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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

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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)

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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16
Q

Of all the problems with pMDIs….which is the greatest problem (statistically) for patients?

A

A slow inhalation (30L/min)

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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

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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)

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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

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20
Q

What is a Nebuliser?

A

A drug contained within a sterile solution

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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

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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

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23
Q

What is the goal of new/recent nebulisers?

A

Enhance output

Shorten nebulisation time

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24
Q

What is the key change in salbutamol, making it selective to B2 receptors?

A

Replacing the phenol with a Hydroxymethylene group

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25
Q

What are the key SAR points for Beta agonists (from cathecholines)

A

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

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26
Q

Give a few examples of where lead compounds (in SAR) can be found?Why aren’t these compounds used directly as clinical drugs?

A

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

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27
Q

What is the function of Neuraminidase and Haemagglutinin?

A

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

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28
Q

What do the following class of drugs act on?And what do they block?B2 AgonistsAntimuscarinics

A

B2 Agonists –> Bind to adrenergic receptors, blocking noradrenaline

Antimuscarinics –> Bind to muscarinic receptors, blocking ACh

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29
Q

Why is prednisolone more active than cortisone?

A

As it is flatter, so it binds to the receptors with more affinity/potency.

Whereas cortisone has sp2/3 groups, so its not flat

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30
Q

What is the influenza vaccine?

A

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

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31
Q

What was the main problem with ACh as a drug?And how did SAR end with Ipratropium?

A

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

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32
Q

What are the first line and second line drugs for the treatment of TB?

A

First Line –> Isoniazid (or streptomycin), Rifampicin, Pyrazinamide and Ethambutol

Second Line –> Ciprofloxacin (or another fluroquinolone)

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33
Q

Explain the basis behind Zanamivir (Relenza) and Oseltamivir (Tamiflu) And when are these drugs most important?

A

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 inhalerOseltamivir –> Modification made to improve BA

Tablets or a syrup

Most important during epidemics, as there is no protection!

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34
Q

Describe the structure of influenza

A

ssRNAEnveloped

An orthomyxovirusHas both Neuraminidase (cleaves sialic acid from glycoconjugates) and Hemmaglutinin (binds to sialic acid receptors)

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35
Q

Explain the 4 types of influenza?

A

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

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36
Q

What is the purpose of mineralcorticoids?

A

They regulate electrolyte balance, especially salt levels (Na+)

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37
Q

What is Antigenic drift? (in relation to influenza A)

A

The gradual accumulation of mutations in AA code, changing the form of influenza A –> allowing it to avoid produced antibodies

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38
Q

Why can’t we always fight off influenza?

A

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)

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39
Q

Whats the difference between cortisone and cortisol?

A 
Cortisone = Ketone at carbon 11
Cortisol = Alcohol at carbon 11
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40
Q

What must always be present at the 11 position of steroids?

A

A hydrogen bonding capable molecule (eg, OH/C=O)

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41
Q

Whats the difference between pandemic and seasonal influenza?

A

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

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42
Q

Describe the 2 types of influenza treatments

A

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

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43
Q

What are the limiting factors of the influenza vaccine?

A

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

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44
Q

What is Zanamivir (Relenza)?

A

A transition-state analogue

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45
Q

Draw adrenaline

A
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46
Q

Draw Acetylcholine

A
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47
Q

How does normal cholinergic signalling work and with what feedback loops?

A

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

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48
Q

What specificity does Roflumilast have?And what does this cause?

A

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

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49
Q

Explain Histone acetyltransferase (HAT) and Histone Deacetylase, and their effects in inflammation

A

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

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50
Q

Why does an increase in excitatory nerve activity lead to hyperresponsivness?

A

As more ACh binds to M3 (GPCR), activating PLC… which ends up forming more Ca2+ –> which causes contraction of smooth muscle

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51
Q

COPD is a term used to describe conditions such as Chronic Bronchitis and Emphysema…. explain these

A

Chronic Bronchitis –> Productive cough (excessive sputum) present for years

Emphysema –> Alveolar wall destruction and irreversible enlargement of terminal air spaces

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52
Q

Describe what the structure of Tuberculosis is

A

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

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53
Q

What is the main reason for a drop in FEV1 in COPD patients?How could we stop this?

