Pharmacology and Therapeutics

Question 1

State some of the abnormal treatments for COPD

Answer 1

Mucolytics –> N-acetyl cyteine and DNAse

Question 2

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

Answer 2

Aspirin/Ibuprofen inhibit COX (prostaglandin formation)

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

Question 3

How do glucocortiocids work?

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

Answer 3

By inhibiting PLA2, and so the formation of arachidonic acids

LTRAs inhibit 5-lipoxygenase (zileutin) and leuktotrienes (montelukast)

Question 4

What is so good about Aclidinium?

Answer 4

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

Question 5

What’s the difference between homotropic and heterotropic inhibition?

Answer 5

Homotropic –> Acts on the same cell type

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

Question 6

What does sodium cromoglycate do?

Answer 6

Reduces the activity of airway sensory nerves

Question 7

What does PEFR and FEV1 stand for?

And what do they mean in terms of asthma sufferers?

Answer 7

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

Question 8

What are the functions of the subtypes of (A) and (B) adrenoceptors?

How do these work?

Answer 8

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

Question 9

How would you diagnose active and latent tuberculosis?

Answer 9

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

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

Question 10

How do the 4 anti-TB drugs work?

Answer 10

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

Question 11

What are liposomal sprays?

Answer 11

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

Question 12

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

Answer 12

Glucocorticoid insensitivity…..so inflmmatory transcription will carry on

Question 13

What is a cough?

Answer 13

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

Question 14

What specificity does Rofluimase have?

And what does this cause?

Answer 14

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

Question 15

What is the main reason for a drop in FEV1 in COPD patients?

How could we stop this?

Answer 15

Mucus blockage

Muscarinic antagonists (eg, tiotropium)

Neurokinin antagonists

Question 16

Explain the 4 stages of primary tuburculosis progression

Answer 16

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 tubercules. 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

Question 17

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

Answer 17

Histone acetyltransferase (HAT) –> Unpacks chromatin, allowing transcription to occur….allowing more inflammation gene expression

This is inhibited by glucocorticoids –> which promotes inflammation!!

Histone Deacetylase –> Wraps DNA closely, not allowing transcription

We need more of this as it will prevent transcription of inflammation markers….. but cigarrete

Question 18

What treatments would you give for the following…..

Plaque Psoriasis (trunk and limbs)

Scalp Psoriasis

Face/Flexural/Genital Psoriasis

Answer 18

Plaque Psoriasis (trunk and limbs) - An emolient and potent topical corticosteroid

Scale Psoriasis - Potent topical corticosteroid (and maybe coal-tar shampoo)

Face/Flexural/Genital Psoriasis - An emolient and mild corticosteroid

Question 19

What is dry eye syndrome? (ketoconjunctivitis sicca)

Answer 19

A lack of tear production, or too much tear evaporation

Caused by a problem with the tear film

Main complications = Keratitis and conjunctivitis

Question 20

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

Answer 20

Increased eosinophil adhesion and migration

Increased mucous secretion

Tissue remodelling

Increases airway smooth muscle contractibility

Anti IL-13 and IL-13 receptor antibodies avaliable (but not in the UK)

Question 21

Define Difficult Asthma

Answer 21

Asthma with symptoms despite being on step 4/5 plus….

An event of acute severe asthma which is life threatening, requiring invasive ventilation within the last 10 years OR

Requirement for oral corticosteroids for at least 6 months at a dose of 7.5mg prednisolone daily OR

2 hospitilisations in the last 12 months OR

Fixed airflow obstruction with a post bronchodilator FEV of less than 70% of predicted normal

Question 22

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

Answer 22

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

Question 23

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

Answer 23

Hyperplasia = More muscle cells

Hypertrophy = Bigger muscle cells These are both stimulated by inflammation

Question 24

What does Theophylline do?

Answer 24

Inhibits phosphodiesterase so cAMP is not broken down –> bronchodialation

Question 25

How does **Omalizumab** work?

Answer 25

**Binds to the Fc part of IgEs**, so they cant bind to mast cells....so no degranulation can occur Only recommended if glucocortiocids dont work first

Question 26

What is the main cause of **emphysema**?

