Person centred care: Disease, medicines and patients Flashcards
Organisation of the nervous system:
Nervous system
into
Central Peripheral
I I
Brain and Somatic
spinal cord autonomic
What’s the 3 protective layers that protect the brain and spinal cord called ?
The Meninges
What are the 2 types of matter the spinal cord consists of ?
1) Grey matter
2) White matter
Grey matter:
cell bodies
and UNmyelinated neurones
makes up outer layer of brain
White matter:
Myelinated axons containing ascending (carry sensory info) and descending tracts ( carry motor info).
Function of the Cerebellum ?
Voluntary muscle contraction and posture
Whats the Mesencephalon ?
Mid brain
helps motor skills
mainly for eyes and ears.
mmmmmmmmmmid
What are the 2 parts that make up the “mesencephalon” ?
1) Tectum- 2 pairs of colliculi
Auditory function (inferior) and visual function (anterior).
2) Tegmentum-
Grey matter round
Substantia nigra ( body movement)
What makes up the 2 parts of the Diencephalon ?
1) Thalamus
2) Hypothalamus
What is the cerebrum also known as ?
The cerebral cortex
2.4 mm thick
contains folds and grooves
What is the function of the limbic system ?
Regulation of feeding,fightand flight
What is the function of the basal ganglia ?
Connected to substantia nigra
- controls large automatic movement of the skeletal muscles.
What are the two types of primary motor cortexs ?
1) primary motor cortex
2) Primary somatic cortex
Primary motor cortex :
- frontal lobes
- specialised for control of movement
Primary somatic cortex ?
- posterior lobes
- specialised for perception.
Receives information such as:
pain
touch pressure
temperature
-Also primary visual and auditory cortex.
What is the function of the association cortex ?
Receives info from primary cortex.
- involved in processing high amount of information.
- any damage caused to this cortex, such as pain pressure temp and touch or auditory senses.
Small molecule transmitters in the CNS (3) :
1) Monoamines
2) Acetylcholine
3) Amino acids
What is the large molecule transmitter in the CNS ?
Neuropeptides
Where are nicotinic receptors found (Acetlycholine) ?
On muscle fibres
Where are the muscarinic receptors found ( Acetylcholine) ?
Found both peripherally, and in the CNS
What are the 3 catecholamines produced from tyrosine ?
1) Adrenaline
2) noradrenaline
3) Dopamine
These are all monoanimes
What is the function of noradrenergic receptors ?
involved in controlling alertness
What is the function of dopamine ?
Movement
Attention
Learning
What are the receptors for dopamine ?
D1,D2,D3,D4,D5
What does the degeneration of the dopaminergic neurone of the nigrostrital tract lead to ? ( what disease):
Parkinsons
What dopamine receptor has been related to schizophrenia ?
D2
What is the the precursor of serotonin ?
-Tryptophan
Which helps to make serotonin and melatonin.
melatonin helps regulate sleep cycle
serotonin regulates APPETITE, SLEEP, MOOD AND PAIN.
What are the 3 main amino acid transmitters (in the CNS) ?
1) Glutamic acid (glutamate)
2) GABA( Gabba amino butyric acid)
3) Glycine
What are the 3 ionotropic receptors ( Glutamic acid) ?
1) NMDA receptors
2) AMPA receptors
3) Kainite
What is synaptic plascity ?
The ability of neurones to strengthen their connections
NMDA receptors :
Controls a ion channel, ion channel is entry of sodium and ca+ ions
and exit of K+ ions.
- This ion channel requires glycine as a co-agonist.
ion channel is inhibitied by Mg 2+ ions
Is GABA an inhibitory or excitatory type of amino acid ?
inhibitory
important in controlling neural activity, as well as preventing seizures.
What type of ion channel is GABBA associated with ?
Cl - ion channel
Divided into 2 different types : Type A and Type B
Type A
(GABBA A receptor)
- When GABBA binds Cl- channel opens.
Type B receptor
(GABBA B receptor)
- Receptor recognises different agonists/ antagonists
bringsabout inhibitory effects via G proteins
Glycine:
inhibitory transmitter
- Also enhances the effects of NMDA receptors.
Located in the spinal cord and lower brain.
- Similar to GABBA A receptor.
Where does Glycine bind to ?
binds allosterically to GLUTAMATE receptors.
Neuropeptides:
Around 50 qualify as actual neurotransmitters.
- most well known are “opiates” in the CNS which bind to receptors in the brain.
What is the blood brain barrier (BBB):
A layer of epithelial cells in the brain.
Which has tight junctions between the cells.
Main function is to prevent entry of harmful toxins into the brain.
With regards to Blood brain barrier, what does adding more polar groups to molecules trying to get through the BBB do ?
will make it harder for them to pass through the BBB
In drug development and design, is it good or bad if frug enters the brain ?
Good if carrying out neurological treatment,
bad if carrying out any other type of treatment,
as to avoid neurological side effects.
What does ABC transporter stand for ?
ATP-binding cassette (ABC) transporter.
Whats an example of an ABC transporter ?
(ATP-binding cassette)
p-glycoprotein
This transporter can eject a lot of molecules, even before therapeutic concentration is reached.
^ not goog famalam
What are Nociceptors ?
Free nerve endings that are receptors for pain, everywhere except the brain.
sharp fast pain:
Carried out by A-fibres
0.1 seconds after stimulus
slow pain:
What type of neurones carry this out ?
carried out by unmyelinated C fibres.
1 second after stimulus.
What is superficial somatic pain ?
pain from nociceptors on the skin.
What is deep somatic pain ?
pain in a joint or tendon etc
What’s Visceral pain ?
Pain from organ nociceptors.
What are NSAIDs ?
Non-steroidal anti-inflammatory drugs.
How do local anaesthetics wot=rk ?
They work by reversibly blocking action potential
being carried along nerves.
E.g. by blocking Na+ voltage operated channels.
so nociceptor nerves can’t carry pain signals. Analgesia occurs
On a general basis during action potential generation is there more Na+ or K+ ions outside the cell ?
more Na+ ions INSIDE the cell
And more K+ ions OUTSIDE the cell
what are the 3 sequence of events that generally occur during the firing of an action potential ?
1) Polarisation ( Na+ ion channel opens, Na+ rushes into the cell)
2) Depolarisation (positive charge distributed)
3) Repolarisation ( K+ ion channel opens, K+ rushes out of cell, more negative potential on the inside).
Hence, the cell is repolarised
What does it mean when we say local anaesthetics are “use dependent” ?
This means that the faster the fire rate of a nerve (normally for smaller diameter neurones),
the more efficient the anaesthetic will be at blocking it.
This means they are more likely to enter Na+ VOCs that are open.
What is the general chemical structure of a local anaesthetic ?
1) Lipid-soluble hydrophobic AROMATIC group
2) Charged hydrophilic AMIDE group.
The bond between these groups determine whether the drug is a (amide or an ester)
For local anaesthetic what type of bond is stronger ?
The amide bond
is stronger than ester linkage
ester linkage can be easily broken.
If an ester linkage is more easily broken than an amide bond, what does this mean ?