A

Mucus blockage

Muscarinic antagonists (eg, tiotropium)
Neurokinin antagonists
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54
Q

What’s the difference between homotropic and heterotropic inhibition?

A

Homotropic –> Acts on the same cell type

Heterotropic –> Acts on different types of cell
This is usually inhibition using ACh and NA

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55
Q

Explain the 4 stages of primary tuburculosis progression

A

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

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56
Q

How does Omalizumab work?

A

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

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57
Q

Describe Muscarinic receptors

A

Postganglionic receptors –> GPCRsM1 –> Create slow EPSP due to closing K+ channels, so does cause depolarisation eventually

M2 –> Increases K+ conductance, so causes hyperpolarisation via a slow IPSP

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58
Q

What is the difference between Hyperplasia and Hypertrophy of muscle cells?

A

Hyperplasia = More muscle cells

Hypertrophy = Bigger muscle cells

These are both stimulated by inflammation

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59
Q

State some of the abnormal treatments for COPD

A

Mucolytics –> N-acetyl cyteine and DNAse

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60
Q

What does Theophylline do?

A

Inhibits phosphodiesterase so cAMP is not broken down –> bronchodialation

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61
Q

How would you diagnose active and latent tuberculosis?

A

Active –> Chest X-ray, sputum tests and molecular assays

Latent –> Tuberculin skin test (forms a skin lesion) and molecular tests

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62
Q

What subtypes of (A) and (B) adrenoceptors are more selective to NA or A?

A

Adrenaline –> More selective to B2 and A2

Noradrenaline –> More selective to B1 and A1

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63
Q

What are the natural mechanisms of bronchodilation?

A

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

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64
Q

What are the functions of the subtypes of (A) and (B) adrenoceptors?How do these work?

A

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

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65
Q

How do glucocortiocids work?And how do LTRAs (eg, Zileutin and Montelukast) work differently?

A

By inhibiting PLA2, and so the formation of arachidonic acidsLTRAs inhibit 5-lipoxygenase (zileutin) and leuktotrienes (montelukast)

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66
Q

What is the main cause of emphysema?

A

Lung elastases that degrade elastin, the basement membrane and connective tissue

These are derived from neutrophils and macrophagesIncreased after smoking

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67
Q

Explain the differences in how Salmeterol, Formoterol and Salbutamol interact with B2 receptors

A

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

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68
Q

Explain some of the mechanisms of COPD

A

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

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69
Q

What are common in mast cells granules?

A

Histamine (less in the lungs, so antihistamines can’t be used)

Cytokines (eg, TNF)
Proteases
Heparins
Leukotrienes and Prostanoids

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70
Q

What are some of the actions of IL-13 and IL-4?

A

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)

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71
Q

What is Alondronate?

A

A biphosphonate used in osteoporosis

Causes apoptosis of bone-reabsorbing osteoclasts, and inhibits their activation

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72
Q

In terms of arachiodonic acid metabolism, what bad effect can be caused as a result of aspirin/ibuprofen?

A

Aspirin/Ibuprofen inhibit COX (prostaglandin formation)

This causes more arachidonic acid to be converted to leukotrienes via 5-lipoxygenase

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73
Q

Explain how extrinisic allergy (asthma) occurs?

A

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

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74
Q

Why dont asthma drugs work well in COPD?

A

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

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75
Q

Why is tiotropium better than ipratropium?

A

As tiotropium binds more selectively to M3 than M2, allowing the negative feedback loop to be retained –> which decreases ACh production

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76
Q

What is COPD sputum enriched with?

A

NeutrophilAsthma –> Eosinophilic

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77
Q

What is so good about Aclidinium?

A

Its a muscarinic antagonist that has a fast ‘off’ time at M2 receptors….so the negative feedback loop is preserved

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78
Q

What does PEFR and FEV1 stand for?And what do they mean in terms of asthma sufferers?

A

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

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79
Q

How does pre/post-synpatic modulation occur? (excluding ACh and NA)

A

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)

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80
Q

How do the 4 anti-TB drugs work?

A

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

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81
Q

What is a cough?

