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Pharmacology Flashcards

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1
Q

What are examples of the 2 types of receptors?

A

1) Ligand gated ion channels, respond to the binding of a ligand with a conformational change that opens a pore into the cell.
eg. nicotinic receptors at the ganglion synapses, responds to ACh and ATP.

2) G protein coupled receptors, respond to binding of ligand by activating second messenger systems within the cell (alpha and beta subunits).
eg. muscarinic (parasympathetic) and adrenoreceptors (sympathetic) at effectors, responds ACh and Adr/NAdr respectively.

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2
Q

What is the definition of a receptor?

A

Specialised proteins embedded in the membrane.
Can form ion channels. (pores)
Can link to intracellular enzymes (cAMP+PKA)

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3
Q

How many pharmacological phenotypes of nicotinic receptor exist?

A

4 (including specific ganglion phenotype)

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4
Q

How many pharmacological phenotypes of muscarinic receptor exist?

A

5 (M1-5)

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5
Q

Which muscarinic phenotypes are bound to a Gq (excitatory) protein?

A

2, 4

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6
Q

Which muscarinic phenotypes are bound to a Gi (inhibitory) protein?

A

1, 3, 5

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7
Q

Give the location and an example of an M1 receptor

A

Found in the CNS and peripheral ganglions.

It has an excitatory effect.

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8
Q

Give the location and example of an M2 receptor

A

Found in the heart.
Involved in slowing the heart rate down by the parasympathetic
pathway from the vagus nerve.

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9
Q

Give the location and example of an M3 receptor

A

Found in the secretory glands and smooth muscle.
Stimulation leads to contraction of visceral smooth muscle, BUT vasodilation in the vasculature.
Because it causes increased synthesis of nitric oxide on vascular endothelial cells. This diffuses to adjacent vascular smooth muscle cells and causes dilation.

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10
Q

Give the location and example of an M4 receptor

A

Found in the CNS.
Inhibitory autoreceptors - present on the presynaptic membrane and are only sensitive to the specific transmitter form the presynaptic membrane. For M4 this is ACh.
Inhibits ACh release in the striatum.

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11
Q

Give the location and example of an M5 receptor

A 
Found in the CNS and PNS.
Triggers adenylate cyclase inhibition,
phosphoinositide degradation,
K+ channel modulation, 
decreased cAMP levels,
down regulates PKA activity.
Phosphodiesterase degrades the phosphodiester bond in the second messenger molecules cAMP and cGMP.
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12
Q

How many pharmacological phenotypes of adrenoceptors exist?

A

2 (alpha and beta)

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13
Q

Which adrenoreceptor phenotype is coupled to Gq?

A

a1 receptor

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14
Q

Which adrenoreceptor phenotype is coupled to Gi?

A

a2 receptor

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15
Q

Which adrenoreceptor phenotype is coupled to Gs?

A

b1, 2, 3 receptor

Function in heart to increase cAMP levels (has an increased effect on PKA levels, so increased heart rate)

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16
Q

Define the word agonist

A

Substance that initiates a physiological response when combined with a receptor.

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17
Q

Define the word antagonist

A

Substance that interferes/inhibits the physiological action of another.

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18
Q

What do Gq proteins do in muscarinic receptors?

A

Gq = excitatory
It activated phospholipase C and produces inositol triphosphate (IP3) + diaglycerol (DAG).
This increases intracellular Ca2+ for muscular contraction, and activates protein kinase C.

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19
Q

What do Gi proteins do in muscarinic receptors?

A

Gi = inhibitory
It reduces cAMP levels and activates K+ channels to hyper polarise cells. Means it takes longer for threshold to be reached so action potential frequency is reduced. Reduces heart rate etc.

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20
Q

Outline the mechanism of the M2 receptor slowing the heart rate

A

Vagus nerve can be activated by baroreceptors (from blood pressure in ANS).
M2 receptor couples with Gi protein. When activated, cAMP production is decreased (less PKA so less Ca2+ channels).
Permeability of K+ channels increases (direct inhibition by beta-gamma subunit of G protein). This action hyper polarises membrane.
Means flow of ions is slower and takes longer to reach threshold, so action potential in heart is slower to reach. Results in a slower heart rate.

