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BP Theme 2 Flashcards

1
Q

what is the peripheral nervous system made up of

A

sensory nervous system
autonomic nervous system
somatic nervous system

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2
Q

what is the autonomic nervous system made up of

A

sympathetic and parasympathetic ns

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3
Q

what occurs in the sympathetic (fight or flight) response

A 
Pupils dilate (peripheral vision)
Lens of eye adjust for far vision
Airways in lungs dilate
Respiratory rate increases
Heart rate increases
Blood vessels to limb muscles dilate
Blood vessels to visceral organs constrict
Salivary secretions reduced
Brain activity general alertness
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4
Q

what occurs in the parasympathetic (fight or flight) response

A 
Pupils constrict 
Lens of eye readjust for closer vision
Airways in lungs constrict
Respiratory rate decrease
Heart rate decrease
Blood vessels to limb muscles constrict
Blood vessels to visceral organs more dilated
Salivary secretions normalise
Brain activity normalise
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5
Q

what are the pre and post ganglionic neurotransmitters for the sympathetic system

A

preganglionic- ACh

postganglionic- NA

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6
Q

what are the pre and post ganglionic neurotransmitters for the parasympathetic system

A

preganglionic ACh

post ganglionic ACh

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7
Q

what is the organisation like for the somatic efferent system

A

ACh released at neuromuscular junction

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8
Q

what are the exceptions for the sympathetic nervous system

A

sweat glands
-the pre and post ganglionic fibres contain ACh

adrenal glands
-adrenaline is released from the adrenal glands. ACh activates adrenal medulla which releases adrenaline into the blood stream

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9
Q

what is the pharmacology of ACh

A

Synthesis- choline/choline acetyl transferase
Storage- vesicles
Release- exocytotic
Receptor interaction- muscarinic/nicotinic
Termination- in synapse by acetylcholine esterase

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10
Q

what are the 2 classes of receptors that the actions of ACh are mediated by

A

muscarinic receptors - affinity for an extract fly agaric mushroom
nicotinic receptors- affinity for tobacco farm

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11
Q

what are the 3 main muscarinic receptor (mACh) subtypes and where are they located

A

M1,2,3
G-protein coupled receptor

Located at postganglionic parasympathetic synapses  on target organs

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12
Q

what are the 2 main nicotinic (nACh) receptor subtypes

A

neuronal type- brain and autonomic ganglia (excitatory)

muscle-type- neuromuscular junction (NMJ) (excitatory)

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13
Q

what are the characteristics of cholinergic muscarinic receptors

A

g-protein coupled
slow response
mainly located on effector tissues
muscarine

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14
Q

what are the characteristics of cholinergic nicotinic receptors

A

ligand gated ion channels
fast response (milliseconds)
located in ganglia and on NMJ
nicotine

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15
Q

what effects to muscarinic receptors mainly mediate

A

parasympathetic effects

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16
Q

what are the effects of muscarinic agonists

A

parasympathetic activation

stimulate muscle receptors-increase in pupil constriction and decrease in focal length

bronchoconstriction- decrease in cardiac output, increase GI motility, increase exocrine gland secretion

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17
Q

what are muscarinic agonists known as

A

parasympathomimetics

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18
Q

what are the effects of muscarinic antagonist

A

pupil dilate
Increase in focal length of the lens

Bronchodilation

  • Increase in cardiac output, (rate & force)
  • Decrease GI motility
  • Decrease exocrine gland secretion(dry mouth decreased sweating)
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19
Q

what are Muscarinic antagonists known as

A

parasympatholytic

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20
Q

what are the clinical uses of muscarinic agonists

A

Pilocarpine used to treat Glaucoma - build up of aqueous humour behind the lens

Treatment of xerostomia

Use Pilocarpine stimulates saliva secretions

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21
Q

what are the clinical uses of Muscarinic receptor antagonist

A

Tropocamide-
Pupil dilation in eye surgery

Atropia
Decrease oral/respiratory secretions before oral procedures and as an adjunct to anaesthesia

Atropine
Resuscitation in bradycardia (causes increase heart rate)

Ipratropium-
Asthma (causes bronchodilation)

Hyoscine
Motion sickness- Orally it decreases gastric motility

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22
Q

where are neuronal type nicotinic receptors receptors located

A

both ps and symp ganglia

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23
Q

what are the effects of agonists for neuronal type nicotinic receptors (nicotine)

A

sympathetic:
vasoconstriction, tachycardia, hypertension

parasympathetic:
bradycardia, hypotension, increase GIT motility, increase secretions

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24
Q

why are Ganglionic\neuronal nicotinic agonists not clinically useful.

A

The effect of agonists activating both systems is autonomic confusion

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25
Q

what are the effects of antagonists for neuronal type nicotinic receptors

A

loss of sympathetic & parasympathetic reflexes, especially cardiac

Ganglionic\neuronal nicotinic antagonists are not of great therapeutic value

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26
Q

where are muscle type nicotinic receptors receptors located

A

Located at the NMJ

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27
Q

what does stimulation of muscle type nicotinic receptors by ACh cause

A

depolarisation (in muscle fibre this is known as an end plate potential (EPP)) and contraction of the skeletal muscle fibre

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28
Q

what does agonist action on muscle type nicotinic receptors do

A

causes contraction of skeletal muscle and antagonist will block this.

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29
Q

what is a clinical example of the agonist for muscle type nicotinic receptors

A

Suxemethonium

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30
Q

what is a clinical example of the antagonist for muscle type nicotinic receptors

A

Tubocurarine

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31
Q

what is the clinical effect of nicotinic agonists at neuromuscular junction

A

Initial depolarisation/EPP and muscle fibre contraction (muscle twitch)

Paralysis / muscle relaxation (for surgery)

Depolarising block

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32
Q

what is the clinical effect of nicotinic antagonists at neuromuscular junction

A

Hyperpolarisation, inhibition of EPPs
Muscle fibre relaxation
Paralysis (for surgery)
Non-depolarising blocker

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33
Q

what is ACh release inhibited by

A

toxins: botulinum toxin, & bungarotoxin

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34
Q

what occurs in BOTOX

A

Botulinum toxin injected locally is used to treat muscle spasm, and in plastic surgery

neuromuscular block and paralysis/loss of wrinkles

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35
Q

what are the Therapeutic targets for drugs affecting cholinergic transmission

A

receptors
drug release
termination

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36
Q

how do anticholinesterases work

A

Acetylcholinesterase the enzyme responsible for the metabolism of ACh and termination of the action of ACh can be inhibited

This will increase ACh transmission

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37
Q

what are the Effects of anticholinesterase on the autonomic nervous system

A

Reflect increased transmission at parasympathetic postganglionic synapses- increase secretions, bradycardia, hypotension, pupil constriction

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38
Q

what are the Effects of anticholinesterase on the neuromuscular nervous system

A

Increased muscle tension and twitching, at large doses causes a depolarising block.

At lower doses Neostigmine used to treat myasthenia gravis (autoimmune disease, circulating antibodies against muscle nicotinic receptors)

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39
Q

what is the drug for anticholineresterases that induce paralysis for surgery

A

neostigmine

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40
Q

which drug is used to treat glaucoma and xerostomia and what class of drug is are they

A

pilocarpine

muscarinic agonists

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41
Q

which drugs are used to decrease secretion and cause pupil dilation in eye surgery and what class of drug is are they

A

atropine
tropicamide

muscarinic antagonist

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42
Q

which drug is used to treat asthma and what class of drug are they

A

ipratropium

muscarinic antagonist

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43
Q

which drug is used to decrease gastric motility and motion sickness and what class of drug are they

A

hyoscine

muscarinic antagonist

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44
Q

what drugs induce paralysis for surgery and what class of drug are they

A

suxamethonium- nicotinic AGONIST

tubocurare- nicotinic ANTAGONIST

neostigmine- anticholineresterase

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45
Q

what is the biochemistry/pharmacology of noradrenaline

A

Precursor of tyrosine
Converted to nor adrenaline in a number of steps
DOPA converted to dopamine
NA taken back up into the neurone after released into synapse, its not broken down like Ach

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46
Q

what are the potential sites for drug action when NA acts as a neurotransmitter

A 
synthesis 
metabolism 
storage/release 
uptake 
receptor
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47
Q

what are the fundamentals of neurotransmission for NA

A

Synthesis

  • tyrosine/tyrosine hydroxylase/DOPA
  • decarboxylase, DA β-hydroxylase

Storage - vesicles

Release - exocytotic

Receptor interaction α, β, receptors

Termination - Uptake and recycled or metabolism by monoamine oxidase

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48
Q

what are the 2 main classes of NA receptors

A

alpha receptors

beta receptors

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49
Q

what are the types of alpha-na receptors

A

alpha1 and alpha 2

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50
Q

where a-noradrenic receptors located and what type of receptor are they

A

in effector tissues/targets of sympathetic system

g-protein coupled receptors(or metatropic receptors)

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51
Q

is the response fast or slow for a-NA receptors

A

Slow (seconds) responses

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52
Q

where in the PNS do NA act as neurotransmitter

A

on the sympathetic tissues

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53
Q

what are the types B- NA receptors and where are they located. what type of receptor are they

A

B1,2,2
Located in effector tissues/targets of sympathetic system

G-protein coupled receptors (metabotropic receptors)

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54
Q

is the response fast or slow for b-NA receptors

A

Slow (seconds) response

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55
Q

Which noradrenergic receptors mediate sympathetic effects?