A

A motor reflex in response to sensing chemicals, particulates and airway excessive mucus

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82
Q

Describe Nicotinic receptors

A

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)

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83
Q

How can TB resistance occur?And what are the 2 types of resistant strains?

A

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

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84
Q

What does sodium cromoglycate do?

A

Reduces the activity of airway sensory nerves

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85
Q

What can oxidant stress cause? In terms of histone decacetylase (HDAT)?

A

Glucocorticoid insensitivity…..so inflammatory transcription will carry on

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86
Q

Exactly how does salbutamol (B2-agonists) work?

A

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

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87
Q

Exactly how does ipratropium (M3 antagonists) work?How would an agonist of M3 work differently?

A

Bind toand 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

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88
Q

What is dry eye syndrome? (ketoconjunctivitis sicca)

A

A lack of tear production, or too much tear evaporation

Caused by a problem with the tear film

Main complications = Keratitis and conjunctivitis

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89
Q

What are liposomal sprays?

A

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

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90
Q

What treatments would you give for the following…..Plaque Psoriasis (trunk and limbs)Scalp PsoriasisFace/Flexural/Genital Psoriasis

A

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
Q

In which direction does RNA polymerase move?And therefore in which direction is mRNA made?

A

3’ –> 5’mRNA

made from 5’ –> 3’

92
Q

What are the stages of the cell growth cycle?

A

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
Q

How is Cortisol secreted in the body?

A

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
Q

Why can chemotherapy cause damage to our own cells, but not always the tumour cells?

A

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
Q

Explain X-linked recessive Alleles?

A

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
Q

Explain the anti-inflammatory effects of glucocorticoids

A

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
Q

What are the 4 normal control mechanisms of the body to prevent loss of function from mutations?

A

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
Q

Describe the characteristics of Adult (Somatic) Stem Cells

A

They can proliferate….but not indefinitelyMultipotent/unipotent cells

Located in stem cell niches

Replace worn out/dead cells –> so important for homeostasis

99
Q

What is the difference between Homodimers and Heterodimers?

A

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) –> 5bpBind direct repeat half sites

100
Q

What will a mutation in the gene IL36RN do?

A

Cause pustular psoriasisIL36RN usually helps regulate inflammation by suppressing cytokines like IL-1

101
Q

Explain two reasons for Atopic Eczema?

A

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
Q

What is an allele?

A

Different forms of the same gene

Can be dominant or recessive

Can predispose to disease –> usually mutated versions (eg, CF)

103
Q

What is the screening that is done for CF?

A

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
Q

What is the difference between Cyclin/CDKs and CKIs?

A

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
Q

Name 2 pharmacological approches for fixing the ASL in patients with CF

A

Calcium-Activated Chloride Channel (CACC) ActivatorsBlocking ENaC –> Amiloride

106
Q

How does 3 person IVF work?

A

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
Q

What are Tumour Suppressor Genes?

A

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
Q

Explain how the differentation of embryonic stem cells occurs

A

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
Q

Explain siRNA mediated RNA interference

A

Short dsRNA (siRNA) binds to a specific part of an mRNA coding region –> Causing mRNA cleavage

110
Q

What’s the difference between Heterochromatin and Euchromatin?

A

Heterochromatin –> Densely packed (condensed) and deacetylated….so not actively transcribed

Euchromatin –> Beads on a string appearance and acetylated….so actively transcribed!

111
Q

What are the 2 types of families of proteins involved in the cell growth cycle?And where abouts are these used?

A

Cyclins –> Transcription dependent

Cyclin-Dependent Kinases –> Activation dependent

Usually by phosphorylation

112
Q

What is a Single Nucelotide Polymorphism (SNP)?And what criteria needs to be filled for something to be called an SNP?

A

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
Q

Generically speaking…. if a molecule involved in cell growth starts with a p (eg, pRb/P53/P16) what do they do?

A

They inhibit cell growth (suppress it)

So mutations in these will cause an increase in cell growth

114
Q

Where are endogenous steroids made?And what different types are made here?

A

The Adrenal Cortex

Mineralocorticoids –> Aldosterone

Glucocorticoids –> Cortisol

115
Q

What is a promoter?