This means that ester drugs are LESS stable and can’t be stored for as long as amide drugs.
Amide anaesthetics are also more heat stable,
and therefore, they can be “autoclaved” (sterilised by heat).
What has a less chance of causing an allergic reaction esters or amides ?
Amides
This is because the metabolism of esters produce PABA, which is associated with allergic reactions.
What does PABA stand for ?
Para-aminobenzoic acid
What are the 4 main ways of adminstering local anaesthetics ?
1) Surface anaesthesia, by topic application to skin or mucous membrane.
2) Infiltration anaesthesia, by subcutaneous injection.
3) Intracerebral anaesthesia
4) Intravenous anaesthesia
How does “infiltration anaesthesia” work ?
How is it administered
By subcutaneous injection,
causing nociceptive nerves to be blocked.
In dentistry “infilatration” is used more.
What is “Epidural” ?
Injecting the anaesthetic outside the “spinal dura mater”
What is intrathecal administration ?
Spinal injection into cerebrospinal fluid in the subarachnoid space.
What is the most commonly used topical anaesthetic ?
Lidocaine.
From what “poppy flower” does opium come from ?
Papaver Somniferum
was taken orally for 200 years as “ Tincture of laudanum”.
What actually is an opioid ?
Anything with “morphine- like actions”
including endogenous and synthetic agents.
What is a Narcotic ?
these drugs are used for opioids.
normally addictive drugs which are illegal.
What are the 3 opioid receptors called ?
1) mu
2) delta
3) Kappa
What type of receptors are the 3 opioid receptors classed as .
G protein coupled receptors,
which inhibit adenylyl cyclase
reducing the amount of intracellular cAMP (Cyclic AMP).
With regards to opioid receptors, what does “reducing 2nd messenger conc” do ?
Affects cell function.
stimulated opioid receptors,
Are able to inhibit the synaptic functions of neurones.
by acting on ion channels.
How do mu and delta opioid receptors, reduce neuronal excitability.
They cause K+ ion channel to open
hyperpolarising the nerve
harder to become depolarised
Reduction in neuronal excitability.
How do mu and delta opioid receptors, control potassium ion channels ?
Whatactually causes the K+ ion channel to open ?
1) Receptor inactive and unoccupied
2) An opioid agonist binds to the receptor and activates it,
and it’s g-protein diffuses across the membrane.
3) Activated g protein causes K+ channel to to open,
allowing the k+ ions to diffuse out the cells
cell loses positive charge, and hence becomes hyperpolarised.
What is the function of activated k-opioid receptors (kappa) ?
inhibits the opening of N-type Ca2+ channels.
How do k-opioid receptors have an affect on neuro transmission ?
inhibiting the n-type ca2+ channel,
will mean fewer vesicles will be released
reducing neurotransmission
Which type of the 3 opioid receptor is associated with producing “analgesia” ?
mu-opioid receptor.
What are the most common side effects of opioids ?
1) Respiratory depression (as respiratory centre becomes less sensitive to co2 in the blood), controlled by mu-receptors in the medulla.
2)Nausea and vomiting
3) Pupillary constriction
4) Constipation
5) Itching, bronchoconstriction, vasodilation, hypotension.
6) Sedation
7) Euphoria, controlled by mu- receptors
What’s the most common lethality from using opioids ?
Respiratory arrest.
What are strong opioids used for ?
to treat dull, visceral pain.
morphine
diamorphine
fentanyl
pethidine
What are weak opioids used for ?
To control mild-moderate pain
codeine (20% the potency of morphine)
What is epimerisation ?
Swapping from R to S chiral centres and vice versa.
Not beneficial
SAR of morphine ?
Exists as a natural single enantiomer
its unnatural enantiomer has no analgesic effect.
What are 2 other uses of opioids ?
1) cough supressing
2) Anti-diarrhoeal preparations.
Whats an example of a drug that acts as an opioid antagonist ?
Naloxone
this has affinity for all opioid receptor sub-types.
What are opiod antagonists used for ?
To reverse problems
such as respiratory depression etc.
Why might opiod antagonists be bad for opioid users ?
In opioid users they may cause unwanted side-effects (dysphoria)
However, in non-opioid users there will be very little effect.
Sigma receptor (for opioids):
These receptors are not blocked by naloxone.
not classified as true opioid receptors.
- non-opioid drugs are also able to bind to sigma receptors (e.g. phencyclidine)
balances euphoric effects, with dysphoric.
What is the definition of “tolerance” ?
Tolerance is the increase in dose needed,
to produce a given pharmacological effect.
4 advantages of a tablet ?
1) Simple n convenient
2) allows for accurate dosing
3) can be used for both local and systemic treatment
4) cost effective (established manufacturing technologies).
3 Disadvantages of a tablet ?
1) may be difficult to administer to very young/elderly patients.
2) slow onset of action
3) Absorption and bioavailability can be difficult.
how to create extended release tablets ?
reduce solubility.
Delayed release tablet:
Drug is released after a certain period of time (e.g. 4-6hours).
The drug reaches the small intestine,
a change in pH causes the API to be released.
what is the most common type of delayed release tablets ?
Enterically coated tablets (EC).
the coating is gastro-resistant, and can withstand acidic conditions.
What 7 things are required for tablet formulation:
1) Diluents (fillers): bulk up the API. (e.g.lactose,starch)
2) Binders: Hold particles together (e.g. starch, modified cellulose, sugars)
3) Disintegrants: Break up the tablet into drug particles, to allow dissolution and absorption. (e.g. starch)
4) Glidants: Improve power flowability. (e.g. silicon dioxide)
5) Lubricants: to avoid punch face filming. (e.g. Mg and Ca)
6) Wetting agents: to improve interaction of water molecules with the tablet body and surface during disintegration and dissolution. (e.g. Sodium dodecyl sulphate SDS).
7) Others- ( colouring, sweetener and flavour).
- Usually for chewable and effervescent tablets.
E.g. Riboflavin (orange) colourant.
Why have “tablet coatings” ?
- increase palitibility by smoothening the surface
- minimise unpleasant tastes
- improve visual appearance
- anti-counterfeiting measures
- contain highly potent compounds in the body.
- protect stomach from irritation, to to protect API from acidic stomach environment.
what are the 4 types of tablet coatings ?
1) film coating ( water based) 2-5% of tablet’s weight.
2) Sugar coating (20-50% of tablet’s weight)
3) Gelatine
4) Enteric coating
What are 3 factors that affect the rate of bioavailability ?
1) Disintegration (tablet breaks up into granules)
2) Deaggregation( granules break up into particles)
3) Dissolution( release of API)
At each stage the SA of the particles increases,
which means rate of dissolution increases.
what are caplets ?
Capsule shaped tablets
what makes up a big component of effervescent tablets ?
High sodium carbonate/bicarbonate content.
- not usually formulated with a binder.
what are the most common drugs to treat neuropathic pain ?
gabapentin and Pregabalin.
can also be used to treat epilepsy.
What is neuropathic pain ?
