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Year 2 LCRS > Introduction to Pharmacology (Term 1) > Flashcards

Introduction to Pharmacology (Term 1) Flashcards

1
Q

Describe the 2 types of acetylcholine receptor.

A

Nicotinic receptor - at all autonomic ganglia, type 1 (ionotropic), stimulated by nicotine and ACh.

Muscarinic receptor - at all effector organs innervated by postganglionic parasympathetic fibres (and also sweat glands (sympathetic)), type 2 (G-protein coupled), stimulated by muscarine and ACh

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2
Q

Briefly classify muscarinic cholinergic receptors.

A

M1 - neural (CNS) + salivary glands
M2 - cardiac
M3 - salivary glands, bronchial/visceral SM, sweat glands, eye.

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3
Q

Give drug target sites

A

Receptors, ion channels, transport enzymes, enzymes (all of these are proteins).

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4
Q

Contrast full and partial agonists.

A

A full agonist is a drug which can generate a maximal response. A drug which can never produce this is a partial agonist.
When a partial agonist is delivered with a full agonist, the drug has some antagonist activity.
An agonist has affinity and efficacy, an antagonist has affinity but NO EFFICACY.

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5
Q

What are the 2 types of receptor antagonist?

A

Competitive (same site as agonist, surmountable, D-R curve shifts right).
Irreversible (binds tightly or at different site, insurmountable).

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6
Q

Give the 4 types of drug antagonism.

A

Receptor blockade, physiological antagonism, chemical antagonism, pharmacokinetic antagonism.

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7
Q

Define drug tolerance.

A

Gradual decrease in the responsiveness to a drug with repeated administration.

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8
Q

Give the types of receptor families.

A

Type 1: ion channel linked (fastest, ms response)
Type 2: G-protein linked (slower, s)
Type 3: kinase-linked (insulin/growth factors, mins)
Type 4: Intracellular steroid type (DNA transcription regulation, hours).

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9
Q

Describe how drug tolerance can arise.

A

Pharmacokinetic factors, e.g. increase in rate of metabolism.
Loss of receptors, e.g. membrane endocytosis and receptor downregulation.
Change in receptors, e.g. conformational changes in receptors.
Exhaustion of mediator stores.
Physiological adaptation, e.g. homeostatic responses.

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10
Q

How do M1, M3 (and M5) receptors produce effects?

A

Linked to G-protein q, causing an increase in IP3 and DAG (from PIP2).

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11
Q

How do M2 receptors produce effects?

A

Linked to G-protein i, cause a decrease in cAMP.

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12
Q

What are the effects of muscarine on the eye?

A

Contraction of ciliary muscle (to accommodate near vision).
Contraction of sphincter pupillae (miosis) which opens a pathway for aqueous humour drainage via Canals of Schlemm, reducing intraocular pressure.

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13
Q

How does ACh affect the vasculature if it lacks parasympathetic innervation?

A

ACh acts on vascular endothelium to produce NO (nitric oxide) via M3 AChR. Induces vascular smooth muscle relaxation.

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14
Q

How does ACh affect non-vascular smooth muscle?

A

Causes contraction via parasympathetic innervation (note this is the opposite effect than what ACh mediates on vascular smooth muscle).
Bronchoconstriction, micturition, increase peristalsis.

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15
Q

What is pilocarpine?

A

A non-selective muscarinic agonist. Useful as a treatment for glaucoma.

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16
Q

What is bethanechol?

A

A M3 AChR selective agonist, used to assist in emptying the bladder and gut motility.

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17
Q

What do indirectly acting cholinomimetic drugs target?

A

Acetylcholinesterase.

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18
Q

Contrast acetylcholinesterase and butyrylcholinesterase.

A

Acetylcholinesterase is found in all cholinergic synapses, whereas butyrylcholinesterase is found in plasma and most tissues.
Butyrylcholinesterase has low substrate specificity and hence is responsible for low plasma ACh levels.
Acetylcholinesterase is highly selective for ACh and very rapid (>10000 reactions per second).

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19
Q

Name a reversible and an irreversible anticholinesterase drug.

A

Reversible: physostigmine.
Irreversible: ecothiopate.

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20
Q

What does the Henderson-Hasselbalch equation indicate about the polarisation of drugs in different pH environments.

A

The higher the pH environment for drugs behaving as WEAK ACIDS, the more ionised the drug is.
The higher the pH environment for weak bases, the more unionised it is.

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21
Q

How does tissue localisation affect drug distribution?

A

For example, highly fat soluble drugs will rapidly diffuse into fat tissues (up to 75%) despite fat only accounting for 2% of blood supply.

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22
Q

What factors affect drug distribution?

A

Regional blood flow, extracellular binding (plasma-proteins), capillary permeability, localisation in tissues.