A

A DNA sequence that determines the site of transcription initiation for an RNA polymerase /Transcription factors

116
Q

What is the link between LL37 and Psoriasis?

A

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
Q

What is NFkB?

A

Nuclear Factor of Kappa (light chain) in B cellsCauses the activation of inflammatory genes

Inhibited by IKb which binds across the Rel domain

118
Q

What are the characteristcs of embryonic stem cells?

A

They will continue to proliferate almost indefinitely

They will form tumours in immunocompromised rats

They are pluripotent

119
Q

Alkaline phosphotase surface expression is exclusive to what type of stem cell?

A

Pluripotent embryonic stem cells

120
Q

How does the CRISPR/Cas system work in bacteira to prevent viral infection?

A

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
Q

What’s the difference between miRNA and siRNA?And their effects?

A

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
Q

Explain what oncogenes are?And what can they can cause?

A

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
Q

When are bone-marrow transplants done?And what are the types?

A

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
Q

What is the principal cause of mortality in people with Cystic Fibrosis?

A

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
Q

How do glucocorticoids work?

A

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
Q

Explain a few ways that antisense/siRNA/gRNA can be transported into the body

A

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
Q

How does Antisense work?

A

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
Q

Define..Functional GenomicsPharmacogeneticsPharmacogenomics

A

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
Q

What mutations cause CF and Sickle Cell Anaemia

A

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
Q

Define what a Stem Cell is, and the different types

A

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
Q

What is a Simple Sequence Repeat (SSR)?

A

A tandem repeat of between 2-8 base sequences

Eg, TGTGTGEach person will inherit a different number of these SSRs, which creates a biological fingerprint

132
Q

Explain the effects of losing the CFTR channel in terms of the Air-Surface Liquid (ASL)And how can these effects be dampened?

A

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
Q

When will a mutation affect the function of a protein?

A

When the mutation occurs in the coding region of the gene

134
Q

Name 3 new drugs that are being used to treat specific mutations of CF?

A

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
Q

What are the characteristic features of the lung damage done in patients with CF?

A

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
Q

What is AP-1?

A

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
Q

What is stem cell differentation driven by?

A

Growth factors and other extracellular mediators

138
Q

Name the two main things that can move through damaged skin?

A

Allergens –> Bypass the innate system and directly activate B cells (which create IgE)

Bacteria –> Activate the innate and then adaptive immune systems

139
Q

What are translocation mutations?

A

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
Q

What type of inheritance is associated with both huntingtons disease and hypercholesteremia?

A

Autosomal Dominant

141
Q

Name a few examples of diseases that are caused by X-linked Recessive alleles?

A

Haemophillia
Colour Blindness
Muscular Dystrophy

142
Q

What are the 3 types of closed wounds?

A

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
Q

What are the main characteristics of liposomes?

A

Biodegradable

Biologically inert –> So weakly immunogenic and has a low toxicity

Can alter tissue distribution of the drug they are carrying

144
Q

Describe what hydrogels are, and how drugs are released from them

A

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
Q

When will dry phospholipids spontaneously swell?

A

When in water above Tm

146
Q

Explain macromolecular compound gels

A

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
Q

What is a wound?

A

Any defect, or damage, to the skin as a result of physical/chemical/thermal factors, or as a result of an infectious disease

148
Q

What are the negatives of SLNs?And how do Nanostructured Lipid Carriers (NLCs) fix these?

A

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
Q

What are the 3 types of ethosome?

A

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
Q

Explain the 3 phases of the wound healing process

A

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
Q

What are…OrganogelsXerogelJelly

A

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
Q

What does cross-linking do in hydrogels?

A

Increases the hydrophobicity of the gel

Decreases the diffusion rate of the drug

153
Q

What is the difference between an incision and a laceration?

A

Incision –> A regular wound thats caused by a clean sharp-edged object

Laceration –> A rough irregular wound caused by crushing or ripping forces

154
Q

What are pericytes?

A

Cells that can migrate from the vasculature and into the wound site

They contract and deposit down collagen

Similar to myofibroblasts

155
Q

What are niosomes?