When nerve fibres become damaged.
they send incorrect nerve signals to other pain receptors.
what do benzodiazepines do ?
make the actions of GABA more potent.
binds to regulatory site,
causiing change in shape of the GABAA receptor,
allowing it to bind more efficiently, giving a greater effect.
what do azapirones (buspirone) try to do ?
Reduce the release of 5-HT.
to try reduce anxiety.
What is ischaemia ?
when blood flow is restricted
causing the concentration of oxygen to be reduced
What does CECS stand for ?
Chronic exertional compartment syndrome
Usually during exercise.
lack of muscle control
blood can flow into an area, but can’t drain out
causing discomfort and swelling
what does DOMS stand foor ?
Delayed onset muscle soreness
muscle stiffness and muscle tenderness.
What is eccentric exercise ?
Exercise where your muscles act as “brakes”
e.g. when you try to slow down whilst running
Do muscles shorten or lengthen during eccentric exercise ?
They lengthen
What may cause DOMS what type of exercise might cause DOMS ?
Eccentric exercise
what is the normal path of treatment for “mild sport injuries” ?
NSAIDs
e.g. ibuprofen
What are “autacoids” ?
molecules which can alter the functions of other cells.
NSAIDs work by interfering with autacoids
They inhibit COX
what does Cyclo-oxygenase stand for /
COX
it is a derivative of arachidonic acid
What are the 2 isomers of cox ?
COX 1 : involved in homeostatic regulation
COX 2: present in low levels normally, but present in high levels during inflammation
what happens during inflammtion ?
Blood flows to the affected area
causing increased redness and warmth.
what makes up a group of eicosanoids ?
prostaglandalins
how do prostaglandins make histamines more potent ?
They increase post capillary venule permeability
causing swelling to be enhanced
what does anti-pyretic mean ?
Reduced temperature and fever
what’s an non-selective NSAID ?
inhibits both COX-1 and COX-2
What can inhibition of COX-1 lead to ?
reduced mucosal protection of the stomach,
And GI ulcers may be formed
What can inhibition of Cox-2 lead to ?
Therapeutic effect
Due to reduction in prostanoid synthesis
are NSAIDs OTC/P/POM ?
Mainly POM
Some may be OTC
what happens when an NSAID binds to a cox enzyme ?
binds reversibly
This binding, renders platelets unable to produce TxA2.
So they are not stimulated
and phospholipase C is not stimulated
So no inositol triphosphate is produced
which means Ca2+ levels does not increase and platelets remain inactive
viscosity of the blood DECREASES
CAn aspirin be used as an “antiplatelet” drug ?
yes
but only at low doses for mild to moderate pain
Also aspirin can bind to cox 1 irreversible
If aspirin binds irreversible to cox-1, how can we combat this ?
by producing NEW platelets
(takes 7-10 days)
the only way to bring platelet function back to normal
For arterial thrombosis, what is more effective “anti platelet drugs” or “anticoagulants” ?
Anti platelet drugs
What are the side effects of NSAIDs ?
- gastric discomfort
- nausea vomiting
- indigestion (dyspepsia)
- skin rashes
what happens if an asthmatic patient takes an NSAID ?
Their lung alveoli constricts.
may lead to an asthmatic attack.
NSAIDs must not be supplied to asthmatic patients
How do NSAIDs affect renal function ?
They reduce renal function
Why is renal function reduced when taking NSAIDs ?
inhibition of prostaglandins,
Causes renal artery to contract
which means blood flow to the kidneys is reduced
This may even lead to renal failure
Therefore NSAIDs are not supplied to patients with kidney injuries (AKI: Acute kidney injury)
What are the 3 main uses of NSAIDs ?
1) Analgesic
2) anti-inflammatory
3) anti pyretic
After a sports injury, how long must the patient wait before taking NSAIDs ?
48 hours
as first you want the natural healing mechanism from the “inflammatory pathway” to kick start the healing.
why were COX-2 inhibitors developed ?
To help remove the unwanted side effects that occurred by “COX-1 inhibition”.
E.g.(negating the effects COX 1 have on the gastrointestinal mucosa lining, allwoing it to be protected)
What is the difference between COX-1 and COX-2 binding sites ?
COX-2 has a bigger binding site and contains a “side-pocket”
COX-1 has a narrow binding site
do non-selective NSAIDs bind to COX-1/2 binding sites ?
Can bind to both
as they are small enough
How is “clot formation” prevented by cox-1 enzymes ?
They produce PGI
which acts against the TxA, that is released by platelets
preventing clot formation
Does administering a COX-2 inhibitor increase/decrease production of PGI ?
And how could this be dangerous ?
Decreases production of PGI,
but TxA is still produced by platelet COX-1.
which means the balance has shifted towards TxA,
increasing the risk of developing thrombosis.
What are the different ways NSAIDs have been altered, to limit or control side effects ?
1) Enteric coating (protect from stomach ulceration)
2) Soluble preparations- preventing NSAIDs to be concentrated in one area of the stomach.
3) Suppositories: provides an alternative absorption route.
What are the 3 main different types of capsule shell coatings ?
1) Gelatine (some can be used as a suppository as they are soft)
2) HMPC (Hydroxypropyl methylcellulose)
3) PVA ( polyvinyl alcohol)
is bioavailability high or low with capsule formations ?
High
As capsule shells are designed to dissolve rapidly when it comes in contact with GI fluids.
Why is Gelatine actually used to coat capsules ?
- colourless translucent substance, which is tasteless
- readily soluble in biological fluids at body temp
- it is brittle when dry
- And it is elastic when wet and forms a semi-solid gel.
- cost-effective to produce
what are the potential disadvantages of using gelatine capsules ?
- very sensitive to heat and moisture
so special packaging and storage may be required.
- may cause solubility problems with different formulations
what are the components required to create “hard and soft gelatine capsules” ?
1) Gelatine
2) water
3) Colourants
4) Preservatives
5) excipients
Advantages of hard gelatine capsules (3):
1) can make it easier to administer very low doses (micro doses), due to semi-solid formulation.
2) fewer excipients required
3) better oral bioavailability than tablets
Disadvantages of hard gelatine capsules (4):
1) May be difficult to manufacture
2) capsule production used to be slower than tablet production, until “high speed capsule filling equipment was developed.
3) More costly to develop than tablets
4) Not all drugs can be encapsulated.
3 advantages of soft gelatine capsules:
1) A good choice for “non-palatable” solutions
2) Great for delivering lipid soluble drugs at low doses
3) Can be immediate, slow or sustained release, also an enteric coat can be added.
4 Disadvantages of soft gelatine capsules:
1) Restricts formulation that can be encapsulated
2) Hard to optimise manufacturing process
3) If one capsule breaks during manufacturing or whilst in storage, formulation could leak onto others
this leads to increase waste.
4) moisture sensitive drugs are incompatible with the “moist nature” of the soft gelatine capsules
5) They are temperature sensitive (contents inside should not exceed 35 degrees Celsius).
what’s one example of a hard gelatine capsule related to the musculoskeletal system ?
Diclomax SR
what’s one example of a soft gelatine capsule related to the musculoskeletal system ?
Nurofen liquid capsules
What is a pharmaceutical powder ?
