Pharmacology basics

Question 1

What experiments first introduced the idea of receptors? How?

Answer 1

Langley’s experiments with pilocarpine and atropine
Application of pilocarpine resulted in decreased heart rate and increased saliva production
Both were prevented by pre-application of atropine
Later on- nicotine application mimics effects of innervation but curare stopped this
stimulation of a nerve produced a substance the mimicked the effects of nicotine

Question 2

What is the modern definition of affinity?

Answer 2

Tendency of a chemical/molecule to bind to a receptor

Question 3

Ehrlich’s early experiments on blood cells

Answer 3

Proposed chemical interactions occurred between dyes and cells
There was a specificity which is governed by cell type and the chemical structure/solubility of the dye

Question 4

What are chemical mediators?

Answer 4

Extracellular signal molecules that are detected by target cells by receptors
generate intracellular changes that alters the cells behavior

Question 5

Why do cells express different kinds of receptors?

Answer 5

Integration of information
Coordination of responses
Amplification of signalling

Question 6

What is the difference between endocrine and paracrine signalling?

Answer 6

Endocrine- over long distances to target organs through the bloodstream, distributed widely over the body (signalling molecules, mediators)
Paracrine- extracellular signals acting locally without diffusing too far, may be stored in vesicles or produced on demand

Question 7

What does it mean when a cell is autocrine?

Answer 7

When a cell responds to paracrine signalling molecules that it produces itself

Question 8

What are common examples of paracrine signalling?

Answer 8

Inflammation, controlling cell proliferation and wound healing
Smooth muscle relaxation and dilation by nitric oxide
Eciosanoids and endocannabinoids

Question 9

What is contact dependent signalling?

Answer 9

Shortest range of all types of communication

When a cell surface bound molecule binds to a receptor on an adjacent cell

Question 10

What are examples of contact dependent siganlling?

Answer 10

Used widely by the immune system

Immunotherapy to treat cancers

Question 11

What is a bioassay?

Answer 11

Experimental assay in which the concentration or potency of a substance is determined by the biological response it produces

Question 12

How is a mediator defined?

Answer 12

A chemical, peptide or protein that conveys information from one cell to another in response to a stimulus of some kind

Question 13

What are the criteria for a mediator?

Answer 13

It is released from cells in sufficient amounts to produce a biological action on target cells within an appropriate time frame
Application of an authentic sample of the mediator reproduces the original biological effect
Interference with the synthesis, release or action ablates or modulates the original biological response

Question 14

How is regulating the synthesis of small molecule mediators different to synthesis of peptide mediators?

Answer 14

Small molecule- regulated by specific enzymes

Peptide- regulated by transcription

Question 15

What are the two types of chemical mediators?

Answer 15

Preformed mediators- stored in vesicles from which they are released by exocytosis allowing for rapid communication
Mediators produced on demand- released by diffusion or constitutive secretion which are slower and take minutes/hours to act

Question 16

What are examples of preformed mediators and ones that are produced on demand?

Answer 16

Preformed- neurotransmitters, hormones, cytokines, growth mediators and neuromodulators
Produced on demand- nitric oxide, lipid mediators like prostanoids

Question 17

How can drugs effect chemical communication?

Answer 17

Targeting transporters
Increasing release of neurotransmitters by displacing it from vesicles (sympathomimetic action)
Targeting ion channels involved in regulation of neurotransmission

Question 18

What are the 4 classes or ‘super families’ of receptors targeted by synthetic drugs?

Answer 18

Ligand gated ion channels
G-protein coupled receptors
Kinase linked receptors
Nuclear receptors

Question 19

What classes of receptors are found on the cell surface? What features do they have in common?

Answer 19

Ion channels, GPCRs and kinase linked
Transmembrane spanning segments composed of hydrophobic amino acids
Possess extracellular ligand binding domain

Question 20

What type of receptor isn’t found on the surface of a cell membrane? What features do they possess?

Answer 20

Nuclear receptors as they are DNA linked
Regulate gene transcription#
Ligand must be able to cross plasma membrane

Question 21

What are agonists? What are some examples?

Answer 21

Drugs or chemical mediators that bind to a receptor and produce a response
Pilocarpine, nicotine, acetylcholine, morphine

Question 22

What are antagonists? What are some examples?

Answer 22

Drugs that inhibit or prevent the response of an agonist, they may bind to a receptor but they don’t elicit a response
Majority of clinically useful drugs: atropine, curare, naloxone

Question 23

What are the features of ligand gated ion channels?

Answer 23

Involved in fast synaptic transmission
Composed of 3-5 subunits and each subunit has 2-4 transmembrane spanning domains
Central aqueous pore
Agonist binding leads to channel opening

Question 24

What are the features of G-protein coupled receptors?

Answer 24

Formed from a single protein, receptor protein spans the membrane 7 times
Signal transduction occurs via a heterotrimeric GTP binding protein (G protein)
Effectors may be an enzyme or an ion channel

Question 25

What are secondary messengers?

Answer 25

Small diffusible molecules that spread the signal

Question 26

Structure of G proteins

Answer 26

3 subunits- alpha, beta and gamma | GPCRs activated by encouraging alpha unit to release it's GDP and replace it with GTP

Question 27

What are the three different types of enzyme G proteins? How do they allow signal transduction?