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23
Q

What is bioavailability?

A

Fraction of a dose which reaches the systemic circulation unchanged (to be delivered to its target site and exert its pharmacological effect).

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24
Q

Describe phase 1 and 2 metabolism.

A

Phase 1: main aim is to introduce a reactive group to the drug to increase polarity. Reduction, oxidation or hydrolysis.
Phase 2: main aim is to add a water soluble conjugate to the reactive group.

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25
Q

What is a prodrug?

A

An inactive ‘parent’ drug which is metabolised to produce active metabolites.

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26
Q

What are the general effects of drug metabolism?

A

Biological half-life is decreased.
Duration of exposure is reduced.
Accumulation in the body is avoided.
Potency/ duration of the biological activity is altered.

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27
Q

Define “drug”

A

A chemical substance which has effects on physiological function by interacting with a biological system.

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28
Q

Why may excipients be added to drugs?

A

To aid in manufacture.
To improve chemical and biological stability.
To increase acceptability to the patient by improving flavour, fragrance or appearance.

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29
Q

What methods of administration will result in the least first-pass metabolism?

A

Intravenous, buccal, sublingual.

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30
Q

Define the therapeutic index.

A

The ratio of the dose of a drug which elicits a lethal dose in 50% of treated individuals over the dose which elicits a therapeutic effect in 50% of treated individuals.

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31
Q

Why may excipients be added to a drug?

A

To aid in the manufacture of the medicine.
To improve the chemical/ biological stability.
To improve the flavour/fragrance/appearance to improve patient acceptance.

32
Q

Contrast agonists and antagonists in terms of affinity and efficacy

A

Both agonists and antagonists possess affinity: only agonists possess efficacy

33
Q

Give examples of nicotine receptor antagonists, and the alternative name for this family of drugs.

A

Also known as ganglion blocking drugs; examples include hexamethonium and trimetaphan.

34
Q

Explain how the effects of nicotinic receptor antagonists are “use-dependent”.

A

The drugs target the receptor, but also block ion channels. The more open the channel is (because it’s being more heavily used) the more effective the antagonist as the drug can enter the channel more easily. The blockade, however, is incomplete.

35
Q

What effects do nicotine receptor antagonists have and what would you observe in a patient at rest?

A

The effects are based on whichever system predominates when the drug is administered, since both the parasympathetic and sympathetic branches of the autonomic nervous system are affected.
At rest: increases HR, pupil dilation, bronchodilator, detrusor relaxation, decreases gut motility, reduced secretions (sweating and saliva production).

36
Q

Hexamethonium was the first anti-hypertensive drug. How did it achieve this affect?

A

Hexamethonium is a nicotinic receptor antagonist. Causes vascular smooth muscle dilation and reduced renin secretion.

37
Q

Give some muscarinic receptor antagonists and their effects on the CNS.

A

Atropine: normal dose has little effect on CNS. A toxic dose induces mild restlessness and agitation.

Hyoscine: normal dose causes sedation and amnesia. A toxic dose causes CNS depression or paradoxical CNS excitation (associated with pain).

38
Q

How can a hyoscine patch serve as anti-motion-sickness therapy?

A

Hyoscine blocks the cholinergic neuron to the vomiting centre.

39
Q

What is tropicamide used for?

A

It is a muscarinic receptor antagonist, used in the examination of retinae (since it induces mydriasis).

40
Q

Give the nicotinic adrenoceptor present on the lungs, heart, kidneys and cutaneous blood vessels.

A

Skin blood vessels (constriction)= A1
Heart and kidneys = B1
Lungs (bronchodilation) = B2

41
Q

Why are muscarinic antagonists useful as anaesthetic premedication?

A

They induce bronchodilation, useful if the anaesthetic is gaseous.
They reduce secretions, reducing the likeliness of secretions entering the airways.
They raise HR, combating the reduction in HR from the anaesthetic.

42
Q

How are muscarinic antagonists useful in relieving the symptoms of Parkinson’s?

A

Since the D1R is suppressed by the M4R. In Parkinson’s, dopaminergic loss can be mitigated by administering muscarinic antagonist to reduce the inhibition of D1R.

43
Q

Name a drug useful in the treatment of atropine overdose.

A

Physostigmine.

44
Q

How does botulinum cause muscle paralysis?

A

It blocks the SNARE complex involved in the exocytosis of ACh.

45
Q

What are the second messengers used for each of the adrenoceptors?

A 
A1 = PLC, IP3 and DAG
A2 = reduction in cAMP
B = increase in cAMP
46
Q

Compare the selectivity of noradrenaline (norepinephrine) and adrenaline (epinephrine) for different adrenoceptors.

A

Selectivity for NA: A1/2 > B1/2
Selectivity for A: B1/2 > A1/2
N.B. All adrenoceptors are activated by both adrenaline and noradrenaline.