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21
Q

Outline the mechanism of the M3 receptor causing focussing of the eye through muscular contraction

A

M3 couples with a Gq protein so is excitatory. Connected to the IP3/DAG pathway and this increases cellular Ca2+.
More Ca2+ enables more muscular contraction (and secretion in other organs) as it binds to more troponin so more actin binding sites can be uncovered by tropomyosin.
This contraction means that when the ciliary muscle contracts when suspensory ligaments are relaxes the lens of eye is squashed for focussing on objects close by.
When the ciliary muscles are relaxed and suspensory ligaments are contracted this pulls the lens flat for seeing long distance objects.

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22
Q

What condition of the eye can activation of the M3 receptor help reduce and how can this occur?

A

It can help reduce glaucoma caused by increased intraocular pressure. This is because a dilated iris can block side drainage of aqueous humour, but a contracted pupil will prevent this from obstruction.

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23
Q

What kind drugs can help prevent glaucoma through intraocular pressure from occurring?

A

Muscarinic receptor agonists that increase the effect of acetylcholine can help emphasis the effects of the M3 receptor.
This can have side effects of very small pupils and ciliary muscle spasm.

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24
Q

Give examples of drugs that reduce intraocular pressure (M3 receptors)

A

Latanoprost = Prostaglandin analogue, increases uveoscleral outflow
Timolol = Beta adrenoreceptor blocker
Brimonidine = Alpha 2 adrenoreceptor agonist
Inhibitors of carbonic anhydrase enzyme.