API as crystalline solids that can be made into finely divided solids.
what are pharmaceutical granules ?
Like a powder but bigger particle sizes
- big physical aggregates of powder particles.
- help to increase “flow” and “compatibility”.
- easier to handle when exposed to moisture than “powders”.
What are the 2 types of granulation ?
1) Dry granulation
2) Wet granulation
What is Dry granulation ?
Compaction of powder without water
What is Wet granulation ?
Addition of water to powder
followed by mixing and removal of the water.
What are the 2 different types of powders ?
1) Bulk powders: Found in large containers
2) Divided powders: Individually packaged pre measured doses.
4 Advantages of powder/granules formulation:
1) More chemically stable than liquid formulations
2) Easier to dispense in large doses
3) fast absorption rate
4) Advances in packaging tech, means that it is becoming easier to make divided doses easier to separate.
4 Disadvantages of powder/granules formulation:
1) Not as convenient as small containers of tablets
2) more difficult to mask unpleasant taste, to mask taste it has to be converted into “effervescent” form.
3) Hard to administer low doses
4) Can not be used for oral administration
The destruction of “what” causes rheumatoid arthritis ?
- proliferation of synovium
-destruction of cartilage between joints, and also bone by “osteoclasts”.
- inflammation of cytokines.
why might acute phase proteins, bind to infectious agents ?
To function as opsonins
-Enhancing the uptake by macrophages and neutrophils.
What are “autoantibodies” ?
Antibodies that react with “self-antigens”
Whats an example of an “autoantibody”
Immunoglobulin G
Also known as IgG or IgM
- found in all Rheumatoid arthritis patients
Does IgG function as an antibody or an antigen ?
Actually it can function as BOTH and antigen and an antibody
what are the 2 types of “arthritis” ?
RA (autoimmune- body immune system cells attack the joints)
OA (wear and tear)
what are the long term drugs used to treat RA called ?
DMARDs
Disease modifying anti-rheumatic drugs
- causes long term reduced swellings and joint pains
- causes level of plasma acute phase proteins to decrease.
when do the effects of DMARDs start to kick in ?
3 months after
slow onset of action
- in the mean time NSAIDs may be used to reduce symptoms
What is recommended, when starting a treatment with a DMARD ?
“short term bridging treatment” with a corticosteroid
- to help control symptoms.
whilst waiting for the effects of the DMARD to kick in
Why may long term treatment with corticosteroids, not recommended ?
Due to adverse effects that may occur
- wight gain
- mood changes
What are the 2 main types of DMARDs ?
1) DMARDs that supress rheumatic disease process
2) Cytokine modulators (biologics) derived from antibodies
DMARDs that supress “rheumatic disease process” :
They supress or modify immune response
But this can also mean an increase risk of infections
due to interfering with the normal immunological response
How long does it take for the effects of “DMARD methotrexate treatment” to kick in when trying to treat RA ?
Takes 1 month
And treatment can then be long term with appropriate monitoring
How many times a week is DMARD methotrexate given ?
Once a week ONLY
usually by oral admin
What are the potential side effects of taking more DMARD methotrexate than recommended ?
- nausea
- stomatitis (inflammation of buccal lining)
- liver cirrhosis
- pneumonitis (inflammation of lung tissue)
Why might taking NSAIDs whilst on methotrexate be toxic ?
NSAIDs may reduce the rate of renal clearance of methotrexate
leading to increase risk of toxicity
what else might be harmful take, whilst on treatment with DMARD methotrexate ?
Trimethoprim
- if taken together could lead to agranulocytosis or neutropenia
Agranulocytosis- deficiency of granulocytes in the blood, causing an increase in vulnerability to infections.
Neutropenia- low number of white blood cells in the blood
could be fatal
what can be taken to reduce the toxicity of methotrexate treatment ?
Folic acid
But should only be taken Once a week ONLY
and should not be taken on the same day as methotrexate.
What is Azathioprine ?
It’s a prodrug that acts as an immunosuppressant
by inhibiting the increase of B and T lymphocytes
What is a common use of the immunosuppressant “azathioprine” ?
To stop rejection from transplanting organs.
Side effects of Azathioprine ?
- nausea
- diarrhoea
- vomiting
- liver toxicity
-bone marrow suppression
- increase risk of infections (due to potential over suppression of lymphocytes)
What is bone marrow suppression ?
Fewer blood cells being produced in the bone marrow
What is the first symptom of bone marrow suppression ?
Sore throat
What are Antimalarials ?
Drugs with long half lives
used to treat mild RA
- not as effective as other DMARDs
When taking antimalarials, what type of examination is required ?
Eye examination
as retinopathy could occur (damage of retina) by taking antimalarials
- patients may be advised to wear sunglasses
What does penicillamine treat ?
RA
but can mess up taste buds
and its enantiomer (L-penicillamine) is toxic as it inhibits the action of pyridoxine.
What does Sulfasalazine treat ?
A DMARD with fewer side effects than other DMARDs
reduces lymphocyte proliferation and cytokine production.
Treat ulcers and chron’s disease, and inflammation in the bowels.
Whats one way to reduce GI irration ?
Enteric coating
What are the 2 main types of corticosteroids ?
1) Mineralocorticoids (regulate salt and water balance)
2) Glucocorticoids ( regulate carbs, fats and proteins in response to stress).
What are corticosteroids used for ?
Anti inflammatory and immunosuppressant agents
by inhibiting phospholipase A2 and COX-2
What happens during adrenal suppression ?
1) Glucocorticoid levels rise in the blood
2) this is detected by the hypothalamus
3) Causes pituitary gland to secrete less adrenocorticotrophic hormone (ACTH).
4) Glucocorticoid synthesis is reduced
What do steroids kinda do ?
Kinda decrease the functions of the adrenal gland
What is “Cushing’s syndrome” ?
Redistribution of body fat
- puffy facial cheeks
- Thin skin- harder to heal from wounds and injuries.
- Osteoporosis (weak bones)
caused by excess amount of corticosteroid hormones being released
What are “osteoclasts” ?
Cells that reabsorb bone by digging “pits”
What are osteo blasts ?
Cells that secrete “osteoid” (bone matrix) into the “pits” that osteoclasts dig.
- The osteoid is then mineralised, resulting in calcium phosphate crystals being made.
What are bones made up of ? ( 3 things)
calcium
Phosphate
protein mesh work
What hormone controls the secretion of Ca2+ ions ?
Parathyroid hormone (PTH)
PTH is secreted by the parathyroid gland when Ca2+ conc is low.
What stimulates the activation of viatamin D ?
The reabsorption of Ca2+ ions by the kidney.
what does the hormone “calcitonin” do ?
-Inhibits “calcium mobilisation” (from bone to blood).
-And also decreases reabsorption from the renal tube.
What is “osteopenia” ?
Reduction of minerals in the bone
What is “osteoporosis” ?
Reduction in actual bone mass
How to treat osteoporosis ?
1) Hormone replacement therapy
2) Selective Oestrogen receptor modulators (SERMs): may help to (E.g. Raloxifene)
- increase osteoblast activity
-reduce osteoclasts
Raloxifene has a low bioavailability but is well distributed around the body.
