Pharmacology and Therapeutics Flashcards
State some of the abnormal treatments for COPD
Mucolytics –> N-acetyl cyteine and DNAse
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 arachiodonic acid to be converted to leukotrienes via 5-lipoxygenase
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)
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
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 inhibiton using ACh and NA
What does sodium cromoglycate do?
Reduces the activity of airway sensory nerves
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
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
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
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
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
What can oxidant stress cause? In terms of histone decacetylase (HDAT)?
Glucocorticoid insensitivity…..so inflmmatory transcription will carry on
What is a cough?
A motor reflex in response to sensing chemicals, particulates and airway excessive mucus
What specificity does Rofluimase 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
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
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 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
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 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
What treatments would you give for the following…..
Plaque Psoriasis (trunk and limbs)
Scalp Psoriasis
Face/Flexural/Genital Psoriasis
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
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
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 avaliable (but not in the UK)
Define Difficult Asthma
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
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
What does Theophylline do?
Inhibits phosphodiesterase so cAMP is not broken down –> bronchodialation
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
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 acivate M3, causing Gq to upregulate PLC –> which increases calcium levels. This stimulates MLCK which causes vasoconstriction
Describe what the structure of Tuberculosis is
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
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
Explain the differences in how Salmeterol, Formoterol and Salbutamol interact with B2 receptors
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
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
According to the GOLD guidlines, what therapy route should you follow if they are in group D?
LAMA
LAMA+ LABA
LAMA + LABA + ICS
+ Roflumilast if FEV1 under 50% of predicted and chronic bronchitis
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)
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
Whats the pharmacological pathway that should be followed in asthma?
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)
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
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 bronchodialation
Also activates K+ channels and myosin phosphotase –> decreasing smooth muscle contractility
Describe Nicotinic receptors
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)