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25
What are 2 therapeutic uses of the muscarinic receptor agonist Pilocarpine?
1) Glaucoma (eyedrops) | 2) Relieves dry mouth (xerostomia)
26
Name a muscarinic receptor agonist that can relieve paralytic ileus after abdominal surgery?
Oral Bethanechol
27
Name a muscarinic receptor agonist that can relieve urinary retention?
Bethanechol (but catheterisation is more normal)
28
Name a muscarinic antagonist anywhere it is derived from
Atropine, derived from the deadly nightshade plant
29
What is atropine (muscarinic antagonist) used for in operations/premed?
1) Atropine is used to raise the heart rate in an emergency. | 2) Used as an antispasmodic in GI endoscopies.
30
What is glycopyrrolate (muscarinic antagonist) used for in operations/premed?
1) Reducing secretions in airways. 2) Raise heart rate in surgery to protect against vasovagal attacks. 3) Reduce muscarinic effects from cholinesterase inhibitors (reverses neuromuscular paralysis).
31
What is tropiccaminde (muscarinic antagonist) used for as an eye drop?
1) Hydroylysable ester used for dilating the pupil (mydriasis) for retinal examination, only temporary to reduce risk of intraocular pressure.
32
What is atropine (muscarinic antagonist) used for as an eye drop?
1) Long lasting to prevent ciliary muscle paralysis (called cycloplegia, prevents contraction so the muscle can heal and recover after surgery).
33
Which muscarinic receptor can help prevent anti cholinesterase poisoning?
Atropine is used to reduce the response to excess ACh. | because there is no cholinesterase to break down the acetylcholine
34
What is ipratropium and tiotropium (muscarinic antagonist) used for through inhalation?
1) To treat smooth muscle spasm (bowels or bronchi) by blocking the receptor. Have to add beta adrenoreceptor agonist and steroid as necessary to prevent over relief. Used for COPD, and in asthma that is resistant to first line drugs.
35
What is hyoscine butyl bromide (muscarinic antagonist) used for?
1) Used to relieve the smooth muscle spasms of irritable bowel syndrome.
36
What is benztrophine and trihexphenidyl (muscarinic antagonist) used for in the CNS?
1) Used to relieve extrapyramidal effects of psychotic drugs (tremors, slurred speech, distress, paranoia). Such as Parkinson's disease.
37
What muscarinic antagonist can be used to prevent motion sickness?
Hyoscine
38
What muscarinic antagonist can be used for urinary urgency and incontinence?
Oxybutynin, tolteroldine, trospium | but is not the first line of treatment
39
What kinds of drugs have antimuscarinic side effects (not the required effect)?
First generation antidepressants, antipsychotic drugs, antihistamines.
40
What is are examples of common drugs that has antimuscarinic side effects?
1) Amityptiline is common at low doses as an antidepressant for antimigrane prophylaxis. Side effects include dry mouth, fast heart rate, constipation, sedation. This dosage must be increased slowly to build tolerance. 2) Diuretic frusemide 3) Anti ulcer ranitidine
41
How can the danger of antimuscarinic antagonists be measured?
Anticholinergic Drug Scale scores the burden of antimuscarinic effects. Level is from 0 - no known effects, to level 3 - marked anticholinergic effects.
42
What is the effect of a dose of ACh to mean arterial blood pressure?
Activates the parasympathetic pathway, and this causes dilation of blood vessels. This means the mean arterial blood pressure decreases. This is a muscarinic effect.
43
What will happen to mean arterial blood pressure if atropine is given after a small dose of ACh?
Atropine is a competitive muscarinic antagonist so will block the muscarinic receptors, so there is no effect of ACh. Mean arterial blood pressure is normal.
44
If a very large dose of ACh is given in the presence of atropine, what will happen to mean arterial blood pressure?
ACh large dose will activate the nicotinic ganglion receptors of the parasympathetic and sympathetic system so the frequency of nervous impulse will increase to the effectors, including the adrenal medulla, which in turn will release more adrenaline and noradrenaline. However atropine blocks the parasympathetic muscarinic receptors so there is only an increased sympathetic response. This means the mean arterial blood pressure rises.
45
What will happen to the mean arterial blood pressure if hexamethonium is added when there is only an increased sympathetic response?
Hexamethonium is a nicotinic receptor antagonist, so when added it blocks the ganglion receptors for the parasympathetic and sympathetic pathway - so less adrenaline and noradrenaline released This will reduce the increased sympathetic response so the mean arterial blood pressure will go back to normal.
46
What is the name of a nicotinic antagonist on skeletal muscle?