3) PTH fragments: Help to increase bone mass by stimulating increase in osteoblast numbers. Given subcutaneously.
They do this by acting on GPCR
activating adenyl cyclase
and raise intracellular CA2+ levels
4) Bisphosphates: Promote apoptosis of osteoclasts, causing bone reabsorption to be inhibited.
- given orally
- due to potential GI irritation caused by food (milk). patient is advised to remain upright for 30 mins after taking drug.
What is “rickets” ?
condition that causes the softening of bones.
to prevent rickets increase vitamin D intake
- In adults rickets is known as “osteomalacia”
What to eat to increase vitamin D intake ?
Eat oily fish (Salmon and mackerel)
eggs
margarine
cereal
sun light
can be administered as calcitriol (active form of vitamin D)
Or ergocalciferol (inactive form of vitamin D).
what is osteoarthritis (OA) ?
joint pain
long term condition
most common type of arthritis in the uk
develops in people over the age 45
Can paracetamol reduce prostaglandin synthesis ?
Sometimes it can in some situations
what is the toxic dose range of paracetomal ?
Around 10-15 grams
- no symptoms occur for 24 hours after overdose.
- but irreversible liver damage reaches peak by 72-96 hours.
How is paracetamol overdose treated ?
Ideally N-acetylcysteine should be administered with the first 8-10 hours of overdose.
- this helps to speed up the replenishment of “glutathione”
- potential liver transplant if damage too severe.
what is “gout” ?
Type of arthritis where crystals of sodium urate form around and inside joints.
- acute joint pain in hands or feet due to excess uric acid.
Acute drug treatments for gout ?
1) Naproxen or NSAID
2) Colchicine - does not cause fluid retention unlike NSAIDs, so can be used in heart patients.
- also may be toxic at high doses.
3) Corticosteroids: for people who cant tolerate NSAIDs.
Can aspirin be used to treat gout ?
No
can inhibit the nephron tubule from uric acid in urine.
causing build up of uric acid
not gooood.
Drug treatments for established gout :
Allopurinol
decreases production of uric acid by non- competitive inhibition of xanthine oxidase.
reverses deposition of crystals.
- not used for for acute treatment.
- painful as reduction in uric acid, causes crystals to dissolve, which escape into joint cavity and inflame the synovium.
What are the 3 steps to manage “nociceptive pain” created by “WHO” ?
(neurology card made late)
made after finished making cards for musculoskeletal.
1) Administer simple analgesics (paracetamol, ibuprofen)
2) Weak opioids
3) Strong opioids
What are the 2 most common drugs used to treat “neuropathic pain” ?
(neurology card made late)
1) Gabapentin (used first line)
2) Pregabalin ( used second line)
What’s a fun fact about gabapentin and pregabalin ?
(neurology card made late)
As well as being able to treat neuropathic pain
They can also treat “epilepsy”.
What do “benzodiazepines” do to GABA ?
(neurology card made late)
Potentiate GABA
by changing the shape of the “GABA type A receptor”, causing it to bind more efficiently to neurotransmitter and give a greater effect.
- Also causes chloride channel to open, causing more Cl- ions to flow through the channel giving a greater inhibitory effect.
What “clinical effects” does the binding of benzodiazepines to its allosteric site produce ?
(neurology card made late)
induce sleep
reduced senses
mild amnesia
reduced muscle tone
What is the function of Azapirones (buspirone) ?
(neurology card made late)
To inhibit release of 5-HT
- well absorbed
- short half life
nausea and dizziness are common side effects.
What are the 2 types of dopamine receptors ?
(neurology card made late)
1) D1 type: D1 and D5 linked to ACTIVATION of adenylyl cyclase
2) D2 type: D2,D3,D4 subtypes
- linked to INHIBITION of adenylyl cyclase
- effective as antipsychotics.
What are the 2 class types for “anti-schizophrenic drugs” ?
(neurology card made late)
1) typical: first generation drugs
- chloromazapine, haloperidol
- binds to D1 and D2 receptors
- may lead to unwanted side effects
2) atypical: second generation
- Clozapine, risperidone
– more selectivity for D2 receptors
- May reduce unwanted side effects (by blocking 5-HT2A receptors)
What is the “cheese reaction” for MAOI ?
(neurology card made late)
A possibility of “hypertension” occurring for people who each cheese whilst taking a MAOI drug.
- caused by an interaction with “tyramine”.
How is MAOI overdose treated ?
(neurology card made late)
To treat the hypertension, “phentolamine” can be given.
To treat hypotension, it is not treated with a drug, due to risk of developing “hypertension”.
How do “Tricyclic antidepressants” (TCAs) work ?
(neurology card made late)
Work by competitively inhibiting the reuptake of neurotransmitter from synapses.
- Which means more NA and 5-HT remain in the synapses
- Eventually, allowing mood to improve.
How is TCA overdose treated ?
And what are the side effects of TCAs ?
(neurology card made late)
- Dry skin ( cant sweat)
- Dry mouth
- blurred vision
To treat administer “activated charcoal”
to prevent further GI absorption.
Seizures can be supressed with “diazepam”
What does SSRIs stand for ?
(Neurology card made late)
Selective serotonin reuptake inhibitors
Commonly prescribed as antidepressants
How do SSRIs work ?
(Neurology card made late)
-Work by INHIBITING 5-HT reuptake
-Causing increase in 5-HT concentrations
What actually happens when 5-HT is inhibited by SSRIs (acute and chronic treatment) ?
(Neurology card made late)
Acute treatment: Initially causes “autotecptors” to be activated
-to inhibit release of 5-HT.
Chronic treatment:
-Causes auto receptors to desensitise.
- causing an increase in the release of 5-HT.
What are the advantages of SSRIs ?
(Neurology card made late)
- reduced antimuscarinic effects
- safer overdose than an overdose of TCAs
- don’t cause “cheese reaction” with MAOIs
Disadvantage of SSRIs ?
(Neurology card made late)
Only treat moderate depression
TCAs treat more severe depression
Why are SSRIs not recommended for patients under 18 years old ?
(Neurology card made late)
It can initially cause to become
Excessively Excited
And even aggressive
And even insomnia
What is the downside of treating with venlafaxine anti depressant) ?
(Neurology card made late)
higher risk of withdrawal effects compared to other anti depressants.
is treatment with anti depressants short term or long term ?
(Neurology card made late)
Long term
At least 9 months
When changing the anti depressant drug being administered, how long do you have to wait before administering a new SSRI or TCA ?
(Neurology card made late)
2-3 weeks following the last MAOI dose.
- And MAOIs can not be introduced again for 3 weeks following TCA and SSRI therapy (5 weeks after fluoxetine).
What is one anti depressant that does not require a “wash out period” ?
(Neurology card made late)
Moclobemide (maoi)
Is overdose risk greater with TCAs MAOIs or SSRIs ?
(Neurology card made late)
TCAs
Except for lofepramine.
What plays an important part in “voluntary muscle control” ?
(Neurology card made late)
The basal ganglia
What is Parkinsonism a result of ?
