1 Flashcards
(224 cards)
1
Q
What are the advantages of inhalation therapy?
A
Drug is delivered to the site of action
Rapid onset of action
Little drug in systemic circulation (unless done on purpose)
Very low doses needed
2
Q
Explain how suspension based pMDIs are made
A
The drug must be insoluble in the propellant (less than 1ppm) and so freely dispersed
Must be micronised/milled beforehand
Need an adjuvant to make it physically stable (eg, SPAN 85, Oleic acid and Soya Lecithins)
3
Q
At what size can particles pass through the lungs?And why?
A
10 micrometers
This is because at this size the forces between each other is greater than gravity (so they become sticky)
4
Q
What are the target sites, and particle size needed, for treatment of resipratory diseases and for systemic drug delivery?
A
Respiratory –> Bronchioles…..5 micrometers
Systemic –> Bronchioles and alveoli……2 micrometers
5
Q
What are the 4 different types of DPIs?
A
Single Unit Dose –> Reusable
Single Unit Dose –> nonreuseable
Multi-unit Dose
Multi-dose Reservoir
6
Q
What are the 3 main mechanisms of deposition in the lungs?And the 2 secondary mechanisms
A
Inertial Impaction –> When a drug is inhaled with force is moves in a straight line until it makes contact with something (mainly large particles in the oropharynx and larynx)
Gravitational Sedimentation –> Occurs when particles velocity is low, and resident time high (in the bronchioles)
Diffusion –> When particles are bombarded by air molecules (important for terminal bronchioles and alveoli.) High residence time is best.
Interception –> Deposition where particles contact walls
Electrostatic Deposition –> Charged particles repel, causing more particles to move towards the airway walls
7
Q
What is an aerosol?And what are the 3 different types?
A
A relatively stable suspension of solid or liquid particles in a gaseous medium
Dust - Solid particles formed by mechanical disintegration
Smoke - A visible aerosol (due to incomplete combustion)
Fog/Mist - Liquid particles formed by condensation/atomisation
8
Q
What are the 3 factors that control aerosol deposition?
A
Aerosol properties –> Particle size and distribution
Mode of Inhalation –> Flow rate, and breath holding
Patient Related Factors –> Obstructive airways disorders, anatomical differences
9
Q
What are the 3 factors that the delivery of a respirable dose is dependent on?
A
Inhalation device resistance
Patient inspiratory flow
Powder formulation
10
Q
Explain the differences between…Van der Waals ForcesElectrostatic ForcesCapillary Forces
A
VDW –> A finite attraction between all atoms over a very small distance. These dominant at low humidity in the absence of electrostatic forces
Electrostatic Forces –> Caused by frictional contact, but over a long range. It can be either attractive or repulsive
Capillary Forces –> Condensation of water vapour between touching molecules….forming a liquid bridge
Usually the dominant force under ambient conditions
11
Q
Why can inhalation therapy be good for systemic delivery?
A
When the particle size is 2 micrometers, it can reach the systemic circulation
No first pass effect (Increased BA)
Extensive blood supply allows rapid absorption
12
Q
Explain how solution based pMDIs are made
A
Always chosen if the solubility and stability of the active drug in the propellant (and co-solvents) are good
Usually need to add co-solvents, like ethanol, to increase solubility, as the amount of drug released with each inhalation is dependent on its solubility
HCl often used to modify the pH of the drug
13
Q
Explain how a pMDI works
A
Delivered as a metered liquid volume, and inhaled upside down
Made at 4 bar (high) pressure, which is maintained by the metering valve…keeping the pressure in the main compartment at all times.
Also done by the liquid-vapour equilibrium
The atomising nozzle boils the gas, producing single droplets
These droplets are then cooled and condensed outside of the inhaler (forming the spray we see)
14
Q
What are the main benefits from using a spacer with a pMDI?
A
Causes the aerosol to slow down
Smaller particles are formed (from the aerosol) as the larger particles contact against the spacer –> these points cause the drug to have less momentum….allowing them to get deeper into the lung
Enables the patient to use tidal breathing
15
Q
What are some of the problems with solution based pMDIs?
A
Polar co-solvents can can cause erosion of aluminium canisters….so plastic coats are needed
The relatively non-volatile co-solvent lowers the internal propellant pressure….and so atomisation is less effective
16
Q
Of all the problems with pMDIs….which is the greatest problem (statistically) for patients?
A
A slow inhalation (30L/min)
17
Q
What type of bond formation is the base of Carrier based systems, and Agglomerated systems?
A
Carrier Based –> Adhesive bonds
Agglomerated –> Cohesive bonds
18
Q
What are Carrier-based formulaitons?
A
The blending of the drug with a carrier (eg, lactose)Allows the accurate metering of small quantities of drug
Improves handling and processing
Particle size distribution/habit (shape) and surface morphology are all important properties that are used to influence Fine Particle Fraction (FPF)
19
Q
What are Agglomerated Powder Systems?
A
For high dose drugs, when carrier-based formulations are not feasible
Produced via cohesive bond formation
Efficient deaggregation is required to allow the particles to get deep into the lungs as discrete particles
Have a high free surface area and energy drug
20
Q
What is a Nebuliser?
A
A drug contained within a sterile solution
21
Q
What’s a Pneumatic Nebuliser?
A
The dominant one pre-2000
Has 2 nozzles
Contains a inertial filter to trap large particles
They are cheap
22
Q
What is a High Frequency Ultrasonic Nebuliser?
A
Electronically powered
Has a fan to drive the aerosol from the device
Aerosol droplet either occurs via Taylor Instability or Cavitation
Produce reproducible results
High Output
Lower aerosol inertia
23
Q
What is the goal of new/recent nebulisers?
A
Enhance output
Shorten nebulisation time
24
Q
What is the key change in salbutamol, making it selective to B2 receptors?
A
Replacing the phenol with a Hydroxymethylene group
25
What are the key SAR points for Beta agonists (from cathecholines)
Phenol groups important for H-bonding
Large N-alkyl groups lead to selectivity for B-adrenoceptors
Protonated N-amine allows for ionic interactions
Aromatic ring --> for VDW forces
26
Give a few examples of where lead compounds (in SAR) can be found?Why aren't these compounds used directly as clinical drugs?
Natural receptor ligands (eg, ACh/NA)
Natural products (eg, muscarine)
Collections of synthetic compounds
These would not be used clinically as they would have many side effects
27
What is the function of Neuraminidase and Haemagglutinin?