A

Bilayered structures that are made of non-ionic surfactant, and cholesterol

These are able to entrap a wide range of chemicals

156
Q

What are the 3 forms of Nanostructured Lipid Carriers (NLCs)

A

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
Q

What affects the rigidity/fluidity of liposomes?And what does this cause?

A

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
Q

Explain what occurs as the concentration of amphiphile increases

A

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
Q

What are physical/supramolecular gels?

A

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
Q

What’s the difference between Unilamellar and Multilamellar liposomes?

A

Unilamellar –> One bilayer surrounds an aqueous core

Multilamellar –> A multitude of concentrically orientated bilayers surrounding the aqueous core

161
Q

What is the definiation of a Gel?

A

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
Q

What are the 3 Solid Lipid Nanoparticles (SLN) types?

A

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
Q

What are transfersomes?

A

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
Q

What are nanomedicines?

A

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
Q

What are the advantages of Lipid Nanoparticle Carriers?

A 
Low toxicity
Small particle size
Increase skin hydration
Reduce skin irritation
Act as a sunscreen
166
Q

What are the 4 types of classification of liposomes?

A

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
Q

Name 3 characteristic features of water soluble gels

A

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
Q

What is one of the main disadvantages with in using natural polymers in wound healing?

A

Batch to batch variability

169
Q

Which type of drugs/molecules are suited to nasal delivery?

A

Acid sensitive drugs
Polar drugs with low BA
Small lipophilic drugs

170
Q

What is the intial hurdle in nasal drug delivery?

A

Drug deposition in the nasal cavity

171
Q

In nasal drug delivery, when would a drug be absorbed via the paracellular route?

A

When hydrophillic and a MW greater than 1kDa

172
Q

What are always added to nasal sprays?

A

Very small amounts of co-solvents –> to improve solubility

Viscosity-modifying agents

Preservatives

Anti-oxidants

173
Q

How can we easily get drugs to the brain?

A

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
Q

Name 4 ways that we can improve nasal drug delivery

A

Alter the mucous layer

Increase the contact time with the nasal epithelium (using mucoadhesives)

Use of penetration enhancers

Specialised devices

175
Q

What is a big problem when giving drugs inter-otically, to the middle ear, to children?

A

Childrens membranes may be more permeable than adults, causing an increase in absorption…..and so possibly more side effects!!

176
Q

What is pseudoplastic flow?

A

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
Q

How does steric stabilisation of suspensions occur?

A

Stabilised by repulsive forces due to absorption of macromolecules or surfactants to their surfaces

178
Q

What is the benefit of topical NSAIDs? When compared to oral NSAIDs.

A

There is a much lower systemic concentration, and so the common GI side effects do not occur

179
Q

Define Thixotrophy

A

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
Q

What are generally the most stable emulsions?

A

Those with a mixture of surfactants and a mixture of HLB values

181
Q

What are the effects of electrolyte concentration on the stability of suspensions?

A

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
Q

What does the ‘ideal’ vehicle for a drug, to permeate the skin have?

A

Has no pharmacological effect

Solubilizes the drug

Will release the drug with appropriate kinetics

Chemically/Physically stable

Cosmetically appealing

Non-allergenic/irritating

183
Q

What are the 4 common types of viscometer?And what materials can be used in them?

A

Capillary –> Newtonian only

Falling Sphere –> Newtonian only

Cup-and-Bob –> Newtonian and non-newtonian

Cone and Plate –> Newtonian and non-newtonian

184
Q

Describe microemulsions

A

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 anotherSeveral surfactants are always used

185
Q

What are the 3 main effects that will cause a change in suspension sedimentation rate?

A

Increased particle size –> Increase

Increased particle density –> Increase

Increased viscosity –> Decrease

186
Q

Explain the theory of colloid stability

A

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
Q

What is dilatant flow?

A

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
Q

If the colloid particles are negatively charged, why would aluminium ions be useful to form a flocculated system?

A

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
Q

What are corneodesmosomes?

A

Major structures in the skin that hold together corneocytes

These need to be degraded for skin to be broken down

190
Q

What will increase/decrease the max flux of a drug across the stratum corneum?