(Neurology card made late)
Imbalance between excitatory and inhibitory inputs.
What is the most common parkinsonism ?
(Neurology card made late)
idiopathic parkinsonism
What causes idiopathic parkinsonism to occur ?
(Neurology card made late)
Neurodegeneration( loss of neurones) of the basal ganglia
causing a reduction in dopaminergic cells of the substantia nigra (modulates motor movement).
- Also a net increase of INHIBITORY GABAergic output occurs.
What percentage of neurones is lost, even before symptoms for parkinsonism develops ?
(Neurology card made late)
Over 80%
What is Bradykinesia ?
(Neurology card made late)
slowness of movement
symptom of parkinsonism
What is tremor ?
(Neurology card made late)
Shaking
Most recognisable symptom of parkinsonism
What is postural instability ?
(Neurology card made late)
Affects ability to balance
increases risk of falling
Symptom of parkinsonism
Initially, what is the most effective oral drug to treat PD ?
(Neurology card made late)
Co-careldopa
Its a pro drug
A drug which must undergo metabolic processes before becoming pharmacologically acitve.
Can dopamine cross the BBB ?
(Neurology card made late)
No its too polar
What’s more polar levodopa or dopamine ?
(Neurology card made late)
levodopa
If levodopa is more polar, how can it cross the BBB ?
(Neurology card made late)
levodopa is an amino acid
so can take advantage of “protein carrier systems”
What happens to levodopa once it is in the brain after crossing the BBB ?
(Neurology card made late)
It is decarboxylated and converted into dopamine.
What enzyme decarboxylates levodopa to dopamine in the brain ?
(Neurology card made late)
Dopa decarboxylase.
What is present in co-careldopa, that causes inhibition oof dopa decarboxylase ?
(Neurology card made late)
Carbidopa
Carbidopa inhibits dopa decarboxylase
And therefore inhibits transformation of levodopa to dopamine.
- causing side effects to be reduced.
What causes Alzheimer’s ?
(Neurology card made late)
Loss of cholinergic neurones in the hippocampus and frontal cortex.
What is used to treat Alzheimer’s ?
(Neurology card made late)
Acetyl-cholinesterase inhibitors
to increase conc of Ach
What the first choice of drug, to treat kids with epilepsy/seizures ?
(Neurology card made late)
valproate
- increases GABA content
- effective against both “Grand and Petit Mal seizures”.
- used in children due to low toxicity
What are 3 examples of AEDs (antiepileptic drugs), used to treat adults with epilepsy/seizures ?
(Neurology card made late)
1) Phenytoin: effective for “absence seizures”
2) carbamazepine: Not effective for “absence, atonic or tonic seizures”.
3) Pregabalin and gabapentin
Do bronchioles have cartilage ?
Nah
They have “smooth muscle tissue” for contraction and to keep air ways open.
What are the sub types of bronchioles ?
Primary Bronchi
Secondary and Tertiary Bronchioles
Terminal bronchioles ( smallest and final branch of bronchioles)
Alveolar sacs
What are alveolar sacs made up of ?
Made up of “alveoli”
O2 enters the blood stream through alveolar sacs and Co2 is eliminated.
What type of cells is the respiratory tract lined with * trachea, bronchi, bronchioles) ?
pseudostratified ciliated columnar epithelial cells.
What do goblet cells do ?
Secrete mucus to trap particles, irritants and any unwanted pathogens.
What is the function of cilia in the respiratory tract ?
To waft mucus away from the tract.
When our breathing changes during exercise, what part of our nervous system responds, and how ?
Sympathetic nervous system
- causes an increase in bronchiole calibre (bronchodilation)
if sympathetic nervous system takes care of our breathing during exercise,
what part of our nervous system takes care of our breathing throughout the day, making minor adjustments to bronchiole calibre when needed ?
parasympathetic nervous system
What happens during bronchodilation ?
1) smooth muscles in the walls of bronchioles RELAX
2) Allowing airways to open up
3) Decreasing air way resistance, and making it easier to breathe.
What is the opposite of bronchodilation ?
bronchoconstriction
What is bronchoconstriction ?
When bronchiole calibre constrict
Usually during periods of relaxation
to avoid inhaling too many small particulates.
- Bronchoconstriction, leads to an increase in airway resistance.
What do bronchial smooth muscles cells secrete?
Beta2 adrenoreceptors
What are adrenoreceptors ?
“Adrenergic receptors”
receptors that respond to adrenaline and noradrenaline
What types of nerves “innervate” the bronchial smooth muscle ?
Postganglionic parasympathetic fibres.
Where are M3 (muscarinic receptors) found ? (2 places)
1) Bronchial smooth muscle for bronchoconstriction
2) Also found on glands to facilitate the secretion of mucus,
-M3 receptors are the most pharmologically important receptors of the 3 types of muscarinic receptors.
What are the 3 types of muscarinic receptors ?
M1, M2, M3
Where are M1 receptors found and what is their function ?
Located in the ganglia on postsynaptic cells
- facilitates nicotinic neurotransmission.
What are M2 receptors and what is their function ?
They are “inhibitory auto receptors”
- They mediate negative feedback on the release of ACh,
from postganglionic parasympathetic fibres.
What do inhibitory auto receptors try to do ?
Reduce release of neurotransmitters.
What are auto receptors ?
Receptors located in the the membrane of nerve cells.
What is Asthma ?
“recurrent reversible obstruction of air flow in the air way,
due to a stimuli which is not considered noxious (harmful),
and would not affect a non-asthmatic patient.
What are some examples of stimuli of asthma ?
Allergens
Such as drugs
aspirin
house dust mites
pollen
emotions
cold air
pollutants in the atmosphere
infections
Symptoms of asthma ?
Wheezing
coughing
tight chest
Difficulty breathing
What is FEV
Forced expiratory volume
in one second.
- This is lower in asthma patients
What are the 2 main factors in asthma that actually cause reduced airflow ?
1) Bronchial hyper responsiveness
2) Inflammation in the airways
What are the stages on an asthma attack ?
1) Immediate bronchospasm (Early phase)
2) Bronchiole inflammation (Blood vessels dilate, oedema forms, excess mucus is produced). (known as “late phase”).
- This is caused by eosinophils releasing inflammatory mediators.
3) Bronchiole smooth muscle contracts, lining of airway become inflamed
4) Leading to reduced airflow.
What is “bronchospasm” ?
Bronchoconstriction due to contraction of smooth muscle
What does it mean to be “atopic” ?
sensitive to allergens
What actually causes “allergic asthma” ?
Activated t cells
with t-helper 2 cells (Th2)
profile of cytokine production in the the bronchial mucosa.
Process that causes allergic asthma” inside the body ?
(Role of T lymphocytes in allergic asthma”)
1) APCs present the antigens of the allergen to CD4 T cells, via MHC class II (major histocompatibility complex).
2) These differentiate into Th0 lymphocytes
3) Th1, and clonal expansion of Th2 lymphocytes.
4) Th2 lymphocytes produce various cytokines
What are the cytokines produced by Th2 from “allergic asthma response”.