Neuraminidase --> An enzyme that breaks down the sialic acid receptor of the cells surface
Haemagglutinin --> Compromised of the globular head and fibrous stem. The globular head binds to the sialic acid receptor
28
What do the following class of drugs act on?And what do they block? B2 AgonistsAntimuscarinics
B2 Agonists --> Bind to adrenergic receptors, blocking noradrenaline
Antimuscarinics --> Bind to muscarinic receptors, blocking ACh
29
Why is prednisolone more active than cortisone?
As it is flatter, so it binds to the receptors with more affinity/potency.
Whereas cortisone has sp2/3 groups, so its not flat
30
What is the influenza vaccine?
A trivalent inactivated vaccine, created by egg propagation
The bacteria/virus is grown in a culture media, then inactivated using heat/chemicals
Benefits --> Safer and stable
Negatives --> Costly, and can cause hypersensitivities
31
What was the main problem with ACh as a drug?And how did SAR end with Ipratropium?
Main problem was that ACh had many rotatable bonds, which allowed a lot of off-target binding
Was found that the ester group was important, as well as a positively charged tertiary nitrogen.
A rigid structure also improved the specificity, for example, aromatic rings
32
What are the first line and second line drugs for the treatment of TB?
First Line --> Isoniazid (or streptomycin), Rifampicin, Pyrazinamide and Ethambutol
Second Line --> Ciprofloxacin (or another fluroquinolone)
33
Explain the basis behind Zanamivir (Relenza) and Oseltamivir (Tamiflu) And when are these drugs most important?
Zanamivir --> A guanadino group was used to replace the 4 OH group near the sialic acid. This allowed neuraminidase specificity, and for H-bonds to be formed with glutamate (on neuraminidase)
An inhaler Oseltamivir --> Modification made to improve BA
Tablets or a syrup
Most important during epidemics, as there is no protection!
34
Describe the structure of influenza
ssRNAEnveloped
An orthomyxovirusHas both Neuraminidase (cleaves sialic acid from glycoconjugates) and Hemmaglutinin (binds to sialic acid receptors)
35
Explain the 4 types of influenza?
A, B, C and D
A and B are causes seasonal epidemics (over winter)
Type C causes respiratory disease
Type D affect cattle and not humans
36
What is the purpose of mineralcorticoids?
They regulate electrolyte balance, especially salt levels (Na+)
37
What is Antigenic drift? (in relation to influenza A)
The gradual accumulation of mutations in AA code, changing the form of influenza A --> allowing it to avoid produced antibodies
38
Why can't we always fight off influenza?
As we only produce antibodies against the strain of influenza that was present (eg, H1N1).....and there are many different subtypes of influenza A!!
Influenza is made up of Neuraminidase (11 subtypes) and Haemagglutnin (18 subtypes)
Therefore many different combinations of influenza can be made (eg, H1N2 or H2N3)
39
Whats the difference between cortisone and cortisol?
```
Cortisone = Ketone at carbon 11
Cortisol = Alcohol at carbon 11
```
40
What must always be present at the 11 position of steroids?
A hydrogen bonding capable molecule (eg, OH/C=O)
41
Whats the difference between pandemic and seasonal influenza?
Pandemic --> When a new strain is formed, in which the body has zero protection against (often from another species). It cannot be predicted!!
Seasonal --> A variant of a previous strain, so a large amount of the population will have some protection
42
Describe the 2 types of influenza treatments
Adamantes --> These interfere with the M2 (transmembrane) protein of Influenza A, so less can get into host particles
Reduce illness duration by 1 day if taken quickly enough Sadly, there is lots of resistance to these
Neuraminidase Inhibitors --> Similar to adamantes, but less toxic
They are competitive inhibitors of influenza active sites These are active against all strains (A, B and C) and serotypes (eg, H1N1 and H2N3) of influenza
43
What are the limiting factors of the influenza vaccine?
Growth potential --> of the least available strain
Potency testing --> Each strain must be tested (which takes time)
Timing of strain selection Licensing --> The annual licence supplement approvement needs to be gained in time for packaging and shipment
44
What is Zanamivir (Relenza)?
A transition-state analogue
45
Draw adrenaline
46
Draw Acetylcholine
47
How does normal cholinergic signalling work and with what feedback loops?
ACh leaves the parasympathetic nerve, binding to M3 receptors (on the cellullar target), which causes Ca2+ to be formed
Other ACh binds to the M2 receptor on the parasympathetic nerve, causing a negative feedback loop....decreasing the amount of ACh that is made and released
48
What specificity does Roflumilast have? And what does this cause?
Its a PDE inhibitor that is selective to PDE IV
PDE IV is present only in leukocytes, and so inhibitors increase cAMP levels, inhibit respiratory burst, and inhibit TNF(a) release
49
Explain Histone acetyltransferase (HAT) and Histone Deacetylase, and their effects in inflammation
Histone acetyltransferase (HAT) --> Unpacks chromatin, allowing transcription to occur....allowing more inflammation gene expression
This is inhibited by glucocorticoids --> which reduces inflammation!!
Histone Deacetylase --> Wraps DNA closely, not allowing transcription
We need more of this as it will prevent transcription of inflammation markers..... but cigarrete
50
Why does an increase in excitatory nerve activity lead to hyperresponsivness?
As more ACh binds to M3 (GPCR), activating PLC... which ends up forming more Ca2+ --> which causes contraction of smooth muscle
51
COPD is a term used to describe conditions such as Chronic Bronchitis and Emphysema.... explain these
Chronic Bronchitis --> Productive cough (excessive sputum) present for years
Emphysema --> Alveolar wall destruction and irreversible enlargement of terminal air spaces
52
Describe what the structure of Tuberculosis is
Acid Fast Bacteria
Cell wall rich in lipids --> therefore very hydrophobic and so resistant to weak disinfectants and drying
This also prevents gram stain tests being successful
53
What is the main reason for a drop in FEV1 in COPD patients? How could we stop this?
Mucus blockage
```
Muscarinic antagonists (eg, tiotropium)
Neurokinin antagonists
```
54
What's the difference between homotropic and heterotropic inhibition?
Homotropic --> Acts on the same cell type
Heterotropic --> Acts on different types of cell
This is usually inhibition using ACh and NA
55
Explain the 4 stages of primary tuburculosis progression
Stage 1 --> Bacilli are inhaled by droplets, which settle in the alveoli and start to grow. They are phagocytosed by macrophages, but not killed!!
Stage 2 --> Multiplies in inside the macrophages. The macrophage then bursts, potentially with the patient asymptomatic for 1 month
Stage 3 --> Immune cells surround the macrophages, forming tubercles. Symptoms start, and collagen fibres are formed
Stage 4 --> Uncontrolled lysis of the macrophage. This can cause enzymes to be released, forming lesions and destroying local tissue
56
How does Omalizumab work?
