PHARM; Lecture 1, 2 and 3 - Intro to ANS, Mechanism of Drug action (I & II)

Question 1

What are the principal target organs of the sympathetic NS?

Answer 1

Eye, Salivary glands, trachea/bronchioles, skin, heart, GI, Liver, adipose, kidney, ureters and bladder, blood vessels

Question 2

What are the principal target organs of the Parasympathetic NS?

Answer 2

Eye, Salivary glands, trachea/bronchioles, heart, GI, ureters and bladder

Question 3

FITB for the action of ANS on target organs

Answer 3

x

Question 4

What transmitters are released from pre and post ganglionic fibres in sympathetic NS?

Answer 4

x

Question 5

What transmitters are released from pre and post ganglionic fibres in parasympathetic NS?

Answer 5

x

Question 6

What is the difference between the PSNS and SNS in terms of response?

Answer 6

SNS is very coordinated with a lot of divergence due to short pre-ganglionic fibres VS PSNS is discrete, localised and with little divergence

Question 7

What is the difference in the innervation of the somatic NS compared to the ANS?

Answer 7

Somatic has a motor neurone which releases ACh then leads onto the effector skeletal muscle

Question 8

What are the membrane bound receptors for ACh?

Answer 8

Muscarinic and Nicotinic

Question 9

What kind of receptor are the nicotinic ones?

Answer 9

Ionotropic, and is stimulated by nicotine/acetylcholine

Question 10

Where are nicotinic receptor situated?

Answer 10

All autonomic ganglia

Question 11

What are muscarinic receptors and where are they situated?

Answer 11

G-protein coupled and located at all effector organs innervated by post-ganglionic PSNS fibres

Question 12

What are muscarinic receptors stimulated by?

Answer 12

Muscarine and ACh

Question 13

Which of the following effects would be observed after blockade of nicotinic acetylcholine receptors in an individual at rest? 1) Bronchoconstriction 2) Increased sweat production 3) Constipation 4) Increased urinary frequency 5) Short-sightedness

Answer 13

Constipation

Question 14

What are the types of muscarinic receptors?

Answer 14

M1, M2, M3, M4, M5

Question 15

What is the function of M1 receptor?

Answer 15

Neural - forebrain; learning and memory

Question 16

What is the function of M2 receptor?

Answer 16

Cardiac - brain; inhibitory autoreceptors

Question 17

What is the function of M3 receptor?

Answer 17

Exocrine and smooth muscle - Hypothalamus; food intake

Question 18

What is the function of M4, M5?

Answer 18

M4: periphery; prejunctional nerve endings (inhibitory). M5: Striatal DA release

Question 19

What are the different types of muscarinic?

Answer 19

x

Question 20

What are the types of adrenoceptors?

Answer 20

Alpha 1, 2 and beta 1, 2

Question 21

Where are adrenoceptors located?

Answer 21

All effector organs innervated by postganglionic sympathetic fibres

Question 22

What are adrenoceptors and what stimulates them?

Answer 22

G-protein coupled and stimulated by NA/Adrenaline

Question 23

Blockade of which of the following receptor sub-types would induce both an increased heart rate and a reduction in sweat production during exercise? 1) Muscarinic receptors 2) α1 adrenoceptors 3) α2 adrenoceptors 4) β1 adrenoceptors 5) β2 adrenoceptors

Answer 23

Muscarinic receptor

Question 24

How is ACh synthesised, released and metabolised?

Answer 24

1) Binding of Acetyl CoA + Choline to form ACh. 2) ACh is placed in vesicles. 3) Ca2+ moves in via VSCC, so vesicle moves to membrane 4) ACh is exocytosed into the synaptic space. 5&6) ACh moves in synapse and attaches with receptor. 7) Acetylcholine esterase breaks down ACh into choline and acetate. 8) Choline is taken up and is used back up.

Question 25

How is NA synthesised, released and metabolised?

Answer 25

x

Question 26

Blockade of which of the following targets would cause the most significant rise in synaptic noradrenaline concentrations? 1) Tyrosine hydroxylase 2) DOPA decarboxylase 3) Uptake 1 transport protein 4) Monoamine oxidase 5) Cathecol-O-methyl transferase

Answer 26

Uptake 1 transport protein

Question 27

What is pharmacokinetics?