Curare
47
What is one exception of adrenoreceptors responding to adrenaline and noradrenaline?
In the sweat glands the sympathetic nervous system releases acetylcholine as a neurotransmitter instead.
48
What principle makes the adrenal medulla similar to a ganglion?
The adrenal medulla is innervated by nicotinic receptors that respond to acetylcholine and ATP (rather than an adrenoreceptor).
49
What is the function of the adrenal medulla in the sympathetic nervous system?
It releases adrenaline and noradrenaline, which can then act on the effectors of the sympathetic nervous system.
50
What receptor is part of the sympathetic and parasympathetic nervous system?
Nicotinic receptors at the ganglion synapses.
51
What receptor is only in the sympathetic nervous system?
Adrenoreceptors
52
What receptor is only part of the parasympathetic nervous system?
Muscarinic receptors
53
From adrenaline and noradrenaline, which is the hormone?
Adrenaline is the hormone. Noradrenaline is a neurotransmitter.
54
Define sympathetic cotransmission
When multiple neurotransmitters released from a presynaptic knob stimulate their own receptors.
55
Give 2 examples of neurotransmitters used in sympathetic cotransmission
1) ATP | 2) Neuropeptide Y
56
Outline the uptake method 1 of removing noradrenaline from the synaptic cleft
1) A noradrenaline transporter on the presynaptic membrane moves Noradrenaline back into the knob. 2) Monoamineoxidase enzymes break down the Noradrenaline on the outer membrane of the mitochondria. 3) Noradrenaline may also be taken back straight into the vesicles by the vesicular monoamine transporter 2 molecule.
57
Outline the uptake 2 method of removing noradrenaline from the synaptic cleft
1) Noradrenaline is taken up into the post synaptic effector cell. In smooth muscle this is carried out by the Oxygen Cation Transporter 3. 2) After being taken up, Noradrenaline is metabolised by catecholomethyltransferase.
58
Why is adrenaline and noradrenaline both able to respond to the same adrenoreceptors?
They are produced by the same metabolic pathway (also same pathway as dopamine).
59
What is a catechol structure?
It is a benzene ring structure with 2 OH groups
60
What are the 5 main subtypes of adrenoreceptors?
Alpha: 1, 2 Beta: 1, 2, 3
61
Which 4 subtypes of receptor is adrenaline selective for?
Alpha: 1, 2 Beta: 1, 2
62
Which 4 subtypes of receptor is noradrenaline selective for?
Alpha: 1, 2 Beta: 1, 3
63
Which 3 subtypes of receptor is isoprenaline selective for?
Beta: 1, 2, 3
64
Which subtype of adrenoreceptor is a Gq protein coupled receptor and what does it cause?
Alpha 1 is Gq. | It stimulates production of phospholipase C, IP3 and DAG.
65
Which subtypes of adrenoreceptor are Gi protein coupled receptors and what do they cause?
Alpha 2 and Beta 3 are Gi. They inhibit production of adenyl cyclase so there is reduced cAMP production. (Beta 3 is mainly Gi linked in the cardiovascular system).
66
Which subtype of adrenoreceptors are Gs protein couples receptors and what do they cause?
Beta 1, 2, 3 are all Gs. | They stimulate production of adenyl cyclase and increase the production of cAMP.
67
What is an auto receptor?
Receptor that is affected by neurotransmitter transmitted from the same cell that the receptor is present on.
68
What is a heteroreceptor?
A receptor that is sensitive to neurotransmitters and hormones that are not released by the cell that the receptor is present on.
69
Outline the way that Alpha 1 adrenoreceptors work
1) Stimulation increases PLC, IP3 and DAG. This leads to increased Ca2+ concentration in cells due to more membrane depolarisation. 2) In smooth muscle this leads to contraction, in the GI tract this leads to contraction of blood vessels and sphincters.
70
Give an example of where alpha 1 receptors can have an effect on blood pressure
The arterioles are innervated by sympathetic nerves that release noradrenaline to alpha 1 receptors to the smooth muscle. This results in vasoconstriction, so greater resistance in the arteriole, therefore a higher blood pressure.
71
Outline the way the Alpha 2 receptors work
1) Stimulation inhibits cAMP production. Since cAMP promotes opening of Ca2+ channels, this means less Ca2+ channels will be open so less exocytosis and less neurotransmitter will be released. 2) Any Noradrenaline that is released can either bind to Alpha 2 receptors of the presynaptic membrane or the receptors on the postsynaptic membrane. 3) If it binds on the presynaptic membrane it causes autoinhibiton by further inhibiting adenyl cyclase and cAMP production. 4) If it binds on the post synaptic membrane it can inhibit cAMP or involve the beta or gamma sub units of the G protein. This can be for smooth muscle contraction, inhibition of insulin release or platelet inhibition.
72
Where are the 3 main places that Beta 1 adrenoreceptors have an effect?