A

a1 –receptors

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56
Q

where is the a2 receptor

A

its a Presynaptic receptor

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57
Q

what does a2 receptor do

A

Inhibits neurotransmitter release (both NA and ACh)

Can be on terminals of other neurones and inhibit the release of nt

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58
Q

how does NA act on presynaptic receptors

A

NA is released and feedbacks onto the receptors on the terminal, it turns off further activity of the neurone thus decreasing further release of neurotransmitter

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59
Q

what are the types of presynaptic (a2) receptors and where are they located

A

autoreceptor- receptor on its own neurone

heteroreceptor- receptor on a different neurotransmitters neurone

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60
Q

what are the Sympathetic effects mediated by B1, B2 and B3 receptors

A

Pupils dilate

Lens of eye adjust for far vision

Airways in lungs dilate

Heart rate increases

Blood vessels to limb muscles dilate

Blood vessels to visceral organs & skin constrict

Brain activity general alertness

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61
Q

what are the effects mediated by a1 – receptors

A

smooth muscle & vaso-constriction

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62
Q

what are the effects mediated by a2 – receptors

A

inhibition of neurotransmitter release

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63
Q

what are the effects mediated by B1 – receptors

A

increase cardiac rate and force

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64
Q

what are the effects mediated by B2 – receptors

A

bronchodilation, ciliary muscle relaxation

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65
Q

what are the effects mediated by B3 – receptors

A

lipolysis/increased metabolism

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66
Q

what are the Noradrenergic agonist drugs acting on NA receptors

A 
Adrenaline
Clonidine
dobutamine
Salbutamol
Clenbuterol
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67
Q

what are the uses of adrenaline and what is the effect of the a1

A

Given subcutaneously (locally) adrenaline can prolong & isolate local anaesthesia

-a1 – mediated vasoconstriction- around the areas of the local anaesthetic prolongs the duration of it as it isolated it

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68
Q

how is adrenaline used to treat an anaphylactic shock and how is this mediated by a1, B1 and B2 receptors

A

intramuscular adrenaline given

a1 - mediated smooth muscle contraction (vasoconstriction, )
b1 – mediated cardiac stimulation
b2 - mediated bronchiol smooth muscle relaxation:

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69
Q

what is clonidine and what does it do

A

an a2 agonist

Presynaptic autoreceptors regulate release, agonist inhibits NA release

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70
Q

what is clonidine used for

A

hypertension (can result decrease sympathetic outflow)

can treat withdrawal symptoms in morphine withdrawal (inhibits central NA release)

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71
Q

what is dobutamine and how are the receptors involved, what does it treat

A

selective b 1 agonist

b1 – receptors: increased cardiac rate and force

Used to treat heart failure.

b 1 – mediated cardiac stimulation (increased firing rate and increased contractile force)

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72
Q

what is Salbutamol and how are the receptors involved, what does it treat

A

selective b 2 agonist

b2 – receptors: bronchodilation

Used to treat asthma.

b2 – mediated bronchiol smooth muscle relaxation

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73
Q

what is Clenbuterol and how are the receptors involved, what does it treat

A

b2 – receptors: bronchodilation

b3 – receptors: lipolysis/increased metabolism

  • Weight loss
  • Muscle gain

Used to treat asthma (b2 )

Increases muscle bulk in athletes/body builders/livestock (b3)

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74
Q

what are the Noradrenergic antagonist drugs

A 
Prazosin 
Tamsulson 
Propranolol 
Atenolol 
Timolol
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75
Q

what is Prazosin and how are the receptors involved, what does it treat, what are the side effects

A

selective a1 -antagonist

blocks a1 – mediated smooth muscle & x
Used to treat hypertension

a1 – antagonism: vasodilation and decreased vascular resistance

Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex

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76
Q

what is Tamsulson and how are the receptors involved, what does it treat, what are the side effects

A

selective a1 -antagonist

blocks a1 – mediated smooth muscle & vaso-constriction
Used to Urination problems in prostate hyperplasia

a1 – antagonism: relaxation of smooth muscle in bladder neck, ease of urinary flow
Side effects: orthostatic or postural hypotension due to some loss in sympathetic reflex

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77
Q

what is Propranolol and how are the receptors involved, what does it treat, what are the side effects

A

b1 b2 antagonist (non selective to b1/b2)

b1– receptors mediate increased cardiac rate and force
b2– receptors mediate bronchodilation

Used to treat hypertension and angina

Blocking b1 receptors decreases cardiac output and also decreases oxygen demand.

However blocking b2 receptors causes bronchoconstriction. Therefore contra-indicative in asthmatics .

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78
Q

what is Atenolol and how are the receptors involved, what does it treat, what are the side effects

A

selective b1 antagonist

b1– receptors mediate increased cardiac rate and force
Used to treat hypertension and angina

Blocking b1 decreases cardiac output and also decreases oxygen demand.

Side effect: can cause rebound hypertension/ angina on abrupt withdrawal probably due to b1 receptor supersensitivity

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79
Q

what is Timolol and how are the receptors involved, what does it treat

A

selective b2 antagonist

b2– receptors mediate ciliary muscle/lens of eye relaxation

Used to treat glaucoma, antagonism of b2– receptors cause ciliary contraction, and decreased intraocular pressure

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80
Q

what does Timolol, b2– receptor antagonist cause

A

ciliary muscle contraction and decreased intraocular pressure

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81
Q

outline the Noradrenergic regulation of salivary glands

A

Direct sympathetic innervation a1, b1, b2

Indirect via innervation of vascular adrenergic innervation.

b1 stimulates protein secretion

a1 stimulates water electrolyte secretions

Clonidine: inhibits NA release, common side effect xerostomia, particular problem given chronic use of clonidine.

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82
Q

what drug affects NA synthesis and how, when is it used

A

Methyldopa acts as false substrate for DOPA decarboxylase

Decreases overall noradrenergic neurotransmission

Used in the treatment of hypertension

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83
Q

what Drugs affecting NA storage, when is it used

A

NA stored in synaptic vesicles

Reserpine disrupts storage of NA in synaptic vesicles

Overall decrease in NA neurotransmission

Used to treat hypertension

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84
Q

what Drugs affecting NA release, when is it used

A

NA release is subject to autoinhibitory control via presynaptic a2 -autoreceptor

clonidine (a2-agonist) causes inhibition of NA release

Overall decrease in NA neurotransmission

Used to treat hypertension

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85
Q

what Drugs affecting NA reuptake, when is it used

A

NA reuptake inhibitors prolong the action of NA in the synapse

desipramine tricyclic antidepressants

reboxetine selective noradrenaline reuptake inhibitors

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86
Q

what Drugs affecting NA metabolism and how

A

monoamine oxidase (MAO), and catecholamine transferase (COMT) metabolise NA after reuptake

By blocking these enzymes the amount of NA available for release is increased.

tranylcypramine blocks MAO and allows more NA to be recycled so increases NA neurotransmission.

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87
Q

what do Tranylcypramine and other MAOIs do

A

they block the metabolism of NA but also block the metabolism of dietary amines

this can have sympathomimetic effect and result in hypertension

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88
Q

which drug inhibits NA synthesis

A

methyldopa

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89
Q

which drug inhibits NA storage

A

reserpine

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90
Q

which drug inhibits NA uptake

A

reboxetine

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91
Q

which drug inhibits NA metabolism

A

tranylcypromine

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92
Q

which drug inhibits NA release

A

clonidine

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93
Q

what are medical analgesics

A 
Non-steroidal anti-inflammatories
Opioid analgesics
General anaesthetics
Local anaesthetics
Anxiolytics
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94
Q

what are non-medical analgesics

A

Alcohol
nicotine/caffeine
cocaine
LSD

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95
Q

what is nociception

A

the process whereby noxious peripheral stimuli are transmitted to the CNS

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96
Q

what receptors sense noxious stimuli

A

peripheral receptors (nociceptors)

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97
Q

what is the difference between nociception and pain

A

pain is personal and subjective- depends on many factors other than the stimulus itself

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98
Q

in most cases, what is the origin for the stimulation of nociceptive endings in the periphery

A

chemical

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99
Q

how is chronic pain caused

A

as a result of chemical mediators

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100
Q

how can you measure nociception

A

Apply electrodes within the periphery and measure how external stimuli increase the excitation of neurons