Binds to the Fc part of IgEs, so they cant bind to mast cells....so no degranulation can occur
Only recommended if glucocorticoids don't work first
57
Describe Muscarinic receptors
Postganglionic receptors --> GPCRs M1 --> Create slow EPSP due to closing K+ channels, so does cause depolarisation eventually
M2 --> Increases K+ conductance, so causes hyperpolarisation via a slow IPSP
58
What is the difference between Hyperplasia and Hypertrophy of muscle cells?
Hyperplasia = More muscle cells
Hypertrophy = Bigger muscle cells
These are both stimulated by inflammation
59
State some of the abnormal treatments for COPD
Mucolytics --> N-acetyl cyteine and DNAse
60
What does Theophylline do?
Inhibits phosphodiesterase so cAMP is not broken down --> bronchodialation
61
How would you diagnose active and latent tuberculosis?
Active --> Chest X-ray, sputum tests and molecular assays
Latent --> Tuberculin skin test (forms a skin lesion) and molecular tests
62
What subtypes of (A) and (B) adrenoceptors are more selective to NA or A?
Adrenaline --> More selective to B2 and A2
Noradrenaline --> More selective to B1 and A1
63
What are the natural mechanisms of bronchodilation?
Circulating adrenaline binds to B2 receptors
Inhibitory Non-Adrenergic Non-Cholinergic transmitter (iNANC) molecules, such as CGRP and VIP (dilator neuropeptides)
Neuronally derived NO --> acting on guanylate cyclase
64
What are the functions of the subtypes of (A) and (B) adrenoceptors? How do these work?
A1 --> Constricts smooth muscle (relaxes GI smooth muscle) - Work through GPCRs (Gq) --> Phospholipase
A2 --> Presynaptic inhibition of neurotransmitters - Work through GPCRs (Gi) --> Adenylyl Cyclase
B1 --> Increases HR and force of contraction
B2 --> Dialates/relaxes smooth muscle
B3 --> Thermogenesis in skeletal muscle - These 3 act through GPCRs (Gs) --> Adenylyl Cyclase
65
How do glucocortiocids work? And how do LTRAs (eg, Zileutin and Montelukast) work differently?
By inhibiting PLA2, and so the formation of arachidonic acids LTRAs inhibit 5-lipoxygenase (zileutin) and leuktotrienes (montelukast)
66
What is the main cause of emphysema?
Lung elastases that degrade elastin, the basement membrane and connective tissue
These are derived from neutrophils and macrophagesIncreased after smoking
67
Explain the differences in how Salmeterol, Formoterol and Salbutamol interact with B2 receptors
Salmeterol --> Highly lipophilic, so interacts with the membrane and diffuses into the receptor laterally (so long acting but slow onset)
Formoterol --> A little lipophilic, so leaches out of the membrane to interact with the membrane (long acting and fast onset)
Salbutamol --> Quite hydrophilic, so has a short duration of action as it gets washed away from the receptors
68
Explain some of the mechanisms of COPD
Macrophages and neutrophils release proteases --> which break down connective tissue, and stimulate mucus hypersecretion
Reactive Oxidant Species --> Damages the epithelium and activates inflammatory genes
Cytotoxic T Cells (CD8+) are produced
69
What are common in mast cells granules?
Histamine (less in the lungs, so antihistamines can't be used)
Cytokines (eg, TNF)
Proteases
Heparins
Leukotrienes and Prostanoids
70
What are some of the actions of IL-13 and IL-4?
Increased eosinophil adhesion and migration
Increased mucous secretion
Tissue remodelling
Increases airway smooth muscle contractibility
Anti IL-13 and IL-13 receptor antibodies available (but not in the UK)
71
What is Alondronate?
A biphosphonate used in osteoporosis
Causes apoptosis of bone-reabsorbing osteoclasts, and inhibits their activation
72
In terms of arachiodonic acid metabolism, what bad effect can be caused as a result of aspirin/ibuprofen?
Aspirin/Ibuprofen inhibit COX (prostaglandin formation)
This causes more arachidonic acid to be converted to leukotrienes via 5-lipoxygenase
73
Explain how extrinisic allergy (asthma) occurs?
TH2 cells and their products (IL-4/13) help B cells make IgE --> which then degranulates mast cells
You can become sensitised, but takes a long time
74
Why dont asthma drugs work well in COPD?
Bronchodilators don't work as bronchoconstriction isn't the main cause of COPD
Glucocorticoids don't work properly as they inhibit neutrophil apoptosis, whereas in asthma they promote their death
75
Why is tiotropium better than ipratropium?
As tiotropium binds more selectively to M3 than M2, allowing the negative feedback loop to be retained --> which decreases ACh production
76
What is COPD sputum enriched with?
Neutrophil Asthma --> Eosinophilic
77
What is so good about Aclidinium?
Its a muscarinic antagonist that has a fast 'off' time at M2 receptors....so the negative feedback loop is preserved
78
What does PEFR and FEV1 stand for? And what do they mean in terms of asthma sufferers?
PEFR = Peak Expiratory Flow Rate
FEV1 = Forced Expiratory Volume in 1 second
These will be low in asthma sufferers, with FEV1 having a bigger drop in correlation with the severity of the asthma
79
How does pre/post-synpatic modulation occur? (excluding ACh and NA)
By using co-transmitters --> molecules that are released from the same neurones as ACh and NA
These are known as Non-adrenergic Non-Cholinergic (NANC) transmitters --> ATP, Neuropeptides and NO
Can allow both fast and prolonged contraction, by mixing say NA (slow contracting) and ATP (fast contraction)
80
How do the 4 anti-TB drugs work?
Rifampicin --> Inhibits RNA polymerase
Isoniazid --> A pro-drug that decreases the synthesis of mycolic acid
Pyrazinamide --> Same as Isoniazid
Ethambutol --> Increases the permeability of M.TB
81
What is a cough?
A motor reflex in response to sensing chemicals, particulates and airway excessive mucus
82
Describe Nicotinic receptors
Preganglionic receptors --> Ligand-gated ion channels which open when ACh is bound
A pentamer --> Made up of 3 (B) and 2 (a) units
Allow Na+ in, and K+ out --> Creating a fast EPSP, which can cause action potentials in the post-ganglionic factors (when the threshold is reached)
83
How can TB resistance occur? And what are the 2 types of resistant strains?
Spontaneous mutations in drug target sites and efflux
MDR-TB --> Strains resistant to 2 (or more) first line drugs
XDR-TB --> Strains resistant to 2 (or more) first line drugs, and 3 to 6 second line drugs
84
What does sodium cromoglycate do?