Heart Juxtaglomerular Apparatus White Adipose Tissue
73
What are the effects of the Beta 1 adrenoreceptors on the heart?
1) An increase of cAMP increases the frequency of action potentials in the SAN. This increases the heart rate - chronotropic change. 2) Ain increase in cAMP increases the influx of Ca2+ from the Ca2+ channels in the cardiomyocytes. A greater conc of Ca2+ means the force of contraction will be stronger. This increases cardiac output so blood pressure is also increased.
74
What are the effects of the Beta 1 adrenoreceptors on the juxtaglomerular apparatus (in the kidney)?
Increased cAMP concentration releases more renin in those cells. This results in production of angiotensin II. This causes increased salt and water reabsorption.
75
What are the effects of Beta 1 adrenoreceptors on white adipose tissue?
Increased cAMP activates hormone sensitive lipase. | This causes lipolysis, which releases 3 fatty acids for use by the body.
76
Where are 5 areas that Beta 2 adrenoreceptors can have an effect?
1) Smooth muscle 2) Pancreas 3) Liver 4) Skeletal Muscle 5) White Adipocytes
77
What is the effect of Beta 2 stimulation on smooth muscle?
Increase in cAMP leads to relaxation. Therefore, bronchodilation, uterine smooth muscle relaxation etc.
78
What is the effect of Beta 2 stimulation on the pancreas?
Beta 2 stimulates insulin release (Alpha 2 inhibits insulin release).
79
What is the effect of Beta 2 stimulation on the liver?
Beta 2 stimulates glycogenolysis, to increase glucose output.
80
What is the effect of Beta 2 stimulation on skeletal muscle?
Beta 2 stimulates glycogenolysis and glycolysis, and release of lactate.
81
What is the effect of Beta 2 stimulation on white adipocytes?
Beta 2 stimulates lipolysis (Alpha 2 inhibits lipolysis).
82
Are Beta 3 receptors stimulatory or inhibitory?
They can be both - they can be linked to Gi or Gs.
83
What is the effect of Beta 3 stimulation on brown adipose tissue?
Since brown adipocytes have high levels of uncoupling protein, more fatty acid oxidation os uncouples from ATP production. The energy produced from this is het energy.
84
What is the stimulatory effect of Beta 3 receptors?
Increased cAMP production stimulates smooth relaxation, eg. on the bladder.
85
What is the inhibitory effect of Beta 3 receptors?
They can stimulate a Gi pathway on the endothelium cells of vasculature. This released nitric oxide, which in turn stimulates vascular smooth muscle relaxation.
86
How is adrenaline administered as a drug?
It in injected into the blood stream as orally it will be digested by enzymes in the stomach.
87
Is adrenaline selective or non selective?
It is non selective so can act on receptors in many places.
88
Describe a clinical use of adrenaline
It activates alpha 1 receptors in the vasculature to vasoconstrict. This prevents local anaesthetic from moving away from the site of injection in the bloodstream.
89
What is the use of noradrenaline as a drug?
Noradrenaline reduces circulatory shock as it stimulates alpha 1 adrenoreceptors to increase the heart rate and stimulates beta 1 receptors that increases contraction and cardiac output. These both increase blood pressure.
90
What type of drug is noradrenaline when administered in the body?
It is an alpha 1 and beta 1 agonist.
91
What is the use of phenylephrine and methoxamine as a drug?
They act as nasal decongestants that reduce constriction in the nose so inflammation decreases.
92
What receptor is phenylephrine and methoxamine an agonist for?
Alpha 1 receptors.
93
Why were the antagonists at alpha adrenoreceptors called ergot alkaloids discontinued?
They caused excessive vasoconstriction which would result info poisoning and a burning sensation.
94
In which two situation were ergot alkaloids used as an alpha 1 adrenoreceptor agonist?
1) Postpartum haemorrhage | 2) Migraines
95
What is the use of brimonidine as an alpha 2 agonist?
In glaucoma to increase constriction of ciliary muscles so that the iris does not block the flow of aqueous humour in the eye.
96
What is the use of dexmedetomidine and clonidine as an alpha 2 agonist?
Used as sedation and was used an a antihypertensive.
97
What is the use of dobutamine on beta 1 receptors?
It is a beta 1 agonist so increases the rate of contraction of the heart.
98
What is the name of the beta 2 agonist used for bronchodilation in asthma?
Salbutamol (and salmeterol)
99
What is the use of mirabegron as a beta 3 agonist?
Used to treat an overactive bladder (relaxation) and possibly to increase thermogenesis of brown adipose tissue.
100
What is hypokalaemia?
It is a reduction of K+ levels in the skeletal muscle cells.
101
The stimulation of which receptor causes hypokalaemia?
Stimulation of the beta 2 adrenoceptors in the skeletal muscle to the Na+/K+ ATPase channels removes more K+ from the cells.