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101
Q

what are the main afferent fibres that sense different levels of pain

A
  • C fibers
  • Alpha delta fibers
  • Alpha beta fibers
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102
Q

what are c-fibres, are they myelinated or unmyelinated

A

Non-myelinated -transmission is slow and unprotected

Low conduction velocity (achy pain)

Nociceptor/ thermoreceptor/ mechanoreceptor

Dull achy pain

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103
Q

what are a-delta fibres, are they myelinated or unmyelinated

A

Myelinated - speed of nociception is greater

Rapid conduction velocity (sharp pain)

Nociceptor/ mechanoreceptor

Terminate in deeper layers in the dorsal horn

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104
Q

what are a-beta fibres, when are they stimulated

A

Mechanoreceptor (pressure)

Only stimulated when there is physical interaction

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105
Q

where does the neural pathways of nociception start and end

A

primary afferent neurones (PANs) to the superficial lamina in the dorsal horn of the spinal cord

secondary neurones go through the brainstem to the mid-brain and to the thalamus in the brain

the fibres get passed over to one of the 3 cortices

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106
Q

what are some chemical mediators (substances which stimulate pain endings in the skin)

A

5-HT

Kinins

Metabolites of intermediary metabolism e.g. lactic acid

capsaicin

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107
Q

what is 5-HT

A

serotonin released from damaged cells can stimulate nociception

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108
Q

what is an ex of a kinins

A

bradykinin

most potent pain mediator
Initiate most nociceptive processes

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109
Q

what is an ex of Metabolites of intermediary metabolism

A

lactic acid

protons from lactic acid can interact with peripheral afferent neurone to cause pains

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110
Q

what is Capsaicin and what does it interact with

A

chemical product in food

vinalloid receptor-associated with burning

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111
Q

what do eicosanoids do

A

enhance the pain producing effects of other agents- they do not stimulate nociceptive endings e.g prostoglandings, prostocyclins

They reduce the sensitivity to other chemical mediators

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112
Q

the process of neural excitation produces NO, how does this affect pain

A

stimulate afferents to signal more to each other and increase the pain further

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113
Q

what stimulates nociceptive modulatory pathways

A

chemical mediatory

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114
Q

what are the effects of non-steroidal anti-inflammatory drugs (NSAIDs)

A

ANALGESIC
relieves pain

ANTI-INFLAMMATORY
reduces inflammation

ANTIPYRETIC
decreases elevated body temperature

ANTIPLATELET
reduces platelet aggregation
useful in patients with blood clotting problems etc.

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115
Q

what is the mechanism of action of NSAIDs

A

inhibition of prostaglandin (eicosanoid) production by irreversibly inhibiting cyclooxygenase (COX) function- this inhibits the inflammatory response

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116
Q

what is COX1

A

enzyme expressed in most tissue (predominantly in GI tract)- produce prostaglandins that helps form the mucus layer that coats the gut

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117
Q

what is COX2

A

induced in activated inflammatory cells (throughout the body)

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118
Q

therapeutic effects relate to the inhibition of COX2, however NSAIDs often inhibit COX1 which can cause side effects such as gut bleeding, why is this

A

NSAIDs are non-specific therefore cannot be selective between COX1 and COX2

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119
Q

how does aspirin act as an analgesic and anti-inflammatory mediator

A

decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc

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120
Q

how does aspirin act as an antipyretic

A

aspirin decreases PGE2 synthesis, PGE2 raises temp

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121
Q

what is aspirin hydrolysed by and whats its half life, how is it given

A

esterases to salicylate

Half-life (4-15 hours) - dose dependent (higher dose higher effect)

orally

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122
Q

what are the unwanted effects of aspirin

A

Low doses; GI irritation, hypersensitivity

Salicylism (high doses); tinnitus, vertigo, decreased hearing

Reye’s syndrome; rare childhood disorder- inflammation of meninges in the brain.

It interacts with warfarin

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123
Q

when does aspirin interact with warfarin and why

A

during phase 1 metabolism so the aspirin can become more therapeutically active

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124
Q

how does ibuprofen act as an analgesic and anti-inflammatory mediators

A

decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc

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125
Q

how does ibuprofen act as an analgesic an antipyretic

A

in fever temp raised due to synthesis of PGE2 due to pyrogens

ibuprofen decreases PGE2 synthesis

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126
Q

what drug is usually the first choice for inflammatory joint disease and why

A

ibuprofen

effective and better tolerated than most NSAIDs

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127
Q

how is ibuprofen administered and how rapidly is it absorbed

A

oral, topical, rectal

Rapid absorption (1-2 hours)

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128
Q

what are the unwanted side effects of ibuprofen and why

A

Relatively uncommon and mild.

Local sensitivity reactions.

Less gastric irritation than aspirin

Can’t tell the difference between COX1 and 2, binds to both.

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129
Q

how is paracetamol an analgesic

A

decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g. 5-HT, kinins etc

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130
Q

is paracetamol anti-inflammatory

A

no, it will help the pain not the cause

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131
Q

how is paracetamol antipyretic

A

in fever temp raised due to synthesis of PGE2 due to pyrogens
paracetamol decreases PGE2 synthesis

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132
Q

do paracetamol have anti-platelet properties

A

no

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133
Q

why may paracetamol exhibit less analgesic activity in inflammatory conditions

A

Suggest that it selects COX3 over 2 and 1

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134
Q

how is paracetamol administered, when does it achieve its peak plasma conc and whats its half life

A

Oral, rectal, IV.

Peak plasma concentrations within 30-60 minutes.

Half-life = 2-4 hours

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135
Q

what is paracetamol mainly conjugated to

A

glucuronic acid or sulphates

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136
Q

what are the unwanted effects of paracetamol

A

Hepatotoxicity in overdose or chronic usage

Allergic skin reactions

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137
Q

what are morphine analogues

A

looks like morphine e.g.
diamorphine (heroin)
codeine

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138
Q

what are synthetic derivatives of opioids

A

pethidine

Dextropropoxyphene

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139
Q

what are opioid neurotransmitters

A

enkephalins
endorphins
dynorphins

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140
Q

what are opioid receptors

A

three types - µ, δ and κ

All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase

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141
Q

which opioid receptor i responsible for most of the analgesic effects of opioids

A

µ

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142
Q

what are the therapeutic effects of opioid analgesics

A

Analgesia

Euphoria and sedation- reducing the excitability of the nociception but also making someone feel good.

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143
Q

what is the ADME of opioid analgesics

A

oral, rectal, i.v., i.m.

erratic absorption from gut

extensive first pass metabolism- dangerous for alternate effects

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144
Q

when are opioids given and which ones

A

moderate to severe pain - strong opioids e.g. morphine, pethidine

mild to moderate pain/cough suppressive/antidiarrhoeal - weak opioids e.g. codeine

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145
Q

what are the adverse effects of opioid analgesics to the CNS

A

drowsiness and sedation

respiratory depression

tolerance and dependence

cough suppression

nausea/vomiting

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146
Q

what are the adverse effects of opioid analgesics to the PNS

A

Constipation- affect the intraneural plexus in the gut

histamine release

pinhole pupils

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147
Q

what are strong opioids and when are they given

A

morphine

  • most valuable for severe pain relief
  • terminal care

Pethidine

  • more lipid soluble than morphine
  • rapid onset/short duration
  • less constipation than morphine
  • prescribed by dentists
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148
Q

what are weak opioids and when are they given

A

dextropropoxyphene

  • very mild analgesic
  • used in combination with

dihydrocodeine

  • Pharmacologically very similar to codeine
  • Nausea and constipation limit dose and duration of use
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149
Q

what is the tolerance for opioids

A

Detected in 12-24 hours

Sensitivity will return on withdrawal

Extends to all pharmacological actions

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150
Q

what is the dependance for opioids

A

Following abrupt withdrawal after chronic treatment

Abstinence syndrome after acute treatment

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151
Q

What are anaesthetics

A

drugs which are used to PREVENT/BLOCK pain for a limited period of time for surgical or other procedures

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152
Q

what is the difference between anaesthetics and analgesics

A

anaesthetics prevent/blocks pain while analgesics CONTROL pain

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153
Q

what are the 2 broad classes of general anaesthetics

A

inhalation anaesthetics

intravenous anaesthetics

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154
Q

what are some inhalation anaesthetics

A

Halothane
Nitrous oxide
Enflurane
Isoflurane

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155
Q

what are some intravenous anaesthetics

A

Thiopental
Etomidate
Propofol

156
Q

what are the two main theories for the mechanism of general anaesthetics

A

lipid theory: meyer overton theory

ion channel theory

157
Q

what is the lipid theory: meyer overton theory

A

Strong relationship between anaesthetic potency and lipid solubility

agents interacted with lipid bilayer of plasma membrane, causing membrane expansion and consequent inability of membrane to facilitate changes in protein configuration and signalling