Reduces the activity of airway sensory nerves
85
What can oxidant stress cause? In terms of histone decacetylase (HDAT)?
Glucocorticoid insensitivity.....so inflammatory transcription will carry on
86
Exactly how does salbutamol (B2-agonists) work?
They bind to B2 adrenergic receptors on bronchial smooth muscle.
The receptors couples with Gs --> activating adenylyl cyclase (AC), which converts adenosine triphosphate --> cAMP
cAMP activates PKA, which decreases calcium secretion....leading to bronchodilation
Also activates K+ channels and myosin phosphatase --> decreasing smooth muscle contractility
87
Exactly how does ipratropium (M3 antagonists) work? How would an agonist of M3 work differently?
Bind to and block M3 (muscarinic) receptor
Usually an agonist would activate M3, causing Gq to upregulate PLC --> which increases calcium levels.
This stimulates MLCK which causes vasoconstriction
88
What is dry eye syndrome? (ketoconjunctivitis sicca)
A lack of tear production, or too much tear evaporation
Caused by a problem with the tear film
Main complications = Keratitis and conjunctivitis
89
What are liposomal sprays?
Soy lecithin (a phospholipid) that is encapsulated within microscopic liposomal vesicles
Sprayed onto the eye-lid (eg, Optrex ActiMist)
They mimic what happens naturally when lipids are secreted from the meibomian glands
90
What treatments would you give for the following..... Plaque Psoriasis (trunk and limbs)Scalp PsoriasisFace/Flexural/Genital Psoriasis
Plaque Psoriasis (trunk and limbs) - An emollient and potent topical corticosteroid
Scale Psoriasis - Potent topical corticosteroid (and maybe coal-tar shampoo)
Face/Flexural/Genital Psoriasis - An emollient and mild corticosteroid
91
In which direction does RNA polymerase move? And therefore in which direction is mRNA made?
3' --> 5' mRNA
made from 5' --> 3'
92
What are the stages of the cell growth cycle?
G0 --> Rest phase (non cyclin phase)
G1 --> Checks whether there is sufficient nutrients, size, and growth stimuli.
S-Phase --> DNA replicated/synthesised (temporarily contains 2x the amount of DNA)
G2 --> Cell prepares for division (Checks DNA integrity)
M-Phase --> Mitosis, spindle formation and cell division
93
How is Cortisol secreted in the body?
Stimuli cause Corticotrophin Releasing Hormone (CRH) from the hypothalamus
This stimulates the pituitary to release AdrenoCorticoTrophic Hormone (ACTH) --> This causes the adrenals to secrete cortisol
94
Why can chemotherapy cause damage to our own cells, but not always the tumour cells?
Because our own cells have p53 (pro-apoptopic) and so the chemo will damage our cells enough to induce apoptosis
However the mutated tumour cells will probably not have any p53, so apoptosis will not be induced!!
95
Explain X-linked recessive Alleles?
The allele is on the X chromosome, so is more prevalent in females (more likely to be carriers as they have two X chromosomes)
Males only need 1 copy of the allele to be a sufferer (as they only have one X-chromosome)
96
Explain the anti-inflammatory effects of glucocorticoids
Inhibits not the innate and adaptive immune systems
Decrease the production of inflammatory mediators (ROS, leukotrienes, complement, histamine and prostanoids) Inhibit Th cells activation --> As well as IL-2 and clonal expansion
Decrease vasodilation --> Preventing wbc to get to the site of infection
97
What are the 4 normal control mechanisms of the body to prevent loss of function from mutations?
Heterozygosity --> 2 versions of the same gene, as there's less chance that both will get mutated
Apoptosis --> Regulated cell death to prevent the transmission of mutated genes
Cell Cycle Control --> Checkpoints during cell division ensures thats no damaged cells become fully grown (but killed by apoptosis)
Regulation of Gene Transcription --> There is a requirement for certain activation signals for gene transcription
98
Describe the characteristics of Adult (Somatic) Stem Cells
They can proliferate....but not indefinitely Multipotent/unipotent cells
Located in stem cell niches
Replace worn out/dead cells --> so important for homeostasis
99
What is the difference between Homodimers and Heterodimers?
Homodimers --> Cytoplasmic and nuclear localisation
Each subunit binds one repeat as an inverted dimer, and as a palindrome
Heterodimer --> Activated by ligands binding in the nucleus
RXR forms a dimer with either...
Vitamin D receptor (VDR) --> 3 base pair spacing
Retionic Acid receptor (RAR) --> 4bpTridothyronine receptor
(T3R) --> 5bp Bind direct repeat half sites
100
What will a mutation in the gene IL36RN do?
Cause pustular psoriasis IL36RN usually helps regulate inflammation by suppressing cytokines like IL-1
101
Explain two reasons for Atopic Eczema?
A change in the Filaggrin gene that encodes for a structural protein in the skin
Genetic tendencies can cause more IgEs to be produced when exposed to certain allergens
102
What is an allele?
Different forms of the same gene
Can be dominant or recessive
Can predispose to disease --> usually mutated versions (eg, CF)
103
What is the screening that is done for CF?
Immunoreactive Trypsinogen (IRT) - Guthrie Test --> If positive, trypsingoen will be present in the blood, due to the duct in the pancreas being blocked
Genetic Screening --> For the most common genetic mutations
Sweat Test --> Cl- above 60mM = CF likely
104
What is the difference between Cyclin/CDKs and CKIs?
Cyclin/CDKs --> Cell growth promoters
CKIs --> Inhibitors.....so cell cycle (growth) suppressors......there are 2 types.....
INK4/p16 --> Inhibit CDK4/6
CIP/Kip (p27) --> Inhibit all CDKs
105
Name 2 pharmacological approches for fixing the ASL in patients with CF
Calcium-Activated Chloride Channel (CACC) Activators Blocking ENaC --> Amiloride
106
How does 3 person IVF work?
The parents embryo is fertilised with the mans sperm
The parents embryo has their nucleus removed, and inserted into a donors embryo that has healthy mitochondria (and no nuclei)
107
What are Tumour Suppressor Genes?
Genes that exert negative effects on cell growth (eg, p53)
So mutations in these will cause an increase in cell growth!!
Usually recessive, so less likely to have full mutations
108
Explain how the differentation of embryonic stem cells occurs
ESCs will form embryoid bodies once they have stopped renewing (around 6 days)
These bodies have three germ layers (endoderm/mesoderm/ectoderm)
After another 10 days, with differentiation factors, the specific cell is formed (for example a cardiomyocyte for the heart)
109
Explain siRNA mediated RNA interference
Short dsRNA (siRNA) binds to a specific part of an mRNA coding region --> Causing mRNA cleavage
110
What's the difference between Heterochromatin and Euchromatin?
