- Example of this drug is torcetrapib

Question 419

Why does torcetrapib show an increase in mortality?

Answer 419

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

Question 420

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

Answer 420

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

Question 421

What are the antipyretic uses of NSAIDs?

Answer 421

• Reduction of fever

- Influenza

Question 422

What are the anti-inflammatory uses of NSAIDs?

Answer 422

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

Question 423

How many deaths are NSAIDs responsible for?

Answer 423

2000 deaths annually

Question 424

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

Answer 424

GI ulceration

Question 425

What are prostanoids?

Answer 425

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

Question 426

What is the mechanism of actions for NSAIDs

Answer 426

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

Question 427

How many prostanoid receptors are there?

Answer 427

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

Question 428

What are the analgesic actions of NSAIDS on Prostaglandin E2?

Answer 428

• 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

Question 429

What are thee unwanted actions of PGE2?

Answer 429

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

Question 430

What are the pyrogenic actions of NSAIDs on Prostaglandin E2?

Answer 430

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

Question 431

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

Answer 431

Prevents or reduces duration of prolonged pain

Question 432

What are the effects of NSAIDs on Prostaglandin E2?

Answer 432

Analgesic
Pyrogenic
Anti-inflammatory

Question 433

What effects does PGE2 have on immune and inflammatory pathways?

Answer 433

• Enhances Th1 cell differentiation and also Th17 expansion.

- Contribute to inflammation

Question 434

What are the desirable actions of PHE2 and other prostanoids?

Answer 434

• Gastroprotection
• Regulation of renal blood flow
• Bronchodilation
• Vasoregulation

Question 435

What is the role of PGE2 in gastric cycoprotection?

Answer 435

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

Question 436

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

Answer 436

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

Question 437

Why can NSAIDs cause renal toxicity?

Answer 437

• 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

Question 438

Why should NSAIDs not be taken by asthmatic patients?

Answer 438

• 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

Question 439

Why can NSAIDs have serious unwanted cardiovascular effects?

Answer 439

• 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

Question 440

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

Answer 440

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

Question 441

Which NSAID selectively inhibits COX-2?

Answer 441

Celecoxin

Question 442

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

Answer 442

• 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

Question 443

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

Answer 443

• 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

Question 444

What cyclooxygenase is the NSAID- Aspirin selective for?

Answer 444

COX- 1

Question 445

What are the effects of aspirin?

Answer 445

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

Question 446

What are the effects of prostanoids on platelet aggregation?

Answer 446

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

Question 447

What is the effect of aspirin on Thromboxane and Prostacyclin?

Answer 447

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

Question 448

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

Answer 448

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

Question 449

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

Answer 449

• 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

Question 450

What is inhibition of prostacyclin proportional to?

Answer 450

Inhibition of COX-2

Question 451

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

Answer 451

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

Question 452

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

Answer 452

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

Question 453

Why is Paracetamol not a NSAID?

Answer 453

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

Question 454

Why can a paracetamol overdose cause irreversible liver failure?

Answer 454

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

Question 455

What is the antidote for paracetamol poisoning?

Answer 455

• 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

Question 456

What are diuretics?

Answer 456

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

Question 457

What is the target organ for all subtypes of diuretics?

Answer 457

The kidney

Question 458

How does passive transport occur in the proximal convoluted tubule?

Answer 458

• 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

Question 459

What do the large gap junction between PCT cells allow?

Answer 459

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

Question 460

How does active transport occur in the proximal convoluted tubule?

Answer 460

• 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.

Question 461

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

Answer 461

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

- Maintained by carbonic anhydrase enzyme

Question 462

What are the two subtypes of carbonic anhydrase enzyme?

Answer 462

• 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

Question 463

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

Answer 463

30%

Question 464

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

Answer 464

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

Question 465

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

Answer 465

• 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

Question 466

Is the DCT permeable to water?

Answer 466

No

Question 467

What carrier proteins are present on the DCT?

Answer 467

• 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.

Question 468

What control are aquaporin molecules under?

Answer 468

Vasopressin

Question 469

What influence is the distal tubule under?

Answer 469

Aldosterone

Question 470

What movement occurs in the collecting duct?

Answer 470

• 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

Question 471

What are the main 5 classes diuretics?

Answer 471

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

Question 472

Where do the 5 main diuretics principally act

Answer 472

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

Question 473

What is the target of osmotic diuretics?