Lipid solubility related to anaesthetic potency

158
Q

what is the ion channel theory

A

Anaesthetics target a number of ligand gated ion channels, including, GABAA, Glycine NMDA,

Ion channels in the membrane that control the excitability of neurones

Drugs interfere with the signalling of these ion channels

159
Q

which one of the theories for anaesthetics is more valid

A

ion channel theory

160
Q

what is Correlation of anaesthetic potency and lipid solubility

A

greater the lipid solubility the greater the potency

Low alveolar concentration then its very potent

161
Q

what is the depth of anaesthesia determined by

A

concentration in the brain and spinal cord

162
Q

what is the blood/gas partition coefficient in inhalation anaesthetics

A

measure of blood solubility and determines potency

lower blood gas coefficient the faster the induction and recovery

163
Q

how is the speed of induction and recovery related to solubility in inhalation anaesthetics

A

the lower the solubility the faster the induction and recovery

e.g. Low (nitrous oxide)-rapid induction and recovery
High (halothane)- slow induction and recovery

164
Q

what is the oil:gas partition coefficient

A

measure of lipid solubility

main factor that determines potency

165
Q

what is the relationship between the oil:gas partition coefficient and potency

A

lower the oil:gas partition coefficient the lower the potency

166
Q

what are the pharmacokinetics important in inhalation anaesthetics

A

Vascularisation of tissue will determine tissue levels of anaesthetic

  • Brain good blood flow: high levels
  • Body fat has poor blood flow so anaesthetic doesn’t accumulate in body fat

Ventilation rate:
-These drugs are not metabolised to a great degree so are removed by ventilation rate.

167
Q

how are inhalation anaesthetics mainly eliminated- outline pathway

A

via lungs

enter through lungs
into arterial blood 
majority into brain and some into tissues 
small component metabolised (toxic) 
excreted 
out through lungs
168
Q

outline the Toxicity of anaesthetics that are metabolised

A

Methoxyflurane: extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion (no longer used)

Halothane 15 % (hepatotoxic)

Isoflurane 0.5 %

Desflurane 0.5 %

Sevoflurane 3 %

169
Q

what are side effects common to inhaled anaesthetics

A 
Malignant hyperthermia
Cardiovascular
Respiration
hepatic toxicity (mainly halothane)
Kidney
170
Q

what is malignant hyperthermia

A

Rare but most common with halothane and isoflurane

hypermetabolism, muscle rigidity, muscle injury and increased sympathetic nervous system activity, hyperthermia.

171
Q

what are the Cardiovascular side effects of inhaled anaesthetics

A

Can cause hypotension (except nitrous oxide)

Decreased output and decreased vascular resistance- exacerbates hypertension

172
Q

what are the side Respiration effects of inhaled anaesthetics

A

Depressed respiration (> with the fluranes, iso>des>sevo)

173
Q

what are the side hepatic effects of inhaled anaesthetics

A 
Hepatic toxicity (mainly halothane)
Anaesthetic is metabolised by liver
174
Q

what are the side renal effects of inhaled anaesthetics

A

Depressed glomerular filtration and urine output: not really a problem because of decreased cardiac output and vasodilation (and infact usually give fluids)

175
Q

what are some intravenous anaesthetics

A

THIOPENTAL SODIUM
ETOMIDATE
KETAMINE
PROPOFOL

Short onset of action (20 seconds

176
Q

where do Thiopental & Etomidate both act on

A

GABAa receptor (on a1/b3 subunit interface)

177
Q

what does etomidate do

A

causes an influx of Cl-, hyperpolarisation, and inhibition of the neurone.

178
Q

why is etomidate safer than propofol

A

wider therapeutic window between anaesthesia and respiratory depression- less risk of overdose

(etomidate TI= 26)
(Thiopental TI =2.5)

179
Q

where does propofol act

A

GABAA receptor on b3 /b3 or a1/b3 subunit interface

180
Q

how does propofol have a very rapid metabolism and why is this good

A

Extrahepatic, elimination via plasma (esterases) and lungs

Rapid recovery
No hangover
Day case surgery

181
Q

what is ketamine

A

NMDA receptor antagonist- influx and Na and Ca, depolarisation and excitation

Less hypotension than the etomidate/propofol

182
Q

why is ketamine rarely used

A

Hallucinations, psychosis

183
Q

what is the difference between local anaesthetic and general

A

prevent localised pain or nociception and also prevent tactile sensation

General anaesthetics also induce loss of consciousness

184
Q

what do local anaesthetics do

A

block electrical signalling in neurones by blocking voltage gated Na+ channels

185
Q

what are the types of neuronal signalling

A

Electrical signalling - the action potential

Chemical signalling – neurotransmission

186
Q

what occurs during an action potential

A

Na+ goes into the cell (concn gradient) via voltage gate Na channels

Membrane potential rises and polarity changes

Na channels close and Na+/K+ATPase moves Na+ out

K+ pours out of the cell (concn gradient) via voltage gate K channels

Membrane potential falls again

187
Q

what subunits is Voltage Gated Ion Channels made up of

A

three subunits a, b1 and b2.

188
Q

what does the alpha subunit of voltage gated ion channel contain

A

single polypeptide. It contains extracellular domains, 4 transmembrane domains each comprising 6 a-helical regions

The α subunit contains, in the hydrophobic domains, voltage sensors that change their orientation when voltage varies

189
Q

what are the beta subunits liked to the alpha subunits of voltage gated ion channel contain

A

b subunits flank the a-subunit.

The b2-subunit is linked covalently to the a-subunit, the b1-subunit is not linked.

The two b-units anchor the a-subunit into the lipid membrane.

190
Q

what is the effect of local anaesthetics on voltage gated ion channels

A

Local anaesthetics are thought to interact with the a- subunit and physically ‘plug’ the transmembrane pore

Local anaesthetics binds in the ionised (hydrophilic) form – binding area is on the intracellular side of the channel

191
Q

whats are the chemical/structural aspects of local anaesthetics

A

Unionised form gains access through nerve sheath and axon membrane

Ionised form binds in channel

Most anaesthetics are weak bases- the pH outside (pH7.4) of the cell is higher than inside the cell (pH7)

192
Q

what is the general chemical structure of local anaesthetics

A

molecules consists of aromatic group , ester or amide group and amine group

basic side chain ensuring that the molecules are ionised at physiological pH

193
Q

what does the aromatic domain of local anaesthetics ensure

A

lipid solubility

194
Q

why is the duration of action of local anaesthetics limited

A

by the hydrolysis of the ester/amide bond and by the lipid solubility of the agent.

195
Q

what is the difference between esters and amides

A

Esters are metabolised in plasma by esterases (except cocaine) Shorter T1/2

Amides metabolised in liver by CYP3A4,1A2 longer T1/2

196
Q

how does local anaesthetic get into the cell

A

anaesthetic, a weak base, is injected as hydrochloride salt in an acid solution (i.e. dissolves in solution).

pH increases due to the higher pH of the tissues and free base released

Lipid soluble free base enters the axon. Inside the axon the pH is lower (the environment is more acidic, pH7), and re-ionization takes place.

The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization

197
Q

How can we manipulate local anaesthesics

A

Restrict site of action and prolong durations of action

Accelerate the speed of onset of the anaesthetic (Use slightly alkaline solution)

198
Q

Do all nerves show similar susceptibility to local anaesthetics?

A

Different types of axons show different sensitivity to local anaesthetics

199
Q

when is block conduction more effective for local anaesthetics

A

Block conduction in small diameter fibres more effectively than in large diameter fibres

200
Q

how does myelination impact the nerves susceptibility to local anaesthetics

A

small myelinated axons* > non-myelinated axons > large myelinated axons

*Nosciceptive (pain) fibres are small diameter and particularly sensitive

201
Q

are Motor axons more or less sensitive to local anaesthetics?

A

Motor axons have a large diameter and are less sensitive

202
Q

what is use dependant block

A

the depth of block increases with an increase in action potential frequency

203
Q

why does use dependant block occur

A

because the anaesthetic gains access to, and has higher affinity for the channels more readily when it is open and/or inactive

204
Q

what are Unwanted side effects of local anaesthetics

A

CNS, confusion and agitation

Cardiovascular, hypotension
–Inhibition of sympathetic activity
–Inhibition of sodium conductance in cardiac tissue

205
Q

why are anaesthetic not very effective in infected or inflamed tissue

A

Infective tissue is more acidic outside the neurones. Anaesthetic cannot cross the membrane and get into the neurone

206
Q

what does chemotherapy eliminate

A

invading cells/microorganisms/organisms

207
Q

what are the properties of effective chemotherapeutic agents

A

toxic to invading species/abnormal cell

relatively non-toxic to the host/normal cells

208
Q

what is selective toxicity

A

refers to the exploitable differences between invading species and host which depend upon evolutionary distance, the extent of these differences has implications for toxicity

209
Q

Why do dentists need to know about selective toxicity?