102
What is hyperkalaemia?
It is an increase of K+ levels in the liver cells.
103
The stimulation of which receptor causes hyperkalaemia?
Stimulation of the alpha 1 adrenoceptors in the liver release more K+ into the cells.
104
What would the effect of the beta 2 agonist salbutamol have on repolarisation of the membrane?
May cause hypokalaemia. | Allows skeletal muscle to depolarise faster after contraction.
105
What would the effect of adrenaline (non selective) agonist be on the alpha 1 and beta 2 receptors?
It would initially cause hyperkalaemia then sustained hypokalaemia.
106
How do sympathomimetic amines work?
1) They resemble Noradrenaline so can be taken up into nerve terminals by the uptake 1 method. 2) In the presynaptic knob, VMAT takes them up into the vesicles in exchange for noradrenaline, which can then be released into the synaptic cleft. 3) Some noradrenaline may be degraded by the MAO before leaving, but high concs will remove noradrenaline by reverse transport so it can act on the postsynaptic receptors. 4) Since exocytosis is not involved, actions do not need an action potential or the presence of Ca2+.
107
What does MAO stand for?
Monoamineoxidase | It is an enzyme that breaks down noradrenaline in the presynaptic knob after its use as a neurotransmitter.
108
What is the purpose of uptake blockers for noradrenaline?
Uptake blockers bind to the Noradrenaline transporter on the presynaptic membrane. This prevents Noradrenaline being taken back into the presynaptic knob so it remains in the synapse for longer. This increases stimulation of post synaptic receptors.
109
What do MAO inhibitors do?
These block monoaminoxidase, so the neurotransmitters that are taken up into he presynaptic knob are not broken down. This results in increased concentration of neurotransmitter in the synaptic cleft, so there is more stimulation. eg. more vasoconstriction.
110
What is the purpose of the baroreceptor reflex?
It combines the effects of increasing the blood pressure and the contraction of the heart in order to make quick changes to blood pressure.
111
What does increased activity of vascular and cardiac sympathetic efferents cause in the baroreceptor reflex?
It causes vasoconstriction and an increased heart rate.
112
What does the baroreceptor reflex detect in order to decrease blood pressure?
Decreased stimulation in the aortic arch and carotid sinuses.
113
How does adrenaline affect the blood pressure?
1) Constriction of smooth muscle through alpha 1 2) Vasodilation of blood vessels in skeletal muscle through beta 2 3) Increased heart rate through beta 1 4) Decreased peripheral resistance stimulates baroreceptors to increased sympathetic stimulation.
114
Overall what occurs to blood pressure at a low dose of adrenaline?
The systolic blood pressure increases. | Means there is little effect on mean blood pressure at a low dose of adrenaline.
115
Overall what occurs at a high dose of adrenaline?
Peripheral resistance and blood pressure increases.
116
How does noradrenaline affect the blood pressure?
1) Dominating vasoconstriction from alpha 1 so increased peripheral resistance 2) Stimulates beta 1 adrenoreceptors in heart to increase heart rate. 3) Increased peripheral resistance causes the baroreceptor reflex to increase parasympathetic stimulation of the heart and decrease sympathetic stimulation.
117
Overall what happens with a dose of noradrenaline?
Heart rate drops due to baroreceptor reflex. | Increase in systolic blood pressure and diastolic blood pressure means that overall the blood pressure increases.
118
How does isoprenaline affect the blood pressure?
1) Relaxation of smooth muscled to mainly beta 2 being stimulated. 2) Increased heart rate due to beta 1 3) Drop in diastolic pressure stimulates the baroreceptor reflex to increase sympathetic stimulation of the heart.
119
Overall what happens with a dose of isoprenaline?
Heart rate and cardiac output increases. | Small increase in systolic pressure, but little overall difference in blood pressure.
120
What is the main function of alpha 1 receptors?
Vasoconstriction
121
What is the main function of alpha 2 receptors?
Presynaptic inhibition of Noradrenaline
122
What is the main function of beta 1 receptors?
Increasing cardiac ionotropy and chronotropy
123
What is the main function of beta 2 receptors?
Vasodilation and bronchodilation
124
What is the main function of beta 3 receptors?
Lipolysis
125
List 3 receptors and how they could be affected to cause vasodilation
1) Agonist of beta 2 receptors 2) Antagonist of alpha 1 receptors 3) Agonist of alpha 2 receptors (less noradrenaline means less vasoconstriction)
126
Name 2 ACE inhibitors
Captopril | Spironolactone

Circulation and Breathing (7 decks)

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