Answer 27

What the body does to the drugs

Question 28

What is pharmacodynamics?

Answer 28

What the drugs do to the body

Question 29

What is a drug?

Answer 29

A chemical substance that interacts with a biological system to produce a physiological effect

Question 30

What are the 4 drug target sites?

Answer 30

Receptors, ion channels, transport systems, enzymes - NB: ALL ARE PROTEINS

Question 31

What are the receptors for drug target sites and what are they activated by?

Answer 31

Proteins within cell membranes, 4 types -\> activated by NT/hormones

Question 32

What is an agonist?

Answer 32

A molecule that stimulates the receptor causing the original action

Question 33

What is an antagonist?

Answer 33

A molecule that blocks the receptor

Question 34

How do ion channels allow drugs to target?

Answer 34

Has selective pores and allows transfer of ions down electrochemical gradients

Question 35

How many types of ion channels and what are they?

Answer 35

2 -\> Voltage sensitive (VSCC) and receptor-linked (nAChR)

Question 36

What are some examples of receptor drugs?

Answer 36

ACh (agonist), atropine (antagonist)

Question 37

What are some examples of ion channels drugs?

Answer 37

Local anaesthetics, Ca channel blockers

Question 38

What are the transport system drug targets?

Answer 38

Transport against conc grad; with specificity for certain species

Question 39

What are some examples for transport system receptors?

Answer 39

Na/K ATPase and Na uptake 1

Question 40

What are some drug examples for transport systems?

Answer 40

Tricyclic anti-depressants, cardiac glycosides

Question 41

What are enzymes that are acted upon by drugs and how do they interact with drugs?

Answer 41

Catalytic proteins interacting by: enzyme inhibitors, false substrates (form false substrates), prodrugs

Question 42

What is an example of an enzyme inhibitor drug?

Answer 42

Anticholinesterases

Question 43

What is an example of a false substrate drug?

Answer 43

Methyldopa -\> Produces fake NA which causes a decreased interaction

Question 44

What is an example of a prodrug drug?

Answer 44

Chloralhydrate -\> triichloroethanol

Question 45

What is an example of an unwanted effect from paracetamol?

Answer 45

It saturates metabolising enzymes, so is metabolised via other pathways producing toxic metabolites

Question 46

What kind of drugs aren't part of the 4 drug target sites?

Answer 46

Non-specific drugs

Question 47

How do non-specific drugs work?

Answer 47

Changing their physiochemical properties, e.g. by changing their active site

Question 48

Give an example of a non-specific drug?

Answer 48

Antacids (neutralise acids not targeting the active site of the cells) and osmotic purgatives

Question 49

What are the different drug-receptor interactions?

Answer 49

Agonist, antagonist, potency, full and partial agonist, selectivity and structure-activity relationship

Question 50

What is an example of an agonist?

Answer 50

ACh, nicotine

Question 51

What is an example antagonist?

Answer 51

Atropine, hexamethonium

Question 52

What does the potency of a drug depend on?

Answer 52

Efficacy and affinity

Question 53

What is the efficacy of the drug?

Answer 53

Ability to produce a change in the receptor -\> the intrinsic activity/ conformational change of receptor

Question 54

What is the affinity of a drug?

Answer 54

How the drug seeks to bind to the receptor

Question 55

What is a full agonist?

Answer 55

The drug causes the maximum response

Question 56

What is a partial agonist?

Answer 56

The drug can't cause the maximum response due to less than max efficacy -\> antagonist activity

Question 57

How can the activity/selectivity of a drug change?

Answer 57

By changing the structure of the drug

Question 58

What are the different types of structure-activity relationship?

Answer 58

Lock and key; agonist-\> antagonist; pharmacokinetics

Question 59

How does an agonist interact with the receptor?

Answer 59

x

Question 60

What does the dose-response curve look like for a full agonist vs a partial agonist (log vs non-log)?

Answer 60

x

Question 61

What is the affinity/efficacy of antagonists?

Answer 61

They have affinity but no efficacy

Question 62

What are the 2 types of receptor antagonists?

Answer 62

Competitive and irreversible

Question 63

What are competitive antagonists?

Answer 63

Act on the same site as the agonist; is surmountable by increasing the concentration of the agonist; shifts the D-R curve to the right

Question 64

Give some examples of competitive antagonists.