A

Chemotherapeutic agents form a major group of drugs in the Dental Practitioners’ Formulary i.e. dentists use them a lot!

Forms part of clinical due care and responsible prescribing

210
Q

what can Invading cells/microorganisms/organisms include

A

neoplastic cells

bacteria
•e.g. Streptococcus species

viruses
•e.g. herpes viruses

fungi
•e.g. candida albicans

parasites
e.g. protozoa, helminths

211
Q

how are bacterial infections managed

A

Treatment of infections

General prophylaxis- prevent infection following surgery in susceptible individuals
Broad spectrum antibiotics can be given in the prophylactic matter

212
Q

what are the modes of action of antibacterial drugs

A

Inhibition of cell wall synthesis
•e.g. β-lactam antibiotics (penicillins)

Inhibition of protein synthesis
•e.g. macrolides (erythromycin), tetracycline

Inhibition of bacterial nucleic acids
•e.g. quinolones

Inhibits bacterial DNA synthesis/degrades DNA
•e.g. metronidazole

213
Q

what do β-lactam antibiotics do

A

prevent the cross-linking peptides from binding to the tetrapeptide side chains

they inhibit transpeptidases- which the enzyme which catalyses cross-linking

214
Q

what are ex of β-lactam antibiotics

A

Penicillins, cephalosporins

215
Q

what do Macrolide Antibiotics do

A

Inhibit ribosomal function- which help tRNA make new amino acid chain

Bacterial ribosomes differ structurally from mammalian ribosomes

216
Q

what are ex of Macrolide antibiotics and how do they inhibit ribosomal function

A

Tetracycline - interacts with protein synthetic pathway at the level of elongation – stops tRNA from binding to the 30 S ribosomal unit

Erythromycin- tops translocation- works at the large subunit to stop formation of peptide chain

217
Q

what do Fluoroquinolones do

A

Inhibit DNA replication or nucleic acid synthesis

Inhibit topoisomerase II (bacterial specific DNA gyrase) preventing normal DNA supercoiling process

218
Q

what are other ways to target bacterial nucleic acid synthesis

A

Inhibit the synthesis of the nucleotides

Altering the base pairing properties of the DNA template

Inhibiting either DNA or RNA polymerase

Directly inhibiting DNA itself

219
Q

what are Antifolates

A

Class of drugs not commonly prescribed in terms of antibiotic function due to side effects
• e.g. sulfonamides, trimethoprim

220
Q

how do antifolates work

A

Different mechanism of action- Targeted inhibition of the bacterial specific folate synthetic pathway.

221
Q

what steps do antimicrobials inhibit in folate biosynthesis, and what are the names of the enzymes that do this

A

dihydropteroate synthetase prevents the conversion of pABA to Folate

dihydrofolate reductase prevents the conversion of folate to tetrahydrofolate

222
Q

what forms does herpes virus exist in

A

Simplex = cold sores

Varicella zoster = chicken pox

Epstein Barr (EBV) = glandular fever

223
Q

what are the symptoms of herpes virus

A

‘flu-like’ symptoms (fever, headache, aches and pains)

blister/ulcer stage.

224
Q

how does the herpes virus occur

A

its due to external stimuli that reactivate the dormant virus, for example it is usually dormant in sensory ganglia in particular on the front of the face, so stimulation of ganglia can cause cold sores in that area

225
Q

how does Aciclovir work to treat herpes and what are the benefits of it

A

it is a synthetic guanosine analogue- nucleotide based sequence with similar structural shape to nucleotides of herpes

Only toxic to an infected the cell
high therapeutic index

226
Q

which herpes virus is Aciclovir specific to

A

simplex

Varicella-zoster:- less susceptible

Cytomegalovirus (CMV):- small and reproducible

EBV:- slightly sensitive

227
Q

aciclovir requires intracellular phosphorylation- metabolic activation, how does it achieve this?

A

Utilises simplex virus specifically, thymidine kinase will phosphorylate the acicolvior into monophosphate form and then into di and tri form.

The triphosphate forms is therapeutically active- Antiviral action

228
Q

outline the Antiviral action of Aciclovir

A

Aciclovir-TP -a DNA chain terminator

Inhibitor of viral DNA polymerase

Host significantly less susceptible

229
Q

what are the superficial (common) fungal infections in dentistry

A

Candidiasis (oral cavity, tongue)

Dermatomycoses (mouth)

230
Q

what are the systemic (rare) fungal infections in dentistry

A

Systemic candiasis

231
Q

why has there been an increase in fungal infections in the last 20-30 years

A

widespread use of antibiotics and increase in immunocompromised individuals (immunospression in cancer treatment, transplant medicine, AIDS)

232
Q

what do fungal cell membranes contain

A

sterol ergosterol

main sterol in mammalian cell membranes is cholesterol

233
Q

what are the 3 key drug classes form antifungal agents

A
  1. Azoles - imidazoles and triazoles
  2. Polyenes- nyastin
  3. Mitotic inhibitors- griseofulvin
234
Q

which drug classes are ergosterol inhibitors

A

azoles and polyenes

235
Q

which drug classes are intracellular inhibitors

A

mitotic inhibitors

236
Q

how do azoles work

A

Inhibit how ergestrol is made in the fungal cell
Affect membrane lipid synthesis

2 types
Imidazoles
Triazoles

237
Q

how do polyenes work

A

Break apart the ergesterol
Form pores in membrane

Nystatin

238
Q

how do mitotic inhibitors work

A

Interferes with fungal cytoskeleton

Griseofulvin- inhibits mitosis of fungal cells

239
Q

how do azoles inhibit the biosynthesis of ergosterol and what does this lead to

A

Block 14-α demethylase cytochrome P450- mediated step in the biosynthesis of it. lack of rigidity and shape in fungal membrane

this causes increased cell wall permeability and inhibition of replication

240
Q

when are azoles effective

A

in treatment of dermatomycoses, candidiasis and some systemic infections

241
Q

what are the subclasses if azoles and what are ex of teh drugs given for eacg each, which one contains nitrogen

A

Imidazoles- does not contains nitrogen
- ketoconazole, miconazole, clotrimazole.

Triazoles- contains nitrogen
- fluconazole.

242
Q

what does ketoconazole do, what are its drawbacks

A

given orally

Causes inhibition of reactions catalysed by cytochrome P450 involved in both steroid biosynthesis and drug metabolism

Has several drug interactions as it can inhibit the metabolism of other drugs- side effects
may cause hepatotoxicity

243
Q

what does Miconazole do and how is it administered

A

Used topically, orally (for oral and intestinal infections) or intravenously (i.v.).

Less toxic than ketoconazole but may also inhibit drug metabolism

Other topical agents include clotrimazole.

244
Q

what does fluconazole do and how is it administered

A

Can be given orally (i.v.)

Relatively non-toxic

Unlike imidazoles does not undergo metabolism and has long half-life (22h)

Not as many drug-drug interactions

Less inhibition of P450 but some drug interactions may occur

245
Q

what do polyenes do and how are they administered

A

Bind to sterols in membrane forming an ion channel.

Binds to ergosterol creating a pore, loss of structural rigidity.
Can be given i.v. as detergent or lipid complex.

246
Q

why are poles effective in fungal cell walls over mammalian cell walls

A

Higher affinity for binding to ergosterol compared with cholesterol.

247
Q

how does griseofulvin work, when and how is it given

A

mitotic inhibitor

Inhibits cell division by interfering with spindle formation

Used orally in treatment of dermatomycoses (hair and nails).

Appears to be taken up selectively by cells which synthesise keratin

248
Q

what are the effects of Anxiolytic-Sedative-Hypnotic Drugs

A

alleviate fear and anxiety
produce a degree of amnesia and analgesia
induce sleep (Hypnotics)

249
Q

Why do dentists need to know about anxiolytic-sedative-hypnotic drugs?