Answer 473

• No protein target

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

Question 474

How does mannitol work?

Answer 474

• 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

Question 475

What are the clinical uses of osmotic diurectics?

Answer 475

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

Question 476

How do carbonic anhydrase inhibitors work?

Answer 476

• 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

Question 477

Which diuretics are the most potent?

Answer 477

Loop diuretics

Question 478

How does frusemide work?

Answer 478

• 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

Question 479

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

Answer 479

15-30%

Question 480

What are the clinical uses of Loop diuretics?

Answer 480

Oedema- heart failure, pulmonary, renal, cerebral

e.g. acute left ventricular failure

Question 481

What are the unwanted effects of Loop diuretics?

Answer 481

Hypovalaemia and hypotension
K+ loss
Metabolic alkalosis

Question 482

How does bendrofluazine work?

Answer 482

• 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

Question 483

What are the clinical uses of thiazide diuretics?

Answer 483

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

Question 484

What are the unwanted effects of Thiazide diuretics?

Answer 484

K+ loss
Metabolic alkalosis
Diabetes mellitus- inhibits insulin secretion

Question 485

What are the different classes of K+ sparing drugs?

Answer 485

1) Aldosterone receptor antagonists e.g. spironolactone

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

Question 486

How do potassium sparing diuretics act?

Answer 486

• 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

Question 487

What is the clinical use of amiloride?

Answer 487

To be used with K+ losing diuretics

Question 488

What are the clinical uses of spironolactone?

Answer 488

Hypertension/heart failure

Hyperaldosteronism

Question 489

What are the unwanted effects of potassium sparing diuretics?

Answer 489

Hyperkalaemia and metabolic acidoses

Spironolactone- gynaecomastia, menstrual disorder, testicular atrophy

Question 490

What are the two major forms of inflammatory bowel disease?

Answer 490

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

Question 491

What are the risk factors of IBD?

Answer 491

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

Question 492

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

Answer 492

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

Question 493

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

Answer 493

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

Question 494

What gut layers are affected in CD and UC?

Answer 494

CD= All layers 
UC= Mucosa/submucosa

Question 495

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

Answer 495

CD= Any part of GI 
UC= Rectum, spreading proximally

Question 496

What are the inflamed areas in CD and UC?

Answer 496

CD= Patchy 
UC= Continuous

Question 497

What is the nature of abscesses in CD and UC?

Answer 497

CD= Common 
UC= Not common

Question 498

In CD and UC, is surgery curative?

Answer 498

CD= Not always curative 
UC= Curative

Question 499

What are the clinical features of IBD?

Answer 499

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

Question 500

What are the supportive therapies for IBD?

Answer 500

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

Question 501

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

Answer 501

• Glucocorticoids e.g. prednisolone
• Aminosalicylates e.g. Mesalazine
• Immunosuppressives e.g. Azathioprine

Question 502

What are aminosalicylates?

Answer 502

Anti-inflammatory drugs with no immunosuppressive action

Question 503

Give 2 examples of aminosalicylates

Answer 503

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

- Olsalazine (2 linked 5-ASA molecules)

Question 504

Are aminosalicylates useful in UC and CD?

Answer 504

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

Question 505

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

Answer 505

• 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

Question 506

Where is Mesalazine absorbed?

Answer 506

Small bowel and colon

Question 507

Where is Olsalazine metabolised?

Answer 507

By colonic flora and absorbed in the colon

Question 508

What are glucocorticoids?

Answer 508

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

Question 509

Give 3 examples of glucocorticoids?

Answer 509

Prednisolone
Fluticasone
Budesonide

Question 510

How are glucocorticoids used to treat IBD?

Answer 510

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

Question 511

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

Answer 511

• 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

Question 512

What are the unwanted effects of glucocorticoids?

Answer 512

• 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

Question 513

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

Answer 513

Azathiprine
Cyclosporine
Methrotrexate

Question 514

What is the use of Azathioprine?

Answer 514

• 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

Question 515

What is the mechanism of immunosuppression in Azathioprine?

Answer 515

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

Question 516

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

Answer 516

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

Question 517

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

Answer 517

T cell apoptosis

Question 518

What are the unwanted effects of Azathioprine?

Answer 518

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

Question 519

How can the microbiome be manipulation?

Answer 519

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

Question 520

How can Rifaximin treat IBD?

Answer 520

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

Question 521

What biological therapies are approved for use in IBD?