Heterochromatin --> Densely packed (condensed) and deacetylated....so not actively transcribed
Euchromatin --> Beads on a string appearance and acetylated....so actively transcribed!
111
What are the 2 types of families of proteins involved in the cell growth cycle? And where abouts are these used?
Cyclins --> Transcription dependent
Cyclin-Dependent Kinases --> Activation dependent
Usually by phosphorylation
112
What is a Single Nucelotide Polymorphism (SNP)? And what criteria needs to be filled for something to be called an SNP?
A variation in a DNA sequence by a single nucleotide, at the same position, in the genome between members of the same species
The variation must occur in at least 1% of the population
113
Generically speaking.... if a molecule involved in cell growth starts with a p (eg, pRb/P53/P16) what do they do?
They inhibit cell growth (suppress it)
So mutations in these will cause an increase in cell growth
114
Where are endogenous steroids made? And what different types are made here?
The Adrenal Cortex
Mineralocorticoids --> Aldosterone
Glucocorticoids --> Cortisol
115
What is a promoter?
A DNA sequence that determines the site of transcription initiation for an RNA polymerase /Transcription factors
116
What is the link between LL37 and Psoriasis?
LL37 is an endogenous antimicrobial thats needed to protect the body when skin is broken
In psoriasis LL37 is over-expressed, allowing more to bind/activate dendritic cells --> Acts as an autoantigen
This triggers an immune response, which causes cytokines like IL-17 to be produced
117
What is NFkB?
Nuclear Factor of Kappa (light chain) in B cells Causes the activation of inflammatory genes
Inhibited by IKb which binds across the Rel domain
118
What are the characteristcs of embryonic stem cells?
They will continue to proliferate almost indefinitely
They will form tumours in immunocompromised rats
They are pluripotent
119
Alkaline phosphotase surface expression is exclusive to what type of stem cell?
Pluripotent embryonic stem cells
120
How does the CRISPR/Cas system work in bacteira to prevent viral infection?
Viral DNA is cleaved by the Cas complex, producing short spacer regions.
These are then inserted into the CRISPR region of the bacterias genome.
The CRISPR is then transcribed and then pairs with TracrRNA to produce a dsRNA that is cleaved by endonuclease III.
This produces (crRNA-tracrRNA) dsRNA sequences.
This binds to Cas9.
This searches for matching DNA from viruses that matches the spacer regions. If found, it is destroyed.
121
What's the difference between miRNA and siRNA? And their effects?
miRNA --> 21 nucleotides long
Target the 3' end of mRNA, causing a prevention of translation
siRNA --> 21 nucleotides long and double stranded
Cleaves mRNA in the coding region
Both interfere using the protein AGO 2
122
Explain what oncogenes are? And what can they can cause?
They are mutated forms of normal genes needed for growth
They are usually dominant, so only one mutation is needed
Point mutations in RAS cause ligand independence (activation without a ligand) due to constitutive activation of EGFR (Epidermal Growth Factor Receptor) and over-expression of genes
123
When are bone-marrow transplants done? And what are the types?
For people whose bone marrow is destroyed during the treatment of myelomas and lymphomas
Autologus --> Self transplant (most common due to lack of rejection)
Allogenic --> Non-self transplant
124
What is the principal cause of mortality in people with Cystic Fibrosis?
Malnutrition due to pancreatic insufficiency
So the pancreas cannot produce the digestive enzymes needed --> so food is not digested properly
Therefore they need Pancreatin (Creon) --> Amylase, Lipase and Protease
125
How do glucocorticoids work?
Bind to intracellular receptors (as GCs are lipophillic)
Bind to their specific receptor inside of the cell, once the receptor has been activated. It is normally held in an inactivated state by the heat shock protein (HSP90)
The complex then translocates to the nucleus to act as a transcription factor. They must bind as dimers to show biological activity
This can cause the repression of anti-inflammatory genes (by controlling gene transcription)
126
Explain a few ways that antisense/siRNA/gRNA can be transported into the body
These are large and negatively charged molecules, so can be hard to get into the body
Packaging of Vesicles --> They are packed inside of a positively charged vesicle (done via negative transfection)
Addition of delivery agents --> Conjugation of cholesterol/peptides with antisense
Electroporation --> Electricity is used to punch holes in the membrane, allowing the molecules to get into them
Viral Carrier --> Lentiviruses can integrate the molecules into the target DNA
127
How does Antisense work?
A single strand of DNA/RNA that is complementary to the mRNA (15-30 nucleotides long) binds
This causes RNase H to split the mRNA into 2, causing it to degrade
128
Define..Functional Genomics Pharmacogenetics Pharmacogenomics
Functional Genomics --> Genomic science in whole cell or in vivo situations
Pharmacogenetics --> The influence of an individuals genetic profile on medicine efficacy and safety
Pharmacogenomics --> Using genetic information in the discovery of new medicines and targets
129
What mutations cause CF and Sickle Cell Anaemia
CF --> 3 nucleotide deletion of phenylalanine in the CFTR (cystic fibrosis transmembrane conductance regulator) channel
Sickle Cell Anaemia --> An SNP (A --> T) of the (B)-globin gene
130
Define what a Stem Cell is, and the different types
Stem Cell --> Unspecialised cells that can proliferate and differentiated into many other cell types
Adult (somatic) / Embryonic (ESC) / Induced pluripotent (iPC)
Totipotent --> Can form all tissues needed for an organism, including the placenta (eg, a fertilised egg)
Pluripotent --> Can form all cells needed for a human, just not the placenta
Multipotent --> Can only form a limited number of cell types (eg, most adult stem cells)
Unipotent --> Can only form one type of cell
131
What is a Simple Sequence Repeat (SSR)?
A tandem repeat of between 2-8 base sequences
Eg, TGTGTG Each person will inherit a different number of these SSRs, which creates a biological fingerprint
132
Explain the effects of losing the CFTR channel in terms of the Air-Surface Liquid (ASL) And how can these effects be dampened?
Usually there is a large layer of mucus (ASL), caused by Cl- ions that are moved by the CFTR channel
However when we remove the CFTR channel, we lost lots of Cl-.... causing a much thinner layer of mucus (ASL), which is dehydrated and sticky.... which makes it harder fo cilia to clear pathogens
Can be partially fixed using hypertonic saline
133
When will a mutation affect the function of a protein?
When the mutation occurs in the coding region of the gene
134
Name 3 new drugs that are being used to treat specific mutations of CF?
Ataluren --> For class I mutations (force through a premature stop codon)
Lumacaftor --> For class II (acts as a chaperone in channel processing) --> Must be with Ivacaftor
Ivacaftor --> For class III (acts as a potentiator)
135
What are the characteristic features of the lung damage done in patients with CF?