A

administered to patients who are unable to handle the emotional stress caused by a visit to the dentist i.e. they experience severe anxiety

250
Q

what is anxiety and what are the symptoms a patient may present

A

feelings of uneasiness, apprehension and tension

palpitations, headache, dizziness, flushing, sweating, tense muscles

some phobic states/panic attacks are not subjective

251
Q

what does the GDC say about conscious sedation

A

can be an effective method of facilitating dental treatment…’

‘…produces a state of depression of the CNS…’

‘…verbal contact with the patient is maintained…’

‘…patient remains conscious, retains protective reflexes and is able to understand and respond to verbal commands…’

‘…deep sedation…must be regarded as general anaesthesia’

252
Q

what are the types of sedation method in dentistry

A

Inhalation- nitrous oxide
Oral- benzodiazepines and H1 antagonists
Intravenous- Benzodiazepines

253
Q

what is nitrous oxide

A

Light and rapid anaesthesia

50% NO in oxygen (Entonox)

Recovery in ~ 4 mins

Mild nausea and vomiting

254
Q

what are the dose dependent effects of sedatives

A

relief of anxiety
sedation
hypnosis
general anaesthesia

255
Q

what are barbiturates and what effect do they have on ion channels

A

Positive allosteric modulator of GABAa receptors

they change how long the Cl- channel is open

256
Q

what do Barbiturates do

A

Increase effects of GABA, and inhibit glutamate neurotransmission
They have a separate binding site on the GABA receptor (unlike benzodiazepine)

257
Q

why is the clinical use of Barbiturates limited

A

increased toxicity in overdose- Severe CNS depression, comas, death

this is due to their direct effect on the opening of ion channels,

258
Q

why do benzodiazepines have less potential to completely suppress the CNS

A

they only work at the frequency of the opening/closing of the Cl- channels, which makes them safer

259
Q

what are the anxiety disorders which benzodiazepines are used to treat

A

Panic disorder- discrete periods of intense fear

Generalised Anxiety Disorder- chronic worry

Simple Phobia- fear of object or situation

260
Q

what is the chemical structure of benzodiazepines

A

Benzos are a 7-membered ring fused to an aromatic ring with 4 main substituent groups which can be modified.

261
Q

what is the pharmacological effects of benzodiazepines

A

Reduction of anxiety and aggression

Sedation and induction of sleep

Muscle relaxation

Anticonvulsant effects

Amnesia

262
Q

how do benzodiazepines cause a reduction of anxiety and aggression

A

Less aggression due to the reduction in CNS function

263
Q

how do benzodiazepines cause sedation and induce sleep

A

Decrease time taken to get to sleep

Increase total duration of sleep

Decrease REM sleep (dreaming)

Decrease SW sleep (deep sleep)

264
Q

how do benzodiazepines cause muscle relaxation

A

Increased muscle tone in a common feature of anxiety

May result in aches and pains e.g. headache

Relaxant effect clinically useful

Anticonvulsant effects

265
Q

what is the mode of action of benzodiazepines

A

they bind to a specific regulatory site on the GABAA receptor

BDZ binding enhances neuronal inhibitory effect of GABA

GABA and BDZ bind to independent sites of the same receptor-Cl-ion channel complex

BDZ do not open the Cl- ion channel by themselves, they increase the affinity of the receptor for GABA

Benzodiazepines change frequency of Cl- channel opening

266
Q

what are the pharmacokinetics of benzodiazepines

A

Well absorbed when given orally

Bind strongly to plasma proteins

High lipid solubility leads to accumulation in body fat- patients will describe a ‘hangover’

Short Acting
Long Acting

267
Q

what are short acting benzodiazepines, how are they metabolised

A

Metabolised to inactive compounds straight away

Short half life e.g. temazepam

Arguably better for minor issues e.g. so no hangover issues

268
Q

what are long acting benzodiazepines, how are they metabolised

A

Metabolised to pharmacologically active metabolites with long half-lives

Diazapam is metabolised to nordiazepam which has a half life of ~60h

269
Q

what are the unwanted effects of benzodiazepines

A

Interaction with alcohol- increases the CNS depression

hangover effects’ e.g. drowsiness, confusion

Development of dependence (not the same as addiction)

Sexual fantasies

Amnesia- effects memory recall

270
Q

how are benzodiazepines used in dentistry

A

Sedation as adjunct to local anaesthesia (amnesia)

Pre-anaesthetic medication (anxiolytic effects)

271
Q

what is propranolol

A

β-adrenoceptor antagonists –

272
Q

how does propranolol work

A

Anxiolytic but not sedative
-Reduce physical symptoms (tremor, palpitations etc) of anxiety

Inhibition of somatic or autonomic responses
-Decreased noradrenergic transmission

273
Q

what are the Unwanted side effects of propranolol

A

Cardiac depression, bradycardia

Non-selective β-adrenoceptor inhibition (β1/ β 2)

274
Q

what buspirone

A

5-HT1A agonist

275
Q

how does buspirone work

A

Anxiolytic but not sedative
-Partial agonist of inhibitory autoreceptors (5-HT1A)

Long anxiolytic development time
-> 2 Weeks

Fewer withdrawal effects
-Generally mild nausea or dizziness

276
Q

what are the monoamine neurotransmitters and what do they treat

A

5-Hydoxytryptamine (5-HT, serotonin)
-Depression, anxiety

Dopamine (DA)
-Schizophrenia

Noradrenaline (NA)
-Depression, anxiety

277
Q

what is involved in 5-HT biosynthesis & neurotransmission

A

Tryptophan gets taken up into the neurone and its converted to 5-HTP

Needs to be stored in vesicles

15/16 types of receptor subtypes

Like NA a specific transporter takes the neurotransmitter back up into the neurone

278
Q

what is involved in DA biosynthesis and neurotransmission

A

Similar to NA biosynthesis

In dopamine no extra enzyme in the vesicle

Released into the synapse and acts on receptors

Taken back up and recycled

279
Q

why is DA targeted in schizophrenia

A

Dopamine theory of schizophrenia states that schizophrenia is associated with increased DA function

280
Q

what are the Three main dopamine pathways in the brain

A

Nigrostriatal pathway
mesolimbic pathway
tuberoinfundibular pathway

281
Q

what is involved in the Nigrostriatal pathway

A

projects from the substantia nigra into the dorsal striatum

this mediates fine movement.

This is dysfunctional in Parkinson’s disease.

282
Q

what is involved in the mesocortical/mesolimbic pathway

A

dopamine from ventral tegmental area to frontal cortex/ventral striatum

Dopamine associated with mood and cognition.
Reward/addiction (ventral striatum)

In schizophrenia this is thought to be the pathway overactive

283
Q

what is involved in the tuberoinfundibular pathway

A

Dopamine from hypothalamus feeds onto the pituitary stalk

controls endocrine function- tonic inhibition of prolactin secretion.

284
Q

what is the Role of dopamine in regulation of prolactin secretion

A

the secretion of prolactin is inhibited due a prolactin releasing inhibiting factor (PRIF)

285
Q

what is the link between DA receptor antagonists and schizophrenia

A

Dopamine theory of schizophrenia states that schizophrenia is associated with increased DA function

Use D2 receptor antagonists to counteract this increase in DA function

D2 antagonists are effective antipsychotics

286
Q

what is the Dopamine theory of schizophrenia

A

Drugs with a high affinity for the receptor are required at a low dosage

D2 receptor antagonism underlies pharmacological mechanism

287
Q

what can happen when D2 receptors are blocked

A

we block D2 in the extrapyramidal area which can induce Parkinson’s.

288
Q

what are the symptoms of Parkinson’s syndrome

A

Tremor
Muscle rigidity
Loss of facial expression

289
Q

what are the symptoms of • Tardive dyskinesia

A

Repetitive rhythmical involuntary movements,

lip smacking, chewing,
rocking, rotation of the ankles or legs,
marching in place, and
repetitive sounds such as humming or grunting

290
Q

what are the extrapyramidal side effects (EPS) of D2 antagonism in the nigrostriatal DA pathway

A

Parkinson’s syndrome

Tardive dyskinesia-video

291
Q

what are the side effects of D2 antagonism in the tuberoinfundibular DA pathway

A

hyperprolactinaemia

  • Galactorrhoea,
  • Gynaecomastea

this is due to primary pharmacology of the drug

292
Q

what receptors do Antipsychotics also have affinity for, and what is this associated with

A

Histamine receptors

  • H1 mediated
  • Sedation, weight gain

Muscarinic

  • M1 mediated
  • Dry mouth, blurred vision, constipation, urinary retention

Adrenergic

  • α1 mediated
  • Postural hypotension

Side effects associated with the secondary pharmacology of the drug

293
Q

what is the Antipsychotic Classification of the drugs based on their side effects for Phenothiazines (outline their side effects)

A

Group I
- Sedation (affinity for H1)

Group II
- Anticholinergic (affinity for M1)

Group III
-EPS (predomantly D2)

294
Q

what phenothiazine drugs are group I, II and III

A

Chlorpromazine (group I)

Thioridazine (group II)

Fluphenazine (50X more potent)
(group III)

295
Q

what are Thioxanthenes

A

Flupenthixol

Similar profile to phenothiazines

296
Q

what are Butyrophenones

A

Haloperidol

Selective to D2

Lack muscarinic and antihistamine activity (no sedation) but EPS a problem

297
Q

what are Limitations Of Classical Antipsychotics

A

Approximately one-third of patients with schizophrenia fail to respond

Limited efficacy against negative symptoms

High proportion of patients relapse

Side effects and compliance issues

298
Q

what are the +ve symptoms of Schizophrenia

A

Disorders of thought/disorganised behavior

Hallucinations (aural and visual)