Answer 521

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

Question 522

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

Answer 522

Crohn’s disease

- Potentially curative

Question 523

What is the mechanism of action for Anti-TNFa?

Answer 523

• 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

Question 524

Give examples of anti-TNFalpha antibodies?

Answer 524

Infliximab

Adalimumab

Question 525

What are the pharmacokinetics of anti-TNFalpha antibodies?

Answer 525

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

Question 526

What are the adverse effects of anti-TNFalpha antibodies?

Answer 526

• 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

Question 527

What is an opiate?

Answer 527

An alkaloid derived from the poppy, Papaver somniferum

Question 528

Name 4 Opiates?

Answer 528

Morphine
Thebaine
Codeine
Papverine

Question 529

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

Answer 529

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

Question 530

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

Answer 530

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

Question 531

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

Answer 531

Oxidises the OH group and lipophilicity increases 10 fold

Question 532

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

Answer 532

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

Question 533

What happens to opioids in the small intestine?

Answer 533

Unionised and more readily absorbed

- First pass metabolism will decrease the bioavailability

Question 534

Why are most opioids largely ionised in the bloody?

Answer 534

Blood pH= 7.4

The

Question 535

Why is heroin more potent than morphine?

Answer 535

It is more lipid soluble

Question 536

How is morphine metabolised?

Answer 536

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

Question 537

What contributes to the pharmacological effects of morphine?

Answer 537

The active metabolite

Morphine-6-glucuronide

Question 538

Where is morphine-6-glucuronide liberated from morphine?

Answer 538

It ends up into the bile and secreted in the gut

Question 539

How is codeine metabolised?

Answer 539

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

Question 540

Why do some people not respond well to codeine?

Answer 540

Have a 2D6 polymorphism

Question 541

What is morphine metabolised by?

Answer 541

Uridine 5 Disphosphate glucoronosyltransferase

Question 542

How do opioids work?

Answer 542

• 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

Question 543

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

Answer 543

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

Question 544

What do endorphins affect?

Answer 544

Pain/mood/CVS

• Associated with exercise
• ‘High’ feeling

Question 545

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

Answer 545

Delta (δ)

Nucleus accumbens, cerebral cortex, amygdala

Question 546

What do enkephalins affects?

Answer 546

Pain/mood/CVS

Question 547

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

Answer 547

Kappa (κ)

Hypothalamus

Question 548

What do dynorphins affect?

Answer 548

Apetite

Question 549

What is the cellular mechanism of opioid?

Answer 549

• 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.

Question 550

What are the pharmacological actions of opioids?

Answer 550

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

Question 551

How do opioids have analgesic action?

Answer 551

• 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

Question 552

How do opioids act as depressants?

Answer 552

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

Question 553

How do opioids increase pain tolerance?

Answer 553

They activate the PAG and by activating the NRPG.

This increases activation of the descending inhibitory pathway

Question 554

How do opioids produce euphoria?

Answer 554

• 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

Question 555

How do opioids act as anti-tussive agents?

Answer 555

• 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

Question 556

How do opioids cause respiratory depression?

Answer 556

• 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

Question 557

How do opioids cause nausea/vomiting?

Answer 557

• 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

Question 558

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

Answer 558

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

Question 559

What is the effect of opioids on the GI tract?

Answer 559

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

Question 560

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

Answer 560

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

Question 561

How may patients grow tolerant of opioids?

Answer 561

• 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

Question 562

What are the problems with prolonged treatment of opioids?

Answer 562

Tolerance

Dependence

Question 563

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

Answer 563

• Psychological craving
• Physical withdrawal
• Resembles flu

Question 564

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

Answer 564

• Coma
• Respiratory depression
• Pin point pupils
• Hypotension

Question 565

What is the treatment for opioid overdose?

Answer 565

Naloxene

• Opioid antagonist
• IV

Question 566

What is an adverse drug event?

Answer 566

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

Question 567

How are adverse drug reaction described?

Answer 567

By:

• Onset
• Severity
• Type

Question 568

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

Answer 568

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

Question 569

How is the severity of an adverse drug reaction distinguished?

Answer 569

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

Question 570

What are the consequences of a severe adverse drug reaction?

Answer 570

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

Question 571

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

Answer 571

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

Question 572

What is a Type A adverse drug reaction?

Answer 572

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

Question 573

Give examples of Type A ADRs

Answer 573

• Atenolol and heart block
• Anticholinergics and dry mouth
• NSAIDs and peptic ulcer

Question 574

What is a Type B ADR?