Interleukin 5 Interleukin 4 , Interleukin 13
What does Interleukin 5 do ?
Promotes differentiation and activation of eosinophils.
What does interleukin 4 and interleukin 13 do ?
Cause B cells and plasma cells to produce and release IgE
And allow the expression of IgE receptors on mast cells and eosinophils.
What does mast cell degranulation cause ?
causes the release of spasmogens (mediators of bronchoconstriction)
- also causes the release of histamines, PGD2, cysLTs (leukotrienes C4 and D4 (LTC4 and LTD4)).
Early phase.
Chemotactic mediators are released in late phase. Late phase is mainly just the progression of inflammatory events from the “early phase”.
can mast cell degranulation happen in non-topic asthma patients ?
Yes
Can also happen in patients with normal levels of IgE.
can be triggered by respiratory tract infections.
Are anti histamines effective or not very effective against treating asthma ?
Not very effective.
How can EARLY PHASE bronchospasm be “reversed” ?
By treating with:
- Beta2 adrenoreceptor agonists
- CysLT receptor antagonists
- Theophylline.
How can LATE PHASE bronchospasm be “reversed” ?
Inhibited by Glucocorticoids.
What can cross linking of over expressed IgE on mast cells lead to ?
Mast cell degranulation
General process of Early phase asthma ?
1) Allergic trigger or non specific trigger
2) Mast cells
3) Bronchoconstrictors and chemotactic mediators (Histamine, cysLT, PGD2)
4) Bronchospasm
General process for late phase asthma ?
1) Infiltration of Th2 cells and their cytokines they produced, and activation of eosinophils
2) mediators of inflammatory response
(CysLTs, adenosine, neuropeptides)
AND toxic proteins AND growth factors (smooth muscle cell hypertrophy, hyperplasia)
3) Airway inflammation/ air way hyper-reactivity (if epithelial is damaged)
4) Bronchospasm, coughing and wheezing.
What is smooth muscle hypertrophy ?
Increased size of smooth muscle cells and thickening of smooth muscle around airways.
What is hyperplasia ?
increased size of tissue or organ
due to excessive cell production
If epithelial is damaged what is likely to happen to the airways ?
Airway hyper reactivity
airways become very sensitive
-leads to a “steeper slope on the dose response curve”
-and also a greater “maximal response “ to the agonist.
What are the 2 types of drugs used to treat asthma ?
1) Bronchodilators- help to reverse bronchospasm
2) Anti inflammatory agents- help to prevent or inhibit the inflammatory components and causes of asthma.
Can some bronchodilators also have “anti inflammatory actions” ?
Yes
What type of receptors are b2-adenoreceptors ?
G protein coupled receptors
They need the help of a “g protein” to go between it and its target.
In what location do B2-adenoreceptors, need to form a “second messenger” ?
in bronchial smooth muscle
Process of how B2-adenoreceptors agonists cause “relaxation of bronchial smooth muscle”
1) Salbutamol/adrenaline bind to activated b2-adenoreceptor
2) This causes the G protein to activate.
3) The G protein then diffuses across the cell membrane, and comes into contact with “adenyl cyclase”
4) Adenyl cyclase then converts ATP into cAMP (Secondary messenger).
5) cAMP then diffuses into the cell and comes into contact with Protein kinase A (PKA), and activates it.
6) Activated PKA causes phosphorylation of the myosin-light chain kinase (MLCK).
7) This causes smooth muscle contraction of bronchi to be inhibited. Relaxation of smooth muscle.
8) Results in bronchodilation. Reducing asthmatic symptoms.
As well as smooth muscle relaxation, what other positives can B2-adenoreceptor agonists induce ?
Increased mucus clearance by an action on cilia in the airway.
- inhibit mediators being released from “mast cells”
- inhibits release of tissue necrosis factor-alpha.
What happens if too much salbutamol is being administered and how might this affect other areas of the body negatively ?
Too much salbutamol
means B2-adenoreceptor occupancy in airways is high
so any excess salbutamol will start to bind to other receptors
could bind to receptors in the heart
- which could cause palpitations or tachycardia. (by binding to B1-adenoreceptors)
could bind to receptors in the skeletal muscle by binding to b2-adenoreceptors. This may cause muscle tremor.
How is salbutamol synthesised from aspirin ?
1) “Fries rearrangement” of aspirin, causes a ketoacid to be produced
2) The keto acid is then esterified.
3) Bromination of the ketone allows for the introduction of an amino group by nucleophilic substitution.
4) Methyl ester and ketone then undergo reduction, and the N-benzyl group is removed.
What can be changed to the chemical strucutre of salbutamol, to increase the duration the drug acts for ?
Replacing the tert-butyl group with large alkyl groups
This lead to the production of the drug “Salmeterol”
- twice as potent as salbutamol, and has an extended action of 12 hours. usually given twice a day.
Another long duration of action drug is “indacaterol”. Usually only given once a day.
What is the function of a muscarinic antagonist drug ?
To relax bronchiole constrictions
mainly used for treating COPD
by antagonising M3-muscarinic receptors on bronchial smooth muscle cells to cause relaxation.
- may also have inhibitory effects on mucus secretion in asthmatic
Whats an example of a muscarinic antagonist drug ?
Ipratropium
- Administered by inhalation.
- max effect occurs after 30 mins
- lasts for 3-5 hours
What happens if too high dose of ipratropium is being administered ?
May go rogue
may not be able to differentiate between muscarinic receptor subtypes.
E.g. May bind to M2 instead of M3-muscarinic receptors
- causing more Ach to be released
- causing more vagally-mediated bronchoconstriction.
- This may cause a reduction in M3 antagonism at high doses of ipratropium.
What an example of a long lasting muscarinic antagonist drug ?
Tiotropium
lasts for at least 24 hours
time to increase FEV1 ( forced expiratory volume in one second) = 30 mins
time to increase to PEAK FEV1 (max effect) = 1.5-3 hours
How does parasympathetic innervation, cause bronchoconstriction ? (process)
1) Acetylcholine released from postganglionic parasympathetic nerves
and binds to M3 recepetors on bronchial smooth muscle cells
2) Sub unit of the g protein activates phospholipase C, which hydrolyses phosphatidylinositol 4,5-bisphosphate(PIP2) into diacylglycerol(DAG) and inositol 1,4,5-triphosphate (IP3)
3) IP3 binds to IP3 receptor located on he endoplasmic reticulum (ER)
4) Ca2+ released from intracellular stores of the ER
5) Ca2+ binds to calmodulin to activate myosin light chain kinase (MLCK)
6) Smooth muscle contracts when myosin light chain undergoes phosphorylation.
- DAG may also stimulate entry of Ca2+ ions.
What part of ipratropium’s structure, makes it unable to cross the blood brain barrier ?
It’s quaternary nitrogen”
- Ipratropium also has low systemic absorbance.
What is an epoxide functional group ?
Three membered ring containing oxygen.
What functional group does tiotropium contain ?
Epoxide group
- very reactive
- but hard for nucleophiles to enter “inside” the ring. Not enough space
What happens if intracellular levels of cAMP increase ?