Paranoia

299
Q

what are the -ve symptoms of Schizophrenia

A

Blunted emotions/anhedonia

Social withdrawal

Apathy/loss of energy

300
Q

what are atypical antipsychotics

A

Clozapine, Olanzapine, risperidone, amisulpiride, quetiapine

301
Q

what are the benefits of atypical antipyschotics

A

Better EPS side effect profile (without loss of antipsychotic efficacy)

Better at treating negative symptoms

  • Lower affinity for D2 receptor!
  • High affinity for D3, D4 receptors (D2 family) and 5 HT2A receptor
302
Q

what are the what are the drawbacks of atypical antipyschotics

A

High incidence of metabolic syndrome, weight gain, become diabetic (Risperidone, olanzapine)

clozapine associated with agranulocytosis

303
Q

what is the Hypothesis for mechanism of action atypical antipsychotics

A

Atypicals do have affinity for D2 receptor, however they have a much faster dissociation rate from the D2 receptor (Koff) (loose binding)

These drugs can be displaced by physiological phasic bursts of DA transmission (important in DA striatal pathways)

Results in less distortion of physiological DA signalling in striatal pathways

Cannot exclude the role of 5-HT2

304
Q

what is the Distinction between typical and atypical based antipsychotics based on

A

Incidence of extrapyramidal side effects

Efficacy in treating treatment resistant patients

Efficacy against negative symptoms

305
Q

what are some Antidepressant drugs

A

Tricyclic antidepressants (TCA’s)

Selective serotonin reuptake inhibitor (SSRI’s)

Monoamine oxidase inhibitors

306
Q

what are Tricyclic antidepressants (TCAs)

A

First developed antidepressant
Tricyclic structure
Inhibit reuptake of 5-HD and noradrenaline

e.g. amitriptyline, imipramine, lofepramine

307
Q

what are the consequences of Tricyclic antidepressants (TCAs) and what effect on which receptors is this due to

A

Block M1 receptors
- Dry mouth, blurred vision, constipation, urinary retention

Block H1 receptors
-Sedation, weight gain

Block α1 receptors
-Postural hypotension

308
Q

when is TCA not used

A

Elderly

Cardiac patients (increase chance of conduction abnormalities)

Hepatic insufficiency

Suicidal patients (overdose)

Drivers (sedation)

Workers (sedation)

309
Q

when is TCA useful

A

Severe treatment resistant depression

Where sedation is also required

Where disease history indicates efficacy and tolerance

and TCA are cheap!

310
Q

what are the 2nd generation antidepressants and what is their pharmacology

A

SSRI: selective serotonin reuptake inhibitor

SNRI: serotonin/ noradrenaline reuptake inhibitor (venlafaxine)

NARI noradrenaline reuptake inhibitor (reboxitine)

311
Q

what are the 2nd generation antidepressants selective for

A

5-HT or NA transporter and do not have affinity for postsynaptic receptors (fewer side effects)

The target the transporter but they do not have affinity for post synaptic receptors so don’t exhibit the same side effects as above

312
Q

what are the side effects of SSRIs

A
  • Sexual dysfunction (impotence)
  • Gastrointestinal
  • Precipitate anxiety
  • Do not cause sedation or anticholinergic side effects
313
Q

what are other uses of SSRIs

A

panic disorder,
obsessive compulsive disorder,
eating disorders

314
Q

SSRIs have a better adverse side effect profile than TCAs, why is this important

A

important for the a lag time for the onset of therapeutic effects

315
Q

what are the 2 isoforms of Monoamine oxidase inhibitors (MAOIs)

A

MAOA breaks down 5-HT, NA, ( and a bit of DA)

MAOB breaks down DA

316
Q

what did old MAOIs do

A

blocked both isoforms irreversibly

Stimulant effects,
Dangerous in overdose

317
Q

what do new MAOIs do

A

selective for MAOA, reversible (reversible inhibitors of monoamine oxidase A (RIMA) (e.g. moclobemide)

Less stimulant and safer

318
Q

what are the interactions of MAOI

A

MAOI & cheese effect - - hypertensive crisis, resulting from and excess of dietary tyramine

MAOI & SSRIs

  • Serotonin syndrome,
  • hyperthermia, confusion hypertensive crisis

Releasing agents e.g (MDMA) and MAOI
- Serotonin syndrome

Antiparkinson drugs
-Severe hypertension

319
Q

what is a hormone

A

A chemical substance synthesised by specific tissues and secreted into the blood stream, whereby it is carried to non-adjacent sites in the body and exerts its actions.

320
Q

what is a neurotransmitter

A

A chemical substance synthesised by neurone and secreted directly onto adjacent neurones or tissue, whereby it exerts its actions. Do not circulate the blood stream

321
Q

how is the endocrine system organised

A

Endocrine glands/cells secrete the hormones into the blood stream

All tissues are exposed to the hormones and it circulated through the body but they will only respond if they have the receptors

322
Q

how is cortisol synthesised

A

hypothalamic nuclei releases CRH which acts on the anterior pituitary. this causes it to secrete ATCH which acts on the adrenal cortex to synthesise cortisol

323
Q

how is the cascade for the synthesis of cortisol turned off

A

strong negative feedback system

324
Q

what is the function of cortisol

A

increase and maintain then normal glucose levels in the blood

increase gluconeogenesis

decrease glucose uptake in to muscle and adipose tissue

decrease in protein synthesis (amino acids are free for gluconeogenesis)

325
Q

how is blood glucose regulated by insulin

A

insulin secreted by the pancreas acts on insulin receptors in liver in muscles

insulin involved in the uptake and storage of glucose

326
Q

outline how cortisol regulates metabolism

A

increase and maintain normal glucose in blood

increase gluconeogenesis

decrease in protein synthesis

role in regulating brain function

immune response/inflammation

327
Q

what are disorders of cortisol

A

cushings syndrome- cortisol hypersecretion (excess cortisol secretion)

328
Q

what are the causes of cushings syndrome

A

adrenal or pituitary tumour

side effect of chronic glucocorticoid therapy

329
Q

how is cushings syndrome treated

A

removal of tumour

inhibition of cortisol synthesis by metyrapone

330
Q

what does the treatment of cushings with metyrapone involve

A

11ß-hydroxylating enzyme can be blocked by metyrapone so decreasing the amount of cortisol available for secretion

331
Q

at high levels what can cortisol (cortisol-like compounds) do

A

can inhibit inflammation and the immune response

332
Q

what is the process by which extracellular insulin is released from the B cells of the islets of langerhans

A

glucose is taken up by a glucose transporter into the cell and glycolysis occurs

this causes an increase in ATP, ATP blocks the K+ channels causing depolarisation

ca2+ channels open causing the release of insulin

333
Q

what is involved in diabetes mellitus

A

insulin hyposecretion

insulin receptor hyposensitivity

334
Q

what is involved in type 1 diabetes

A

Insulin hyposecretion due to a loss of -cell

Substitute with insulin

Background intermediate acting (e.g isophane insulin)

+ short term fast acting (soluble insulin) before meal

335
Q

what is short acting insulin

A

soluble insulin

sc (routine) & iv administration (emergency)

rapid onset and short duration (important in emergencies)

336
Q

what is intermediate acting insulin

A

insulin complexed with zinc salts or protamine as particles

insulin slowly released from particles

337
Q

what is long acting insulin

A

insulin complexed with zinc salts as crystals (large particle size)

insulin even more slowly released

Insulin glargine/detemir
o Soluble insulin but released slowly & evenly due to precipitation in tissues

338
Q

what is type II diabetes

A
  • Metabolic demands of obesity
  • Desensitization of insulin receptors
  • Pancreatic insufficiency- some functioning beta cells

Attempt to increase the insulin secretion from the beta cell that are there

339
Q

what do sulphonylureas do and what are they used to treat

A

type II diabetes
block the KATP channels so cause depolarisation and increase insulin secretion independently of glucose levels (need partially functioning Beta cells).

340
Q

Oral contraceptives and regulation of the Hypothalamic-pituitary-ovarian axis

A

hypothalamus releases GRH which acts on the pituitary. this releases FSH and LH the ovaries which causes ovulation

341
Q

what are the Physiological effects of estrogen on endometrium

A

sensitises LH releasing cells in pituitary

proliferation of endometrium- preps the development of the uterus

Inhibits FSH so regulates cycle- don’t want to have high FSH

342
Q

what are the Physiological effects of Progestrone on endometrium

A

renders the endometrium suitable for implanting of a fertilized ovum-

Inhibits further release of GRH, FSH, and LH so regulates cycle and ovulation

343
Q

what are the options after ovulation takes place

A

Fertilization

No fertilisation

344
Q

what occurs if no fertilisation takes place

A

corpus luteum regresses, progestrone levels drop.