Structural changes --> Bronchial wall thickening, and lung collapses
Mucus plugging
Chronic infections
Epithelial Damage
Massive neutrophil infiltration of the airways --> frustrated phagocytosis caused by an inability to clear infections (so neutrophils die)
136
What is AP-1?
Regulates cell growth as well as early response genes
Made up of a dimer of Fos (needs to be transcribed) and Jun (needs to be phosphorylated)
137
What is stem cell differentation driven by?
Growth factors and other extracellular mediators
138
Name the two main things that can move through damaged skin?
Allergens --> Bypass the innate system and directly activate B cells (which create IgE)
Bacteria --> Activate the innate and then adaptive immune systems
139
What are translocation mutations?
Where there are crossovers of chromosomes during cell division
An example is the translocation of bcl-2 which comes under the control of the Ig promotor (as a result of the translocation)
Therefore lots of bcl-2 is produced, and as it is an anti-apoptopic protein, it causes a decreased ability of cells to die by apoptosis
140
What type of inheritance is associated with both huntingtons disease and hypercholesteremia?
Autosomal Dominant
141
Name a few examples of diseases that are caused by X-linked Recessive alleles?
Haemophillia
Colour Blindness
Muscular Dystrophy
142
What are the 3 types of closed wounds?
Contusions (Bruises) --> Blunt force trauma causing tissue damage under the skin
Hematoma --> Damage to the blood vessles under the skin, causing blood accumulation
Crushing Injuries --> Blunt force causing a pressure injury over a long period of time
143
What are the main characteristics of liposomes?
Biodegradable
Biologically inert --> So weakly immunogenic and has a low toxicity
Can alter tissue distribution of the drug they are carrying
144
Describe what hydrogels are, and how drugs are released from them
They can retain large quantities of water (100x their dry weight) but are still water insoluble
Highly hydrated --> Diffusion occurs through pores
Low Hydration --> Drug is dissolved in the polymer, and is transported between the chains
Hydrogels can also swell and cause the drug to be released...dependent on Heat/pH/Application/Electrical current
145
When will dry phospholipids spontaneously swell?
When in water above Tm
146
Explain macromolecular compound gels
Either formed with covalent bonds (thermally irreversible) or physical interactions (thermally reversible)
Type 1 --> 3D network formed with covalent bonds between the macromolecules (thermally irreversible)
Formed by the polymerisation of monomers of water soluble polymers (in the presence of an X-linker)
Type 2 --> Held together by weak intermolecular bonds (thermally reversible)
When cooled below point T, PVA is formed....which are viscous in water --> Allowing for use in topical applications
147
What is a wound?
Any defect, or damage, to the skin as a result of physical/chemical/thermal factors, or as a result of an infectious disease
148
What are the negatives of SLNs? And how do Nanostructured Lipid Carriers (NLCs) fix these?
The crystalline structure causes little space for the actual drug, with it becoming more ordered time goes along (to go to its lowest energy form), expelling the drug! NLCs have a more diverse matrix structure, so there is more room for the active compound
149
What are the 3 types of ethosome?
Classical --> Soft-liquid vesicles composed of phospholipids, water and ethanol (in high conc)
Binary --> The addition of another type of alcohol (PG or isopropyl alcohol (IPA))
Transethosomes --> The addition of a penetration enhancer or surfactant (edge activator) to a classical ethosome
150
Explain the 3 phases of the wound healing process
Inflammatory Phase --> Bleeding occurs to remove toxins before vasoconstriction occurs
The clotting mechanism then kicks in, along with inflammatory mediators much as histamine release.
Vasodilation happens allowing phagocytes to enter the wound
Proliferative Phase --> Granulation occurs, which is the effect of fibroblasts and macrophages stimulating the production of fibrous tissue
Fibroplasia creates a new collagen bed, pulling the wound edges together.... whilst new capillaries are formed (angiogenesis)
The Remodelling Phase --> Fibroblasts create collagen to increase tensile strength. As the collagen matures it X-links
151
What are...OrganogelsXerogelJelly
Organogels --> Organic liquid containing (eg, petrolatum)
Xerogel --> When the liquid is removed, and so only the matrix remains (eg, gelatin sheets)
Jelly --> When the matrix is rich in liquid (ephedrine sulphate jelly)
152
What does cross-linking do in hydrogels?
Increases the hydrophobicity of the gel
Decreases the diffusion rate of the drug
153
What is the difference between an incision and a laceration?
Incision --> A regular wound thats caused by a clean sharp-edged object
Laceration --> A rough irregular wound caused by crushing or ripping forces
154
What are pericytes?
Cells that can migrate from the vasculature and into the wound site
They contract and deposit down collagen
Similar to myofibroblasts
155
What are niosomes?
Bilayered structures that are made of non-ionic surfactant, and cholesterol
These are able to entrap a wide range of chemicals
156
What are the 3 forms of Nanostructured Lipid Carriers (NLCs)
Imperfect --> A blend of solid and liquid lipids with different molecular structures
Amorphous --> Lipid solid matrix in the amorphous state
Multiple Type (O/F/W) --> The drug solubility in oils (liquid lipids) is greater than in solid lipids
157
What affects the rigidity/fluidity of liposomes? And what does this cause?
The alkyl-chain length and degree of unsaturation (saturation = rigid)
Cholesterol --> Makes it more rigid
The more rigid the structure the more stable it is, and so the longer the encapsulated drug will stay inside of the liposome (prolonged release)
158
Explain what occurs as the concentration of amphiphile increases
Phospholipids become ordered into vesicles
Then into a hexagonal columnar phase (middle soap phase)
Then into a lamella phase (neat soap phase) --> where sheets of amphiphiles are separated by water
159
What are physical/supramolecular gels?
Gels that are derived from low molecular mass compounds
Formed through self-aggregation of small gelator molecules to form Self-Assembled Fibrillar Networks (SAFINs)
These SAFINs are formed via many non-covalent interactions, so they are thermally reversible
160
What's the difference between Unilamellar and Multilamellar liposomes?
Unilamellar --> One bilayer surrounds an aqueous core
Multilamellar --> A multitude of concentrically orientated bilayers surrounding the aqueous core
161
What is the definiation of a Gel?
Viscoelastic, solid-like materials comprised of an elastic cross-linked network and a solvent
Mainly composed of the solvent
Relatively unaffected by thermal motion
162
What are the 3 Solid Lipid Nanoparticles (SLN) types?