Answer 27

Regulation of levels of secondary messengers Gs- increase in adenylyl cyclase leads to an increase in cAMP Gi- decrease in adenylyl cyclase leads to a decrease in cAMP Gq- increase in phospholipase C leads to increase in IP3, DAG, Ca2+ conc

Question 28

What is PKA? how is it regulated by cAMP?

Answer 28

Protein kinase A | PKA regulated by phosphorylation of target proteins, which in turn regulates their functions

Question 29

What happens when phospholipase C is activated by GPCRs?

Answer 29

Generation of secondary messengers IP3 + DAG Increased intracellular Ca2+ Activation of protein kinase C

Question 30

What parts of the body are innervated by the sympathetic nervous system only, unlike most tissues?

Answer 30

Sweat glands, hair follicles, blood vessel smooth muscle and the adrenal medulla

Question 31

Neuronal organisation of the ANS

Answer 31

Preganglionic neurons are always short and cholinergic Postganglionic neurons have nicotinic receptors for ACh, are long and are adrenergic Target tissue expresses alpha and beta adrenergic receptors for norepinephrine

Question 32

Where are chromaffin cells located? How do they work?

Answer 32

Adrenal medulla Function similar to postganglionic neurons but release mainly epinephrine Target alpha and beta adrenergic receptors Allows diffuse sympathetic activity

Question 33

Neuronal organisation of the parasympathetic NS

Answer 33

Long cholinergic preganglionic neurons from brain stem and sacral spinal cord Short cholinergic postganglionic neurons Target tissue expresses muscarinic ACh receptors

Question 34

What are the essential components of the ANS in the CNS?

Answer 34

Spinal cord- mediates autonomic reflexes, receives sensory afferents and brain stem outputs Brain stem nuclei- mediate autonomic reflexes Hypothalamus- integration and coordination of behavioral processes Forebrain and visceral inputs control cortical functions

Question 35

How do drugs directly and indirectly target ANS receptors?

Answer 35

Direct- agonists and antagonists | Indirect- synthesis, storage, breakdown

Question 36

What blocks muscarinic ACh receptors?

Answer 36

Atropine

Question 37

How do M1, M3 and M5 work?

Answer 37

Gq protein coupled receptors Increase in phospholipase C Increase in IP3 and intracellular Ca2+

Question 38

How do M2 and M4 receptors work?

Answer 38

Gi protein coupled receptors Decrease in adenylyl cyclase so decrease in cAMP Increase in GIRK Decrease in voltage gated Ca2+ channels

Question 39

Where are M1 receptors found in the body?

Answer 39

Autonomic ganglia Gastric oxyntic glands Lacrimal and salivary glands Cerebral cortex

Question 40

Where are M2 receptors found in the body?

Answer 40

Atria of the heart | Widely distributed in the CNS

Question 41

Where are M3 receptors found in the body?

Answer 41

``` Exocrine glands Smooth muscle Gastrointestinal tract Eye, airways, bladder Endothelium of blood vessels ```

Question 42

Where are M4 receptors found?

Answer 42

CNS

Question 43

Where are M5 receptors found?

Answer 43

Substantia nigra Salivary glands Iris and ciliary muscles

Question 44

What does M2 activation cause?

Answer 44

Cardiac slowing Decreased force of contraction in the atria Inhibition of atrioventricular conduction

Question 45

What does the activation of M1 and M3 receptors cause?

Answer 45

Stimulation of smooth muscle- bronchoconstriction and GI motility Stimulation of secretion from endocrine glands- increase in mucus in the lungs

Question 46

What is the effect of muscarine poisoning?

Answer 46

Decrease in blood pressure Increase in saliva, tear flow, sweating Abdominal pain, death from cardiac/respiratory failure

Question 47

What can pilocarpine be used to treat?

Answer 47

Glaucoma | reduces pressure in the eye

Question 48

What are the effects of atropine?

Answer 48

``` Inhibition of secretion Smooth muscle relaxant Pupillary dilation Decrease in GI motility Increase in body temp ```

Question 49

What are examples of muscarinic antagonists and what do they treat?

Answer 49

Pirenzipine- M1 selective and used to treat peptic ulsers Darifenacin- M3 selective and used to treat overactive bladders Atropine can be used to reverse poisoning by anticholinesterases

Question 50

What are cholimimetic drugs? How do they do this?

Answer 50

Drugs that act indirectly to enhance cholinergic transmission Inhibition of cholinesterase, can be topic and used in medicine (physostigmine) or long lasting (sarin, organophospates and pesticides)

Question 51

Where are noradrenergic receptors found?

Answer 51

Tissues responding to postganglionic sympathetic neurons

Question 52

Clinical uses of adrenoceptor agonists

Answer 52

Adrenaline- cardiac arrest, anaphylaxis | B2 selective- ephedrine used for nasal decongestants, salbutamol used for bronchial dilation

Question 53

How do amphetamines work?

Answer 53

Structurally related to noradrenaline, sympatomimetic drug Indirectly acting- increase endogenous release of noradrenaline Also work on dopamine and 5HT Repeated use leads to tolerance due to depletion of neurotransmitter

Question 54

Clinical uses of adrenoceptor antagonists?

Answer 54

Hypertension- prazosin (a1 selective) Heart failure- carvediol (a + b selective) Anxiety- propanolol (B1 + B2 selective)