Answer 574

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

Question 575

Give examples of Type B ADRs

Answer 575

• Chloramphenicol and aplastic anaemia

- ACE inhibitors and angioedema

Question 576

What is a Type C ADR?

Answer 576

• Associated with long-term use

- Involves dose accumulation

Question 577

Give examples of Type C ADRs

Answer 577

• Methotrexate and liver fibrosis

- Antimalarials and ocular toxicity

Question 578

What is a Type D ADR?

Answer 578

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

Question 579

What do Type E ADRs include?

Answer 579

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

Question 580

What is a Type I allergic reaction?

Answer 580

Immedate, Anaphylactic

• IgE mediated
• E.g. anaphylaxis with penicillins

Question 581

What is a Type II allergic reaction?

Answer 581

Cytotoxic antibody

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

Question 582

What is a Type III allergic reaction?

Answer 582

Serum sickness

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

Question 583

What is a Type IV allergic reaction?

Answer 583

Delayed hypersensitivity (T cell) 
e.g. contact dermatitis

Question 584

What are pseudoallergies?

Answer 584

Not immunologically determined, but pharmacologically determined ‘allergic’ responses

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

Question 585

What are common causes of ADRs

Answer 585

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

Question 586

How are ADRs detected?

Answer 586

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

Question 587

What is the process of reporting adverse drug reactions?

Answer 587

ADR suspecting
ADR confirmed
Frequency estimated
Prescribers informed

Question 588

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

Answer 588

• 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

Question 589

What are the three types of drug interactions?

Answer 589

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

Question 590

What are pharmacodynamic drug interactions?

Answer 590

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

Question 591

Give examples of pharmacodynamic drug interactions

Answer 591

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

Question 592

How can pharmacokinetic drug interactionss result?

Answer 592

• Alteration in absorption
• Protein binding effects
• Changes in drug metabolism
• Alteration in elimination

Question 593

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

Answer 593

Chelation

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

Question 594

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

Answer 594

• 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

Question 595

What are the possible routes of drug metabolism and elimination?

Answer 595

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

Question 596

What does phase I metabolism involve?

Answer 596

Oxidation
Reduction
Hydrolysis

Question 597

What does phase II metabolism involve?

Answer 597

Conjugation

• Glucuronidation
• Sulfation
• Acetylation

Question 598

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

Answer 598

• 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’

Question 599

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

Answer 599

CYP3A4

CYP2D6

Question 600

Give examples of CYP450 inhibitors

Answer 600

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

Question 601

Give examples of CYP450 inducers?

Answer 601

• Rifampicin
• Carbamazepine
• St John’s wort

Question 602

Give an example of a good drug elimination interaction

Answer 602

Probenecid and penicillin

Question 603

Give an example of a bad drug elimination reaction

Answer 603

Lithium and thiazides

Question 604

Where to drug elimination interactions almost always take place?

Answer 604

Renal tubule

Question 605

What drug interactions are deliberate to produce a therapeutic benefit?

Answer 605

• Levodopa & Carbidopa
• ACE inhibitors & thiazides
• Penicillins & Gentamicin
• Salbutamol & Ipratropium

Question 606

What is nausea?

Answer 606

Subjective unpleasant sensation in throat and stomach, often precedes vomiting

Question 607

What is vomiting?

Answer 607

Forceful propulsion of stomach contents out of the mouth

Question 608

What are vomiting and nausea preceded by?

Answer 608

• Salivation
• Sweating
• Increased heart rate

Question 609

What pathways are involved in vomiting?

Answer 609

• 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

Question 610

How do acute, chronic and severe vomiting differ?

Answer 610

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

Question 611

What is promethazine?

Answer 611

A phenothiazine derivative

Question 612

What is the mode of action of promethazine?

Answer 612

• 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

Question 613

How is promethazine used as an anti-emetic?

Answer 613

• 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

Question 614

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

Answer 614

• Relief of allergic symptoms
• Anaphylactic emergency
• Night sedation; insomnia

Question 615

What are the unwanted effects of promethazine?

Answer 615

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

Question 616

What dopamine receptor antagonists are used as anti-emetics?

Answer 616

Metoclopramide

Domperidone

Question 617

What is the mode of action of Metoclopramide?

Answer 617

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

Question 618

What suppresses intestinal motility?