Homogenous Matrix --> A release form from day 1
Drug Enriched Shell --> A fast compound delivery system (due to the particles being at the edge)
Drug Enriched Core --> A slow, controlled released form (as the drug is in the middle)
163
What are transfersomes?
Ultra-deformable liposomes, composed of phospholipids and additional surfactant/emulsifier ('edge activator')
Elastic vesicles that can permeate in-tact skin
Localised at higher concentrations (in the SC)
Can cause some irritation if the edge activators aren't very pure
164
What are nanomedicines?
The application of technologies on the scale of 1-500nm to diagnose and treat diseases
They are too small to be detected by the immune system
Allow the drug to be delivered to the site of action with smaller doses... so less side effects
Increased drug penetration and stability
165
What are the advantages of Lipid Nanoparticle Carriers?
```
Low toxicity
Small particle size
Increase skin hydration
Reduce skin irritation
Act as a sunscreen
```
166
What are the 4 types of classification of liposomes?
Conventional --> Neutral or negatively charged, and used for targeting of the cells of the mononuclear phagocyte systems (MPS).
Contain mainly phospholipids and/or cholesterol
Sterically Stabilised ('Stealth') --> Has hydrophobic coatings (commonly PEG) to prolong circulation times
Immunoliposomes ('Antibody-targeted') --> These can be conventional or sterically stabilised. Specific antibodies on their surface to enhance target site binding
Cationic --> Positively charged, used for transporting genetic material.
These can cause complement to be activated
167
Name 3 characteristic features of water soluble gels
Large increase in viscosity above gel point (critical polymer concentration)
Appearance of rubber-like elasticity
The gel retains shape under low stress, but will deform at higher stress
168
What is one of the main disadvantages with in using natural polymers in wound healing?
Batch to batch variability
169
Which type of drugs/molecules are suited to nasal delivery?
Acid sensitive drugs
Polar drugs with low BA
Small lipophilic drugs
170
What is the intial hurdle in nasal drug delivery?
Drug deposition in the nasal cavity
171
In nasal drug delivery, when would a drug be absorbed via the paracellular route?
When hydrophillic and a MW greater than 1kDa
172
What are always added to nasal sprays?
Very small amounts of co-solvents --> to improve solubility
Viscosity-modifying agents
Preservatives
Anti-oxidants
173
How can we easily get drugs to the brain?
Via the nose
The olfactory epithelium is an area in which the BBB is not present, so drugs can move through this and into the brain via paracellular diffusion (eg, cocaine)
174
Name 4 ways that we can improve nasal drug delivery
Alter the mucous layer
Increase the contact time with the nasal epithelium (using mucoadhesives)
Use of penetration enhancers
Specialised devices
175
What is a big problem when giving drugs inter-otically, to the middle ear, to children?
Childrens membranes may be more permeable than adults, causing an increase in absorption.....and so possibly more side effects!!
176
What is pseudoplastic flow?
As sheering stress increases, the polymer molecules align themselves more orderly... meaning that as more pressure is added... it becomes less viscous
Viscosity decreasing can also be caused by the release of some of the solvent
This has no yield value!
177
How does steric stabilisation of suspensions occur?
Stabilised by repulsive forces due to absorption of macromolecules or surfactants to their surfaces
178
What is the benefit of topical NSAIDs? When compared to oral NSAIDs.
There is a much lower systemic concentration, and so the common GI side effects do not occur
179
Define Thixotrophy
An isothermal and comparatively slow recovery, on standing of a material, of a consistency lost through shearing
So only occurs for sheer-thinning systems
The down curve is down and to the left of the original up curve
The extent of thixotrophy is defined by the the area between these 2 lines (known as the area of hysteresis)
180
What are generally the most stable emulsions?
Those with a mixture of surfactants and a mixture of HLB values
181
What are the effects of electrolyte concentration on the stability of suspensions?
Low conc --> No secondary minimum is formed, which is needed for pharmaceutical suspensions.
But a large primary maximum
Medium conc --> A secondary minimum is formed, and a suitable primary maximum is also shown (preventing coagulation at the primary minimum)
High conc --> No primary maximum or secondary minimum
182
What does the 'ideal' vehicle for a drug, to permeate the skin have?
Has no pharmacological effect
Solubilizes the drug
Will release the drug with appropriate kinetics
Chemically/Physically stable
Cosmetically appealing
Non-allergenic/irritating
183
What are the 4 common types of viscometer? And what materials can be used in them?
Capillary --> Newtonian only
Falling Sphere --> Newtonian only
Cup-and-Bob --> Newtonian and non-newtonian
Cone and Plate --> Newtonian and non-newtonian
184
Describe microemulsions
Homogenous, transparent, low viscosity colloidal solutions that are very thermodynamically stable (so will form spontaneously)
Eg, small droplets (5-140nm) of one liquid dispersed in another Several surfactants are always used
185
What are the 3 main effects that will cause a change in suspension sedimentation rate?
Increased particle size --> Increase
Increased particle density --> Increase
Increased viscosity --> Decrease
186
Explain the theory of colloid stability
Attractive forces are inversely proportional to the distance apart (so closer = more attraction)
Repulsive forces increase exponentially with distance apart (so closer = less repulsion)
187
What is dilatant flow?
The opposite of a pseudoplastic system.... so as sheering stress is increased, it becomes more viscous
When the stress is removed it will return to its original state
This works by the particles spreading out when under pressure, and their being insufficient vehicle to fill the voids
188
If the colloid particles are negatively charged, why would aluminium ions be useful to form a flocculated system?
As they are positively charged
So they attract the colloid particles via weak interactions, holding them together loosely at the secondary minimum
This prevents caking
189
What are corneodesmosomes?
Major structures in the skin that hold together corneocytes
These need to be degraded for skin to be broken down
190
What will increase/decrease the max flux of a drug across the stratum corneum?
Increase --> An increase in Log P
Decrease --> An increase in Molecular Weight
191
What type of ionization of drugs are best absorbed by the skin?
Unionized
192
Explain the relationship between TransEpidermal Water Loss (TEWL) and the size of the stratum corneum
The less SC that is present, the more water than escapes down its concentration gradient
193
Is a cream containing 0.1% of clobetasone bioequivalent with 0.1% of a clobetasone ointment?
No
As they produce different pharmacological effects
194
Explain how percutaneous absorption occurs
The drug is placed on the skin and moves through the SC via intercellular transport.
It is then uptaken into the blood via passive diffusion
It then diffuses to where it's needed in the body, before partitioning and then diffusing into the capillaries.
It is important that the drug is lipophilic to move through the SC, but not too lipophilic that it cannot move around the body
195
Explain the effect of Propylene Glycol (a co-solvent) on a very lipophillic drug?
