Block 1 - Foundations of Medicine - Week 4 Flashcards
1
Q
Why is sigalling needed
A
Cognition, development, growth, homeostasis, infections, injury, movement
2
Q
Give 10 examples of chemical and electrical signals
A
Amino acids, cytokines, gases, growth factors, hormones, ions, light, neurohormones, neurotransmitter, peptides
3
Q
What are neurohormones
A
Hormones released by neurones
4
Q
How do target cells produce responses
A
Signal transduction pathway
5
Q
4 examples of short range signalling
A
Direct, intacrine, autocrine, juxtacrine
6
Q
What happens during direct signalling?
A
GAP JUNCTIONS
Adjacent cells have channel proteins which join them together
7
Q
What happens during intacrine signalling?
A
The ligand binds to a receptor on the cell nucleus to regulate intracellular function
8
Q
What happens during autocrine signalling?
A
Cell secretes a substance which binds to the cell membrane of the cell which secreted it
9
Q
What happens during juxtacrine signalling?
A
A protein on the outside of the cell triggers a response on a neighbouring cell which has physical contact
10
Q
What is medium-range signalling called?
A
Paracrine
11
Q
Define neuron
A
Nerve cell
12
Q
Define nerve
A
Enclosed bundle of axons in the PNS
13
Q
What is the difference between a multipolar, bipolar and unipolar nerve
A
Multipolar: many dendrites; one axon
Bipolar: 1 dendrite; 1 axon
Unipolar: bipolar but cell body in another place
14
Q
What are the roles of neuroglia?
A
Supports, insulates and supplies nutrients to neurones Kills dead neurones Regulate extracellular space Immune response Moderates neurotransmission
15
Q
What is the endoneurium?
A
Connective tissue which surrounds each nerve fibre
16
Q
What is the fasciculus?
A
bundles of nerve fibres surrounded by a layer of connective tissue called the perineum
17
Q
What is the epineurium?
A
Layer of connective tissue which surrounds each nerve
18
Q
Define tract
A
Bundle of axons in the CNS
19
Q
5 roles of the cerebral cortex
A
Emotions, memory, motor control, sensory input and voluntary movements
20
Q
What are the 6 lobes of the cerebral cortex and their roles?
A
Frontal: Cognitive thinking, decision making and planning
Parietal: Spacial awareness and interaction
Temporal: Hearing
Occipital: Vision
Cerebellum: Memory
21
Q
What happens in Myasthenia Gravis?
2 symptoms
A
Antibodies against Ach receptors block Ach binding
Weak muscles and droopy eyes
22
Q
What happens in Lambert-Eaton Myasthenic syndrome?
1 symptom
A
Antibodies against calcium channels prevent Ach release
Weak muscles
23
Q
What is the difference between long and short term cell signalling?
A
Short term: Modification and release of proteins which are already there
Long term: Transcription factors are altered permanently to synthesise new molecules
24
Q
How do ligand gated ion channels work?
A
Let the ions into the cell through gated pores
25
Give 3 examples of effector proteins which are activated by the receptor and protein cascade
Cytoskeletal proteins
Gene regulatory proteins
Metabolic enzymes
26
Give 4 examples of second messengers
Calcium
Cyclic nucleotides
Lipids
Phosphoinositols
27
What happens in a protein cascade?
Successive phosphorylation of specific proteins
28
How are cyclic nucleotides formed?
ATP + adenylate cyclase --> cAMP
| cAMP --> 5'AMP (phosphodiesterase)
29
How are phosphoinositols and lipids formed?
Phosphatinfdyl inostiol (PI) --> PIP --> PIP2 --> DAG and IP3
DAG and IP3 are examples of phosphoinositols and lipids
30
How does phosphorylation occur?
By the action of a protein kinase
31
What are the two types of kinases and their roles?
Kinases that phosphorylate serine and threonine
| Kinases that phosphorylate tyrosine
32
What can ATP work as?
A second messenger
33
How are molecules turned off?