Answer 618

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

Question 619

What are the uses of metoclopramide/domperidone?

Answer 619

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

Question 620

What are the pharmacokinetic considerations of metoclopramide?

Answer 620

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

Question 621

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

Answer 621

Absorption and therefore effectiveness of digoxin may be reduced

Question 622

What are the unwanted effects of Metoclopramide in the CNS?

Answer 622

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

Question 623

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

Answer 623

• Hyperprolactinaemia
• Galactorrhoea
• Disorders of menstruation

Question 624

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

Answer 624

Hyoscine

Question 625

What is the mode of action of Hyoscine?

Answer 625

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

Question 626

How is Hyoscine used as an anti-emetic?

Answer 626

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

Question 627

What are the unwanted effects of Hyoscine?

Answer 627

Typical anti-muscarinic side effects

• Drowsiness
• Dry mouth
• Cycloplegia
• Mydriasis
• Constipation

Question 628

What is Ondansetron?

Answer 628

Serotonin receptor antagonist (5-HT3)

- used as an anti-emetic

Question 629

What is the mode of action of Ondanstron?

Answer 629

Acts to block transmission in visceral afferents and CTZ

Question 630

How is Ondansetron used as an anti-emetic?

Answer 630

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

Question 631

What are the unwanted effects of ondansetron?

Answer 631

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

Question 632

Wh is ondansetron used in combination with corticosteroids?

Answer 632

• 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

Question 633

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

Answer 633

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

Question 634

Where is the areas of damage in peptic ulcer disease?

Answer 634

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

Question 635

When is pain felt in a gastric ulcer?

Answer 635

At mealtimes, when gastric acid is secreted

Question 636

What are protective factors?

Answer 636

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

Question 637

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

Answer 637

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

Question 638

What factors may cause damage to the mucosal gastrointestinal barrier

Answer 638

• 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

Question 639

What are the risk factors for peptic ulcer?

Answer 639

• Genetic predisposition
• Stres
• Diet, alcohol, smoking

Question 640

What are the aims of treatment for peptic ulcers?

Answer 640

• Eliminate cause of mucosal damage

- Promote ulcer healing

Question 641

What is the purpose of antibiotics in treating peptic ulcers?

Answer 641

Eradicate H. pylori

Question 642

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

Answer 642

Prevent gastric acid production

Question 643

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

Answer 643

Neutralise gastric acid

Question 644

What is the best practice in treating peptic ulcer disease?

Answer 644

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

Question 645

What drugs inhibit gastric acid secretion?

Answer 645

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

Question 646

What is omeprazole?

Answer 646

Proton pump inhibitor

Question 647

What is the mode of action of omeprazole?

Answer 647

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

Question 648

What are the uses of proton pump inhibitors?

Answer 648

• 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

Question 649

What are the unwanted effects of proton pump inhibitors?

Answer 649

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

Question 650

What are climetidine and ranitidine?

Answer 650

Histamine type 2 (H2) receptor antagonists

Question 651

What is the mode of action of H2 receptor antagonists?

Answer 651

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

Question 652

What are the unwanted effects of H2 receptor antagonists?

Answer 652

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

Question 653

What are cyto-protective drugs?

Answer 653

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

Question 654

Give examples of cyto-protective drugs

Answer 654

• Sucralfate
• Bismuth chelate
• Misoprostol

Question 655

What is Sucralfate?

Answer 655

A polymer containing aluminium hydroxide and sucrose octa-sulfate

Question 656

How does sucralfate act?

Answer 656

• 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

Question 657

What are the unwanted effects of sucralfate?

Answer 657

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)

Question 658

When is bismuth chelate used?

Answer 658

Triple therapy

- Acts like sucalfate

Question 659

What is misoprostol?

Answer 659

A stable prostaglandin analogue

Question 660

How does misoprostol act?

Answer 660

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

Question 661

What is the use of misoprostol?

Answer 661

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

Question 662

What are the unwanted effects of misoprostol?

Answer 662

Diarrhoea
Abdominal cramps
Uterine contractions

Question 663

What are antacids?

Answer 663

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

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

Question 664

What is the mode of action of antacids?

Answer 664

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

Question 665

What are antacids primarily used for?

Answer 665

Non-ulcer dyspepsia (OTC)

Question 666

What are the problems with triple therapy?

Answer 666

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

Question 667

What is gastroesophageal reflux disease?

Answer 667

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

Question 668

How is GERD treated?

Answer 668

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