  • endometrium can not be maintained, menstruation occurs
  • Lack of progestrone also means the clamp on GRH, FSH and LH secretion is released. These hormones are secreted again-cycle starts again, follicle develop
  • Hormones secreted and the cycle starts again
345
Q

what occurs if you lose progesterone

A

you lose your releasing factors

346
Q

If fertilized ovum is implanted

A

ovum secretes human chorionic gonadotrophin, this stimulates corpus luteum to continue secreting progestrone:

  • maintains endometrium and pregnancy
  • Inhibits further secretion of GRH, FSH, and LH, this prevents further follicles developing
347
Q

what is the function of Hypothalamic-pituitary-ovarian axis

A

Maintains endometrium and pregnancy

-ve feedback

348
Q

what do Oral contraceptives target

A

the negative feedback system clamping secretion of GRH FH and LH

349
Q

what do sex hormones in contraception do

A

Oral contraceptives mimic the negative feedback and turn off the releasing factors

They mimic the pregnancy state

350
Q

what do oral contraceptives do

A

Oral contraceptives mimic the negative feedback and turn off the releasing factors
They mimic the pregnancy state

351
Q

what are the 2 main types of oral contraceptives

A

Combined oestrogen and progestrone (combined pill)

Progestrone alone (progestrone only pill/minipill)

352
Q

how does the combined pill work

A

Estrogen inhibits secretion of FSH via –ve feedback, this prevent development of ovarian follicle

Progestrone inhibits secretion of LH, (-ve feedback) prevents ovulation and also makes the cervical mucus less suitable for passage of sperm

Taken for 21 days then a 7 pill free period causes withdrawal bleeding (false period- no ovulation has taken place)

353
Q

how does the progesterone only pill

A

Mainly effective due to effect on cervical mucus.

Does not actually blocked ovulation

Taken continuously, can cause irregular periods

Less reliable than combined pill- ovulation does take place

354
Q

what are drug interactions with contraceptives

A 
Broad spectrum antibiotic (e.g. amoxicillin)
Enzyme inducers (e.g Barbiturates, phenytoin, rifampicin)
355
Q

what is involved Contraception Metabolism

A

Fraction (variable) of exogenous hormone is conjugated in the liver (glucuronidation), and excreted in bile into duodenum

Gut flora with glucuronidase activity cleave the conjugate allowing reabsorption of active hormone. (may represent significant reservoir)

Broad spectrum antibiotic (e.g. amoxicillin), kill gut flora and so remove this reservoir

356
Q

what do exogenous estrogen and progestrone do

A

target negative feedback and inhibit ovulation

357
Q

why do dentists need to know about drugs and blood clotting?

A

Thrombo-embolic diseases are a major cause of death in developed countries

The drugs used affect blood clotting either by modification of blood coagulation or platelet adhesion and activation

Haemorrhage and bleeding of the GIT, mucus membranes, gingiva and urinary tract are common side effects

Since patients taking anticoagulants are on the edge of a haemorrhagic state, appropriate precautions must be taken for dental surgical procedures to be performed safely

358
Q

what is haemostasis

A

the spontaneous arrest of blood loss from damaged blood vessels- essential to life

359
Q

what are the main phenomena involved in haemostasis

A

Vasoconstriction

platelet adhesion and aggregation (eicosanoids)

fibrin formation (coagulation system versus fibrinolytic system)

360
Q

what is a thrombosis

A

the unwanted formation of a haemostatic plug or thrombus within a blood vessel or the heart. This is different from a clot

361
Q

how might a thrombosis occur

A

vascular disease e.g.atherosclerosis

prosthetic heart valves

atrial fibrillation

362
Q

what are the consequences of thrombosis

A

deep vein thrombosis
pulmonary embolism
myocardial infarction

363
Q

what is the difference between a blood clot and a thrombus

A

blood clots have not structure to them whereas thrombus’ have a distinct structure (white head and red tail)

blood clot forms in vitro and thrombus forms in vivo

thrombus’ can be arterial or venous

364
Q

what is the difference between a arterial and venous thrombus

A

arterial- atherosclerotic, large head (platelets)

venous- normal, large tail-small head, gives rise to emboli

365
Q

what are the processes that occur in blood clotting

A

complex series of enzymatic activations
produces active clotting factors from precursors
cascade mechanism which results in fibrin production
controlled by enzyme inhibitors and fibrinolysis

366
Q

what are the main anticoagulants

A

heparin and oral coagulants e.g. warfarin

367
Q

what is involved in the blood clotting cascade

A

blood clots in 4-8 mins

extrinsic and intrinsic pathway

Factor III, VII will stimulate the clotting process

Thrombin- factor 2 converts fibrinogen to fibrin. This can also co-recruit factor 13 which helps to stabilise the clot

368
Q

what is heparin

A

sulphated mucopolysaccharide
found in secretory cells
can be low molecular weight heparins (LMWH)

369
Q

outline the pharmacodynamics of heparin , what does it require for activity

A

heparin can bind to thrombin and antithrombin to inactivate thrombin

requires antithrombin III (a2 globulin) for activity

370
Q

what does antithrombin III do

A

it stops the conversion of a soluble clot into an insoluble clot through the inactivation of:
thrombin, IX, X, XI and XII

371
Q

why do LMWH’s have more consistent activity

A

Only bind to antithrombin not the other precursors

372
Q

outline the pharmacokinetics of heparin

A

inactive orally
administered IV or SC (LMWHs)
short half life <1h (low dose) and 2h (higher dose)
eliminated by renal excretion
side effects include hypersensitivity and bleeding

373
Q

outline the pharmacodynamics of warfarin

A

inhibits hepatic synthesis of vit K1 dependant clotting factors II, VII, IX, X

1-2 days before patient can stop clotting process

genetically determined resistance, reduced binding to vitamin K reductases

side effects - bleeding, skin necrosis

374
Q

how is an overdose of heparin treated

A

overdose treated by IV protamine (binds to heparin and stops it from having a further effect)

375
Q

how is an overdose of warfarin treated

A

vitamin K1 (iv or oral), fresh frozen plasma (thawed!)

376
Q

outline the pharmacokinetics of warfarin

A

Dose - highly variable (1-20 mg/day)

Absorption - rapid, almost total

Plasma protein binding - ~99%

Metabolism - oxidation and reduction just as the vitK can
-Warfarin and vitK looks chemically similar- has the ability to act with reductase enzyme

Excretion - urinary metabolites

Half-life - 15-80h

Warfarin will stay in the body for a longer period of time over heparin

377
Q

how is the effect of heparin monitored

A

partial thromboplastin time (PTT)

378
Q

how is the effect of oral anticoagulants measured (warfarin measured)

A

prothrombin test (expressed as INR)

379
Q

how is anticoagulant therapy monitored

A

Fasting blood taken to establish PT ratios

Issue with thrombosplastin variability required standardisation

Assigned international sensitivity index (ISI)

Patients PT is expressed as an INR (International Normalised Ratio).
-Compare to international standard

Typical Warfarin INR values range 2-4.

380
Q

what are New/Direct oral anticoagulants – N/DOAC’s

A

New drugs that have come out

Still interact with the clotting cascade however target it without antithrombin

(Heparin binds to antithrombin III and turns off thrombin)

381
Q

how do some drugs (name them) potentate THE EFFECT OF ORAL ANTICOAGULANTS

A

drugs which decrease platelet aggregation e.g. aspirin

drugs which inhibit cytochrome P450 e.g. co-trimoxazole

drugs which inhibit the reduction of vitamin K e.g. cephalosporin antibiotics. Clotting cascade dependant on vitK. Aspirins, NSAID, metronidazole etc have a known ability to interfere with vitK

382
Q

how do some drugs (name them) decrease THE EFFECT OF ORAL ANTICOAGULANTS

A

drugs which induce cytochromes P450 e.g. rifampicin, many anticonvulsants

drugs which reduce absorption e.g. sucralfate

383
Q

what does aspirin do

A

Inhibits eicosanoid production to inhibit platelet aggregation

  • platelet-derived TXA2 promotes aggregation
  • endothelium-derived PGI2 inhibits aggregation

aspirin irreversibly inhibits COX enzyme-mediated synthesis of both

endothelium can synthesise new COX, platelets cannot

net effect is an increase in PGI2 and inhibition of platelet aggregation

largely beneficial in disorders of arterial thrombosis

384
Q

what are the dental implications for a patient medicated with Antiplatelet therapies

A

NSAID interaction with antiplatelet function of aspirin – delay NSAID for 1-2 hours.

Patient at increased risk of bleeding if 2 therapies (NSAIDS and aspirin)

Increased risk of bleeding following minor dental surgery with low dose aspirin.

Increased risk of mucosal damage and bleeding with combined NSAIDs.

385
Q

what are the dental implications for a patient medicated with Anticoagulants

A

Antibiotics enhance anticoagulant activity (esp metronidazole, tetracycline)

NSAIDs contraindicated in postoperative pain and inflammation management – high risk of ulcerative bleeding.

Stage 2 (16 decks)

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