A

Increase –> An increase in Log P

Decrease –> An increase in Molecular Weight

191
Q

What type of ionization of drugs are best absorbed by the skin?

A

Unionized

192
Q

Explain the relationship between TransEpidermal Water Loss (TEWL) and the size of the stratum corneum

A

The less SC that is present, the more water than escapes down its concentration gradient

193
Q

Is a cream containing 0.1% of clobetasone bioequivalent with 0.1% of a clobetasone ointment?

A

No

As they produce different pharmacological effects

194
Q

Explain how percutaneous absorption occurs

A

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
Q

Explain the effect of Propylene Glycol (a co-solvent) on a very lipophillic drug?

A

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
Q

What does a high HLB value mean?

A

The surfactant is hydrophilic

Low HLB = lipophilic

197
Q

What is meant by the ‘Metamorphosis of a formulation’?

A

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
Q

What is caking?And how can it be prevented?

A

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
Q

What does ‘Lag Time’ mean in reference to drugs crossing the SC?

A

The time taken before a drug reaches the steady state, where the flux is constant

200
Q

Explain what a Newtonian System is?

A

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
Q

What is plastic flow?

A

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
Q

What is the main benefit of W/O emulsions?

A

They blend easily with SC lipids…..so will increase the BA of lipophilic drugs

Also has a moisturising and cooling effect

203
Q

What’s the difference between a Hydrogel and an Emugel?

A

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
Q

Define Rheology

A

The study of the flow or liquids, and the deformation of solids

205
Q

How would you make a w/o/w emulsion?

A

Emulsify an o/w emulsion with hydrophillic surfactants

206
Q

What is Age-related Macular Degeneration (AMD)?

A

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
Q

What is the difference in effect on the eye when given Pilocarpine or Atropine

A

Pilocarpine = Muscarinic agonist…. so miosis of the eye

Atropine = Muscarinic antagonist…. so mydriasis of the eye

208
Q

How does latanaprost (xalatan) work?

A

A prostaglandin-analogue that reduces intra-ocular pressure via the uveosclereal outflow

209
Q

How does Mydriasis occur?

A

Sympathetic innervation from the superior cervical ganglion causes the stimulation of radial (dilator) smooth muscle

Caused by NA binding to (a)1 adrenoceptors

210
Q

How does Miosis occur?

A

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
Q

What’s the difference between open-angle and closed-angle glaucoma?

A

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
Q

What are the 2 types of iris smooth muscle?And what do they do?

A

Radial –> Dilator

Sphincteric –> Constrictor

So they control the size of the pupil, and so how much light reaches the retina

213
Q

Who is the most at risk of glaucoma?

A

Those with a family history of it

Very short-sighted people
Diabetic
African/Afro-Caribbean
Older

214
Q

In a healthy eye, how does aqueous humour flow?

A

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
Q

How would you treat eye problems caused by allergies?

A

H1 antagonists

Mast Cell Stabilisers –> Sodium cromoglycate)

Glucocorticoids –> Bad in the long run (possible glaucoma)

216
Q

What is glaucoma?

A

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
Q

What is the main contraindication for muscarinic antagonists in the eye?

A

In closed angle glaucoma –> Due to them impairing the drainage of aqueous humour

218
Q

What are cycloplegics?

A

Muscarinic antagonists that paralyse ciliary muscle…..and so block accommodation

219
Q

What is Mitomycin C?

A

A powerful agent that prevents scarring in the eye (post surgery) by inhibiting the multiplication of cells which produce scar tissue

220
Q

How would you treat ‘Wet’ AMD?

A

Photodynamic therapy (Verteporforin) to remove leakly blood vessels

Vascular Endothelial cell Growth-Factor (VEGF) inhibitors (eg, pegaptanib)

221
Q

How/where is aqueous humour formed?

A

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
Q

With regards to GPCRs, describe the signalling cascade that occurs in Gs proteins. Give a few of the receptors that are Gs linked.

A

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
Q

With regards to GPCRs, describe the signalling cascade that occurs in Gq proteins. Give a few of the receptors that are Gq linked.

A

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
Q

With regards to GPCRs, describe the signalling cascade that occurs in Gi proteins. Give a few of the receptors that are Gi linked.

A

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

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