Answer 26

**Lung elastases** that degrade elastin, the basement membrane and connective tissue These are derived from neutrophils and macrophages Increased after smoking

Question 27

Describe **Muscarinic** receptors

Answer 27

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

Question 28

How can some people with **COPD get respiratory acidosis**?

Answer 28

CO2 levels increase to a very high level during an exacberation, which normally would increase breathing rate..... However if given high oxygen levels then this stimuli is suppressed as the patients suddenly have loads of oxygen!! So the CO2 is kept in...caused respiratory acidosis

Question 29

Name **4 steroid sparing** agents

Answer 29

Methotrexate Ciclosporin Gold (oral) Terbutaline (IV) **These all have a lot of side effects**

Question 30

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

Answer 30

Bind to and block M3 (muscarinic) receptor Usually an agonist would acivate M3, causing Gq to upregulate PLC --\> which increases calcium levels. This stimulates MLCK which causes vasoconstriction

Question 31

What is **COPD sputum** enriched with?

Answer 31

**Neutrophil** Asthma --\> Eosinophilic

Question 32

Describe what the structure of Tuberculosis is

Answer 32

**Acid Fast Bacteira** Cell wall rich in lipids --\> therefore very hydrophobic and so resistant to weak disinfectants and drying This also prevents gram stain tests being successful

Question 33

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

Answer 33

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

Question 34

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

Answer 34

**Salmeterol** --\> Highly lipophillic, so interacts with the membrane and diffuses into the receptor laterally (so long acting but slow onset) **Formoterol** --\> A little lipophillic, so leaches out of the membrane to interact with the membrane (long acting and fast onset) **Salbutamol** --\> Quite hydrohpillic, so has a short duration of action as it gets washed away from the receptors

Question 35

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

Answer 35

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

Question 36

How does Mepolizumab work?

Answer 36

**Binds to IL-5** Preventing it (the cytokine IL-5) from binding to its receptor on the surface of eosinophils

Question 37

Why is **tiotropium** better than ipratropium?

Answer 37

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

Question 38

Explain some of the **mechanisms of COPD**

Answer 38

**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

Question 39

According to the **GOLD guidlines**, what therapy route should you follow if they are in **group D**?

Answer 39

**LAMA** **LAMA+ LABA** **LAMA + LABA + ICS** **+ Roflumilast** if FEV1 under 50% of predicted and chronic bronchitis

Question 40

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

Answer 40

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)

Question 41

How should **COPD be diagnosed?**

Answer 41

Using **post-bronchodialator spirometery**

Question 42

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

Answer 42

**Chronic Bronchitis** --\> Productive cough (excessive sputum) present for years **Emphysema** --\> Alveolar wall destruction and irreversible enlargement of terminal air spaces

Question 43

Whats the **pharmacological pathway that should be followed in asthma**?

Answer 43

**SABA** (as reliever) --\> Salbutamol + **Low dose ICS** --\> Beclametasone + **LTRA** --\> Montelukast +/- **LABA** --\> Salmetarol Change LABA and ICS to a **MART therapy** (Fast acting LABA + low ICS) --\> Eg, formaterol Then to mid ICS Then to high ICS Then either LAMA (tiotropium) and SABA (salbutamol) or Phosphodiesterase inhibitor (theophyline)

Question 44

Explain how extrinisic allergy (asthma) occurs?

Answer 44

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

Question 45

What is **Alondronate**?

Answer 45

A biphosphonate used in osteoporosis Causes apoptosis of bone-reabsorbing osteoclasts, and inhibits their activation

Question 46

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

Answer 46

**Adrenaline** --\> More selective to B2 and A2 **Noradrenaline** --\> More selective to B1 and A1

Question 47

What are common in mast cells granules?

Answer 47

Histamine (less in the lungs, so antihistamines can't be used) Cytokines (eg, TNF) Proteases Heparins Leukotrienes and Prostanoids

Question 48

What are the natural mechanisms of bronchodilation?

Answer 48

**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 gunaylate cyclase

Question 49

Exactly how does **salbutamol (B2-agonists)** work?

Answer 49

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 bronchodialation Also activates K+ channels and myosin phosphotase --\> decreasing smooth muscle contractility

Question 50

Describe **Nicotinic** receptors

Answer 50

Preganglionic receptors --\> Ligand-gated ion channels which open when ACh is bound **A pentama** --\> 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)