Protein phosphates form ATP from ADP which removes the phosphate
34
Explain how the G-protein coupled receptor works
The ligand binds to the G-protein receptor which causes a conformational change in the G-protein
GDP which is attached to the G-protein falls off and is replaced by GTP - this is attached to a phosphate which causes downstream signalling
35
Explain how the G-protein is a trimeric protien
Monomeric small molecular weight ATPases:
Single GDP/GTP binding proteins
Heterotrimeric G proteins:
Alpha causes phosphorylation by activating second messengers
Beta and Gamma separate from the alpha subunit and cause stimulation
36
What are the three classes of G protein?
Gq: Phospholipase C
Gi: Adenylate cyclase and cAMP cause a NEGATIVE effect downstream
Gs: Adenylate cyclase and cAMP cause a POSITIVE effect downstream
37
What is the difference between muscarinic and nicotinic receptors?
- receptor
- location and function
Muscarinic: GPCR; decreases heart contraction and increases secretion of salivary glands
Nicotinic: Ion channels; increases skeletal muscle contraction
38
What are the two classes of kinase linked receptors?
Intrinsic tyrosine kinase activity receptors
| Tyrosine kinase linked receptors
39
What is the downstream signalling cascade for kinase receptors?
MAP kinase kinase kinase --> MAP kinase kinase --> MAP kinase
40
Explain how intrinsic kinase linked receptors work
| What is the difference between tyrosine kinase activity receptors and tyrosine kinase linked receptors
Ligand causes dimerisation and phosphorylation which causes downstream signalling
Activity: Transmembrane protein with a domain in the cell
Linked: Single pass transmembrane protein bound to the kinase
41
What are tyrosine kinase activity receptors for?
Receptors for growth factors and insulin
42
What are tyrosine kinase linked receptors for?
Receptors for interferons, interleukins and growth hormones
43
Define drug
Man-made molecule found inside/outside the body which exerts a biochemical physiological effect on the organism which affects its function
44
Define receptor
Protein molecule that recognises and responds to endogenous chemical signals
45
Define endogenous
Inside the cell
46
Define drug targets
Marcomolecules which drugs interact with
47
How do drugs bind to their receptors?
Drugs are ionic so will align the charges on the receptor causing a conformational change in the protein structrue which changes the way that it works
48
What is the timecourse?
| What decreases it?
The time taken for the drug to bind to its receptor
| Higher temperature of interstitial fluid = increased kinetic energy and decreased time
49
Define specificity
The degree to which the effects of a drug are due to one pharmacological action
50
Define affinity
The strength of the non-covalent bonds between drug and receptor are measured by Kd of the drug receptor complex
51
Define Kd
The concentration when half the drug is bound to the receptor at equilibrium
Drug binding is proportional to drug effect
50% response rate = 50% of the drug bound
52
Define pharmacodynamics
The study of drug-receptor interactions
53
Why is the dose-response relationship graph 's' shaped?
The majority of drug change is at small concentrations so the graph is a 'log'
54
Define potency
| What 2 things does it depend on?
The drug dose needed to produce a specific effect of a given intensity
It depends on efficacy and affinity
55
Define efficacy
Emax
| The maximum response achievable from a drug in the target system
56
What happens to Kd if you have a drug with a higher affinity
Drugs with a higher affinity need less drug to get 50% binding
57
Which state of receptor does the agonist, inverse agonist and antagonist work on?
Agonist: Active state
Inverse agonist: Inactive state
Antagonist: Inactive and active state
58
What do drugs target if they bind to ligand-gated ion channels?
Brain
| Cardiac and skeletal muscle
59
What do drugs target if they bind to G-protein coupled receptors?
Alter levels of secretion
60
What do drugs target if they bind to receptor kinases?
Alter duplication, growth and maturation
61
What do drugs target if they bind to nuclear receptors?
Transcription and translation
62
Define pharmacokinetics
Process by which the drug enters the body and becomes bio-available so it can bind to the receptor and create cellular change
63
What are the 4 stages of how drugs work?
Absorption - Distribution - Metabolism - Excretion
64
Define drug absorption
The mechanism of accumulation of the drug into the body compartment that you want it to be in
65
Define haematically sealed
Airtight
66
What two states can drugs be in?
| What does it depend on?
Acid or base
| Differences in IONISATION
67
What is pKa?
log[H+] that gives 50% of H+ bound to the drug molecule
68
Is a drug ionised when pH = pKa?
No
69
Define volume of distribution
What does it quantify?
What are its units?