47
Q

How does noradrenaline control its own secretion?

A

Via the prejunctional A2 receptor, which exerts negative feedback.

48
Q

How is adrenaline used to treat anaphylactic shock?

A 
B2 = bronchodilation.
B1 = tachycardia
A1 = vasoconstriction (A-receptor mediated effect less powerful).
49
Q

Detail phenylephrine.

A

A1R selective agonist. Causes vasoconstriction, mydriasis and nasal decongestant.
Chemically related to adrenaline, more resistant to COMT but not MAO.

50
Q

Describe clonidine.

A

A2R selective agonist - was used in the treatment of hypertension and migraine. Reduces sympathetic tone: A2-adrenoceptor mediated presynaptic inhibition of NA release.

51
Q

What effects does isoprenaline have and why isn’t it used as a treatment?

A

Isoprenaline is a B-selective agonist. It is used to treat cardiogenic shock, acute heart failure and MIs. However, B2 stimulation in vascular SM results in a fall of venous blood pressure - triggering reflex tachycardia via the stimulation of baroreceptors.

52
Q

Why is dobutamine a better drug at treating cardiogenic shock than isoprenaline?

A

It is a B1 selective agonist, so lacks isoprenaline’s reflex tachycardia.

53
Q

Detail salbutamol.

A

A B2 selective adrenoceptor agonist. It is a synthetic catecholamine derivative with relative resistance to MAO and COMT.
Used in the treatment of asthma as it induces the B2 relaxation of bronchial smooth muscle. However, it induces reflex tachycardia, tremor and blood sugar dysregulation.

54
Q

Give 2 dopamine receptor agonists.

A

Bromocriptine and cabergoline.

55
Q

What are the tissue targets for a hypertensive drug? N.B. Beta-blockers are the 4th step in the treatment of hypertension, given alongside either an ACEi or ARB, a CCB and a thiazide-type diuretic.

A 
The heart (to decrease cardiac output by reducing heart rate and force of contraction) - modulated by B1 receptors. 
Sympathetic nerves which release NA (a vasoconstrictor) - B1/2
Kidney (reduce renin release - which affects vasoconstriction and blood volume) - also has B1 receptors.
56
Q

Give names and affinities of various B-blockers used to treat hypertension.

A

Propranolol is a non-selective beta-blocker, which has “equal-affinity” for B1 and B2 receptors.
Atenolol is a B1 selective B-blocker.
Carvedilol is a mixed B-A blocker. The A1 blockade gives additional vasodilation.
Nebivolol is a B1 blocker which also potentiates NO (resulting in vasodilation)
Sotalol is a mixed B-blocker which also inhibits K+ channels (hyperpolarising the membrane to prevent contraction).

57
Q

What is the major advantage of atenolol over propranolol?

A

Atenolol doesn’t cause the negative responses in diabetics and asthmatics to the same degree that propanolol does (B2 receptors cause bronchodilation and gluconeogenesis and glycogenolysis in the liver) as it is B1 selective.

58
Q

What is phentolamine?

A

A non-selective A-blocker, used to treat pheochromocytoma-induced hypertension.

59
Q

Why is phentolamine not very effective at treating hypertension?

A

Since it is a non-selective A-blocker, it also antagonises A2 receptors. This reduces negative feedback of noradrenaline release so more is released into the synaptic cleft. This induces increased competition between noradrenaline and phentolamine for the postsynaptic A1 receptors. Also; the vasodilation causes a reduction in blood pressure which decreases the baroreceptor firing rate, increasing sympathetic innervation to the heart (increasing HR and FOC) to maintain the pressure.

60
Q

What is prazosin?

A

An A1-selective antagonist, which inhibits the vasoconstrictor activity of noradrenaline. It has modest blood pressure lowering effects.

61
Q

What is methyldopa?

A

A FALSE TRANSMITTER. It replaces DOPA in the dopamine production pathway rendering it less active. It is not readily metabolised by MOA, so the concentration gradient is reduced and it’s uptake is slower. Hence, it is more likely to accumulate and displace noradrenaline in the synaptic cleft.

62
Q

How can B-blockers sometimes be helpful in the treatment of arrhythmias?

A

Increased sympathetic innervation to the heart can sometimes precipitate arrhythmias and AV conductance. Propranolol can slow the heart and reduce the arrhythmias.

63
Q

How can B1-selective agents, e.g. metoprolol, be useful in the treatment of angina?

A

Angina is not enough blood flow to the heart. Low doses of B1-selective drugs can reduce HR and contractile activity without affecting bronchial smooth muscle. This reduces O2 demand without affecting O2 exchange.

64
Q

How is pilocarpine, a muscarinic agonist, used as an anti-glaucoma medication and why has it been superseded by other agents?