By adding PG you increase the drugs solubility in water (up to a degree...as too much and it'll like the PG too much to leave!!)
Without any, the drug will like the lipophilic nature of the SC too much, and so not partition into the aqueous phase (blood)
196
What does a high HLB value mean?
The surfactant is hydrophilic
Low HLB = lipophilic
197
What is meant by the 'Metamorphosis of a formulation'?
When a topical formulation undergoes a considerable change once applied to the skin
The matrix of the formulation could be changed due to the rubbing (involved in application) or due to loss of volatile excipients (often solvents) --> Causing an increase in viscosity
These changes can increase or decrease the drug solubility in the residual phase
198
What is caking? And how can it be prevented?
When secondary energy barriers are overcome, and the particles are forced together at the primary minimum
This is irreversible
This can be avoided by adding a flocculating agent
199
What does 'Lag Time' mean in reference to drugs crossing the SC?
The time taken before a drug reaches the steady state, where the flux is constant
200
Explain what a Newtonian System is?
Where stress is directionally proportional to the rate of sheer
So if the top of a pile is pushed, it will move with a velocity that is directionally proportional to its distance from the bottom
201
What is plastic flow?
When van der Waals forces need to be broken to before flow can occur.
This creates a yield value (of sheering/stress) that needs to be reached before flow will occur.
The higher the yield value = the greater the particle flocculation
The line does not pass through the origin
A non-newtonian system, but acts like one once the yield value has been reached
202
What is the main benefit of W/O emulsions?
They blend easily with SC lipids.....so will increase the BA of lipophilic drugs
Also has a moisturising and cooling effect
203
What's the difference between a Hydrogel and an Emugel?
Hydrogel --> Semi-solid system comprising mainly or large molecules that are inter-penetrated by water
Emugel --> A 2 phase system consisting of large molecules that are interpenetrated by water and a small fraction of emulsified lipids
204
Define Rheology
The study of the flow or liquids, and the deformation of solids
205
How would you make a w/o/w emulsion?
Emulsify an o/w emulsion with hydrophillic surfactants
206
What is Age-related Macular Degeneration (AMD)?
The macular is part of the retina, and is vital for sharp vision..... so AMD causes central vision loss
Dry AMD --> Geographic atrophy
Wet AMD --> Neovascular (excessive growth of blood vessels under the retina)
207
What is the difference in effect on the eye when given Pilocarpine or Atropine
Pilocarpine = Muscarinic agonist.... so miosis of the eye
Atropine = Muscarinic antagonist.... so mydriasis of the eye
208
How does latanaprost (xalatan) work?
A prostaglandin-analogue that reduces intra-ocular pressure via the uveosclereal outflow
209
How does Mydriasis occur?
Sympathetic innervation from the superior cervical ganglion causes the stimulation of radial (dilator) smooth muscle
Caused by NA binding to (a)1 adrenoceptors
210
How does Miosis occur?
Parasympathetic innervation of the ciliary ganglion, with post-ganglionic innervation of the sphinteric (constrictor) muscle
Stimulated by Ach binding to M3 receptors
The parasympathetic NS has a high basal tone, so is more active at rest than the sympathetic....so the pupils are small(ish) at rest
211
What's the difference between open-angle and closed-angle glaucoma?
Open-angle --> Obstruction of aqueous humour through the trabecular meshwork and Canal of Schlemm
Closed-angle --> Block of AH from the posterior to anterior chamber due to a narrowing between the iris and cornea
Common in east-asian and inuit populations
212
What are the 2 types of iris smooth muscle? And what do they do?
Radial --> Dilator
Sphincteric --> Constrictor
So they control the size of the pupil, and so how much light reaches the retina
213
Who is the most at risk of glaucoma?
Those with a family history of it
Very short-sighted people
Diabetic
African/Afro-Caribbean
Older
214
In a healthy eye, how does aqueous humour flow?
It is produced by the ciliary body, then flows from the posterior chamber through the iris and into the anterior chamber
Then through the trabecular meshwork/Canal of schlemm and into the vein. Can also exit through the uveoscleral outflow
215
How would you treat eye problems caused by allergies?
H1 antagonists
Mast Cell Stabilisers --> Sodium cromoglycate)
Glucocorticoids --> Bad in the long run (possible glaucoma)
216
What is glaucoma?
Damage of the optic nerve, usually caused by raised intra-ocular fluid pressure (over >21 mmHg)....causing the loss of peripheral vision
This is determined by the rate of formation and drainage of aqueous humour
217
What is the main contraindication for muscarinic antagonists in the eye?
In closed angle glaucoma --> Due to them impairing the drainage of aqueous humour
218
What are cycloplegics?
Muscarinic antagonists that paralyse ciliary muscle.....and so block accommodation
219
What is Mitomycin C?
A powerful agent that prevents scarring in the eye (post surgery) by inhibiting the multiplication of cells which produce scar tissue
220
How would you treat 'Wet' AMD?
Photodynamic therapy (Verteporforin) to remove leakly blood vessels
Vascular Endothelial cell Growth-Factor (VEGF) inhibitors (eg, pegaptanib)
221
How/where is aqueous humour formed?
Formed in the ciliary body epithelium, driven by the active transport of Na+/HCO3- out of the cell
Stimulated by (B) agonists and carbonic anhydrase
Inhibited by (a) agonists
(a) 1 --> Vasoconstrictors
(a) 2 --> Decrease in cAMP production...causing less NA release
222
With regards to GPCRs, describe the signalling cascade that occurs in Gs proteins. Give a few of the receptors that are Gs linked.
Ligand binds to the receptor.
This stimulates adenylyl cyclase to convert ATP into cAMP
cAMP stimulates PKA to increase intracellular Ca2+
- -> Stimulation results in heart muscle contractions
- -> Smooth muscle relaxation (inhibits myosin MLCK here)
B1, B2
H2
223
With regards to GPCRs, describe the signalling cascade that occurs in Gq proteins. Give a few of the receptors that are Gq linked.
Ligand binds to the receptor
This activates PLC and causes cleavage of a phospholipid from the membrane into PIP2
This splits into DAG and IP3
DAG stimulates PKC (phosphorylating effects)
IP3 stimulates the endoplasmic reticulum to release Ca2 intracellularly
--> results in the smooth muscle contraction
H1, A1,
M1, M3
224
With regards to GPCRs, describe the signalling cascade that occurs in Gi proteins. Give a few of the receptors that are Gi linked.
The ligand binds to the receptor
There is an inhibition in adenylyl cyclase produced, so less ATP is converted into cAMP
cAMP causes PKA stimulation to a lesser degree, and hence less Ca2+ is released intracellularly
M2
A2