Answer 64

Atropine, propanolol

Question 65

What are irreversible antagonists?

Answer 65

Bind tightly to same site OR to different site than agonist; it is insurmountable -\> forms tight covalent bonds or e.g. in ion channels

Question 66

Give an example of an irreversible antagonist

Answer 66

Hexamethonium

Question 67

How does the log D-R curve shift with competitive and irreversible agonists?

Answer 67

x

Question 68

Answer 68

C

Question 69

Answer 69

D

Question 70

What are the different types of drug antagonism?

Answer 70

Receptor blockade, physiological antagonism, chemical antagonism, pharmacokinetic antagonism

Question 71

What is receptor blockade antagonism?

Answer 71

Either competitive or irreversible -\> has a use-dependency

Question 72

What is a use-dependency and give an example of such drugs?

Answer 72

Of ion channel blockers -\> i.e. the more active the cell the faster the drug will block the ion channels. Eg: local anaesthetics

Question 73

What is physiological antagonism?

Answer 73

Each drug acts on a different receptor causing opposite effects on the same tissue

Question 74

Give an example of physiological antagonism

Answer 74

Noradrenaline causes vasoconstriction, increasing TPR and BP BUT Histamine increases dilatation which decreases TPR and BP -\> Antagonise but act on different receptors

Question 75

What is chemical antagonism?

Answer 75

The rarest form of antagonism, occurs during interaction in solution

Question 76

Give an example of chemical antagonism

Answer 76

Dimercaprol -\> attaches to heavy metals and forms complexes which can be toxic; acts as a chelating agent

Question 77

What is pharmacokinetic antagonism?

Answer 77

Works as an antagonist, decresing the concentration of active drug at site of action

Question 78

Give an example of a pharmacokinetic antagonist

Answer 78

Barbiturates affect other drugs by decreasing their absorption, increasing their metabolism and excretion (NB: clinically important reaction)

Question 79

What is drug tolerance?

Answer 79

A gradual decrease in responsiveness to drug with repeated administration

Question 80

What is the main drug that is tolerated quickly?

Answer 80

Benzodiazepines

Question 81

What are some reasons for increased drug tolerance?

Answer 81

Pharmacokinetic factors, loss of receptors, change in receptors, exhaustion of mediator stores, physiological adaptation

Question 82

How do pharmacokinetic factors affect drug tolerance and give an example?

Answer 82

Can increase rate of metabolism of drugs -\> barbiturates, alcohol

Question 83

How does loss of receptors affect drug tolerance and give an example?

Answer 83

Receptors are lost from cell surface via endocytosis -\> down-regulated due to over stimulation. E.g. beta-adrenoceptors

Question 84

How does a change in receptors affect drug tolerance and give an example?

Answer 84

Receptors become desensitised due to a conformational change -\> drug will still have affinity to receptor but the efficacy has lowered. E.g. nAChR at NMJ

Question 85

How does the exhaustion of mediator stores affect drug tolerance and give an example?

Answer 85

For example, when amphetamine is used, it causes enhanced release of NA and after a few doses of Amph, the NA stores become depleted and the response is no longer the same

Question 86

How does physiological adaptation affect drug tolerance?

Answer 86

Homeostatic responses in the body change -\> the tolerance is to the drug side effects

Question 87

How many types of receptor families are there and what is each family?

Answer 87

1) Ion channel-linked. 2) G-protein coupled. 3) Kinase-linked. 4) Intracellular steroid type

Question 88

What are the characteristics of ion channel-linked receptors and give an example?

Answer 88

Fast responses (milliseconds) -\> nAChR, GABAa

Question 89

What are the characteristics of G-protein coupled receptors and give an example?

Answer 89

Slower responses (seconds) -\> beta1 adrenoceptors in heart

Question 90

What are the characteristics of kinase-linked type and give an example?

Answer 90

Quite slower respones (mins) -\> insulin/growth factors

Question 91

What are the characteristics of intracellular steroid type receptors and give an example?

Answer 91

Very slow (hrs) as they regulate DNA transcription -\> steroids, thyroid hormones

Question 92

Summarise the location, effector, coupling and examples of the 4 main types of receptors

Answer 92

x

Question 93

Where are the binding domains for each of the 4 types of receptors?

Answer 93

x

Question 94

Answer 94

C

Question 95

x

Answer 95

E