A

It is used as an anti-glaucoma drug because it causes contraction of the sphincter pupillae, opening pathways for the aqueous humour drainage (via the canals of Schlemm) reducing intra-ocular pressure. It has been superseded due to its adverse effects on vision: one loses their ability to respond to light stimuli.

65
Q

What does tropicamide do to the eye, how does this affect ocular parameters and why is it used clinically?

A

It is a muscarinic antagonist, which causes relaxation of the sphincter pupillae, resulting in a significant increase in the size of the pupil. It also causes the ciliary muscle to relax, moving the point of accommodation further from the eye. There is a loss of reflex due to the sphincter pupillae being fixed in position and unable to respond to light stimuli.
It is used clinically to induce mydriasis, useful when inspecting the retina.

66
Q

How do sympathomimetic drugs and beta blockers treat glaucomas?

A

A sympathomimetic drug induces vasoconstriction (A1) in the ciliary body, reducing the amount of fluid available for aqueous humour production. A beta-blocker inhibits the production of aqueous humour in the ciliary body (B1).

67
Q

What are some of the problems with drugs applied topically to the eye?

A

There is only a small reservoir in the eye, so a lot of the drop drips out and may also be diluted in tears. The drug is aqueous and has to cross lipid membranes, but lipid drugs are not very well liked by patients. Once in the eye, since it is so well vascularised, the drug disperses quickly throughout the body to have systemic effects.

68
Q

Why is respiratory depression and heroin’s effect on the eye in an unconscious patient almost pathognomonic of a heroin overdose?

A

Since loss of brain function should cause dilation of the pupils due to the lack of brain stimulation which usually constricts the pupils to some degree. The exception is heroin which causes tight constriction of the pupils by disinhibiting parasympathetic neurons.

69
Q

How are prostaglandin analogues and carbonic anhydrase inhibitors useful in glaucoma treatment?

A

Prostaglandin analogues improve drainage by activating matrix metalloproteinases (clearing cellular debris from venous drainage channels).
Carbonic anhydrase inhibitors prevent aqueous humour production in the ciliary body.

70
Q

Compare the adrenoceptor affinity for adrenaline and noradrenaline.

A

All adrenoceptors can be activated by both adrenaline and noradrenaline. However, noradrenaline preferentially binds to alpha receptors, whereas adrenaline preferentially binds to beta receptors.

71
Q

How is adrenaline useful in the treatment of anaphylaxis?

A

It stimulates B2 receptors, which open the airways by inducing bronchodilation.
It stimulates B1 receptors inducing tachycardia to raise the blood pressure.
It stimulates A1 receptors causing vasoconstriction, increasing blood pressure to combat hypotensive shock (this effect is less powerful as adrenaline preferentially binds beta adrenoceptors).

72
Q

What are the ways in which vascular and non-vascular smooth muscle respond to ACh?

A

Most vascular smooth muscle lacks parasympathetic innervation: ACh acts on these cells to cause NO release (a vasodilator). Induces relaxation of the smooth muscle.
Non-vascular smooth muscle does have parasympathetic innervation and responds in the opposite way (it causes the contraction of the smooth muscle). E.g. bronchoconstriction, increased micturition, increased peristalsis.

73
Q

Why do neuromuscular-blocking drugs not target autonomic ganglia?

A

Since the nicotinic ACh receptor on muscles is different to the ganglionic nAChR.

74
Q

What is the difference between a depolarising and a non-depolarising neuromuscular-blocking drug, and give an example of each.

A

Non-depolarising neuromuscular-blocking drugs act as competitive antagonists, e.g. tubocurarine.
Depolarising neuromuscular-blocking drugs acts as agonists, e.g. suxamethonium.

75
Q

Describe suxamethonium.

A

Extends E.P depolarisation, leading to depolarisation block.
Given i.v. Duration of paralysis only around 5 mins.
Metabolised by pseudo-cholinesterase (butyrylcholinesterase) in liver and plasma.
Used for short surgical procedures, such as endotracheal intubation and as a muscle relaxant.

76
Q

Describe tubocurarine.

A

Competitive nAChR antagonist. 70-80% block necessary. Effects –> flaccid paralysis.
Extrinsic eye muscles, small muscles of face, limbs and pharynx and respiratory muscles affected (in that order).
Used to relax skeletal muscles in surgery and to permit artificial ventilation.
I.v. (highly charged). Doesn’t cross BBB or placenta (safely used in C-section).
Duration of paralysis 1-2 hrs.

77
Q

Detail the unwanted effects of tubocurarine.

A

Hypotension (ganglion blockade leads to drop in TPR).
Tachycardia due to reflex and blockade of vagal ganglia.
Bronchospasm due to excessive secretions and histamine release

Year 2 LCRS (6 decks)

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