Theoretical volume that the total administered drug would have to occupy (if it was uniformly distributed) to provide the same concentration as it currently is in blood plasma
Quantifies drug ability to pass through lipid membranes
(mls)
70
What is the vd of a:
- Very ionised drug?
- Lipophilic drug?
- Drug bound to globulin?
- Very ionised drug: Low as it will stay in the plasma
- Lipophilic drug: High as it will not stay in the plasma
- Drug bound to globulin: High as the dose is higher
71
Define drug metabolism
Chemical alteration of a drug into its inactive form
72
7 ways that the liver metabolises drugs
| What does it require?
Condensation, conjugation, hydration, hydrolysis, isomerisation, oxidation and reduction
High energy
73
When is a prodrug useful?
If you cannot make a drug with the right pKa for absorption
74
Why do you need to be careful about increasing dosage due to the first pass effect?
Some people's livers work better than others due to the environment (e.g. alcohol) or genetics
75
How many cytochrome p450 enzyme gene families are there?
| How do they differ?
74 gene families differing in their gene families and specificity of reactions
76
Which genes are involved in drug metabolism?
CYP1, CYP2, CYP3
77
How do cytochrome p450 enzymes work?
They have a haem group which exchanges electrons causing oxidation and reduction
78
Where are the electrons supplied from for oxidation and reduction by P450's?
Supplied from a flavoprotein which supplies electrons from NADPH to CYP450
79
Define induction
Decreased plasma drug concentration
| 1 drug increases CYP450 so the concentration of the other drug decreases --> decreased therapeutic effect
80
Define inhibition
Increased plasma drug concentration
| 1 drug decreases CYP450 so the concentration of the other drug increases --> toxicity
81
What is phase 2 metabolism
Molecules are conjugated to make them more soluble and ionic so they can be excreted in the bile or urine
82
What happens during glucuronidation?
A protein in the liver changes the drug shape
83
What does adding amino acids do?
What amino acids are added? (2)
Why is this dangerous in neonates?
Changes the drug shape
e.g. lutamine and glycine
Slower in neonates
84
What does adding sulphate esters do?
Makes the drug more polar
85
How is aspirin metabolised?
Aspirin --> Salicyclic acid --> Glucononide
86
4 roles of the kidney
Conserve salt and water
Control pH
Drug excretion
Regulates fluid volume and electrolytes
87
What is Cp?
The concentration of drug in blood plasma
88
What do you assume that Cp relates to?
The drug concentration in the active tissues
89
What does the target concentration strategy use?
Therapeutic drug monitoring
90
What happens during therapeutic drug monitoring?
Guess the dose based on the patients size, lifestyle, fat:muscle ratio and adjust the dose accordingly
91
When is therapeutic drug monitoring used?
For toxic drugs in hospitals
92
3 things that alter Tmax
1st pass effect
Absorption rate
Metabolism
93
Define Kabs
A rate constant that governs the transfer of drug to the central compartment
Proportional to the amount of drug still unabsorbed
94
How will Cp decline after absorption is complete?
At the same t 1/2
95
What does the single compartment model assume?
The body is one compartment
| Once the drug enters the body, it reaches every compartment
96
What is the equation for the single compartment model?
Initial drug concentration (C0) = Drug mass (Q) / Vd
97
How can you estimate C0 and plasma concentration?
Extrapolate the semi log plot of Cp over time to zero
98
What elimination half life (t 1/2)
The time taken for Cp to fall by 50%
99
What 3 things does elimination half life predict?
- How long the drug will be in the system at a pharmacologically active level
- What will happen after the drug has been administered before it reaches a steady state ( when administration = metabolism)
- What will happen when Cp falls to zero (when another dose is needed)
100
3 criticisms of the single compartment model
- Assumes rates of absorption, metabolism and secretion are directly proportional to drug concentration
- Doesn't look at other compartments
- Oversimplified
101
What does the two compartment model assume?
There is a central compartment and a peripheral compartment which drugs enter via the plasma
102
What are the two phases on the Cp timecourse if you are looking at the two compartment model?
Fast phase: Transfer between central (plasma) and peripheral (tissue) compartments
Slow phase: Estimates half life
103
How is the fast and slow phase found?
Experimentally
104
When is the fast and slow phase similar?
When metabolism is fast