Bronchodilation
What are the 3 proposed mechanisms of therapeutic actions of methylxanthines ?
1) Inhibits PDE (phosphodiesterase).
- levels of cAMP increase
- causes bronchodilation
2) Competitive antagonism at adenosine receptors (A1 and A2 receptors)
3) Activation of histone deacetylase
- An enzyme that inhibits the acetylation of core histones, that are required for the transcription of inflammatory genes.
What does the enzyme “histone deacetylase” do ?
Inhibits acetylation of core histones, required for transcription of inflammatory genes.
What are some unwanted effects of methylxanthines ?
1) interfere with sleep patterns
2) vasoconstrict blood vessels but will vasodilate most other vessels
3) GI irritation
What are some additional positive effects of methylxanthines ?
1) Increase renal blood flow, therefore increase glomerular filtration rate
2) Cause increased alertness
What is the recommended therapeutic window for methylxanthines ?
30-100 micromol
> 110micromol can cause adverse effects
> 200 micromol can be lethal
can cause serious CNS and cardiovascular effects, and even seizures.
How are methylxanthines normally administered ?
Either orally
or sustained release
or IV injection, followed by IV infusion
What type of drugs reduce the plasma conc of methylxanthines ?
Drugs which ACTIVATE P450 enzymes
such as
Carbamazepine, phenytoin and rifampicin.
What type of drugs increase the plasma conc of methylxanthines ?
Drugs which INHIBIT p450 enzymes
such as
Erythromycin, ciprofloxacin, diltiazem, fluconazole.
What acid is “leukotriene” produced from ?
Arachidonic acid
- Leukotriene is a major inflammatory mediators
More specifically LTD4 and LTC4 (major mediators of bronchoconstriction)
What is the chemical structure of arachidonic acid ?
20 carbon
with 4 C=C bonds.
Why might aspirin be dangerous for asthmatic patients ?
Less than 10% of asthma patients
are very sensitive to aspirin
which means leukotrienes can not bind to their receptors.
When are leukotriene antagonists usually given ?
As a 3rd line drug along with inhaled corticosteroids and beta2 agonists
- less effective at bronchodilation than salbutamol.
What are 2 examples of leukotriene antagonists ?
1) montelukast
2) Zafirlukast
What is a general rule of thumb for drug types used to treat early phase bronchospasm ?
Bronchodilators help to reverse early phase of bronchospasm
Whereas,
Glucocorticoids inhibit the inflammatory effects that occur during both phases.
Are glucorticoids high or low in lipid solubility ?
High
so crosses the plasma memmbrane easily
Mechanism of action of glucocorticoids ?
1) Cross plasma membrane
2) binds to intracellular receptors which “dimerise”
3) move towards the nucleus and interact with DNA
4) This causes transcription of genes to be modified
5) This induces synthesis of some proteins,
but may also inhibit the synthesis of other proteins.
3 main ways glucocorticoids induce anti-inflammatory actions:
1) enhance expression of lipocortin
- suppressing phospholipase A2
- Reducing formation of arachidonic acid and therefore leukotrienes.
- limited evidence of annexin-1 (lipocortin) having therapeutic use in treating asthma.
2) Decrease the formation of Th2 cytokines
Inhibits:
- Activation of eosinophils
- clonal expansion of b cells dividing into plasma cells to produce IgE.
3) Reduce the synthesis of cytokines
- supressing early phase response to allergens.
Unwanted effects of Glucocorticoids ?
1) Metabolic effects
hyperglycaemia (high blood sugar)
- thinning of skin- easily bruised. Purple/red stretch marks.
- fat redistribution (onto neck shoulders and face)
2) Osteoporosis
3) Reduced growth in kids
4) Reduced ability to heal wounds
5) More susceptible to infection
- It’s anti-inflammatory function may supress features of immune response.
What may happen if glucocorticoids are given over long periods of time ?
Cushing’s syndrome
- too much of the hormone cortisol in the body
-fat on chest,tummy, neck or shoulders
How do glucocorticoids actually help when treating asthma ?
Simply by reducing or preventing inflammatory effects.
How are glucocorticoids given in clinical use ?
- patients who require regular bronchodilators, are also considered to take “beclomethasone” along with it (glucocorticoid).
- patient with acute asthma may require IV hydrocortisone and oral prednisolone (glucocorticoid)
- If severity of clinical condition is deteriorating, a “rescue course” of prednisolone may be administered.
What are patients who inhale steroids advised to do, to avoid developing oral thrush ?
- to gargle after inhaling
- to use “spacers” in their inhalation device.
What is the benefit of using a “spacer” in an inhalation device ?
1) slows down aerosolid particles, increasing the amount of fine particles being deposited into the lungs.
2) Helps patients with reduced manual dexterity. Helps patients who find it hard to activate the pMDI by pressing down on the canister.
3) Reduces deposition of larger particles into the mouth and back of the throat.
What are the two most common agents used in a combination inhaler ?
1) LABA
2) Glucocorticoid
Do all combination inhalers only use 2 ingredients ?
No
Some use 3 agents (trim bow)
Do patients with combination inhalers need to still take theri “reliver inhaler” ?
Yes they do
The combination inhaler is just used prevention treatment.
Reasons why a combination inhaler might be prescribed ?
- might be better at controlling symptoms
- lower doses of inhaled corticosteroids needed: minimising risk of adverse effects.
- More convenient for the patient
- May be more cost effective
2 disadvantages of patients using combination inhalers ?
1) Possible lack of dose flexibility
2) may use inhaler to relieve bronchospasm, which means patient may inhale a much larger amount of steroid than intended.
What is the first line of treatment for asthma ?
salbutamol
for both acute and chronic asthma
What are the potential side effects of salbutamol ?
- tremor in hands
- nervous tension
- headache
-cramps, palpitations
What 2 diseases is COPD a combination of ?
1) Emphysema (alveoli)
2) Bronchitis (bronchi)
What is the most common cause of COPD ?
Smoking
Except smoking what other things may cause COPD ?
- Dust
- exposure to chemicals
- environmental exposures (second hand smoke).
- Genetic (deficienccy of alpha-antitypsin)
What is the common age of COPD patients ?
50-80
What percentage of COPD pateitns have alpha 1-antitrypsin deficiency ?
1-2 %
its rare
lung function decline is faster for these type of patients than smokers.
As there is not enough antitrypsin to inhibit certain enzymes that cause lung damage.
Symptoms of COPD ?
- Breathlessness
- Chronic cough
- Regular phlegm production 9may require antibacterial treatment).
- Bronchitis in the winter
- wheezing
What is winter bronchitis
When COPD patient gets a cold or flu in the winter. May cause winter bronchitis.
- cant maintain normal oxygenation of blood
- lips and tongue may be visibly blue
- may lead to pulmonary hypertension
Clinical treatment of COPD ?
- Bronchodilator therapy
- as well as treatment usiing a nebuliser
- Administering oxygen if needed.
When treating COPD, what can be given as an alternative to nebulisers ?
Aminophylline via IV administration.
For COPD patients how is continuous breathlessness usually treated ?
Short course of oral corticosteroid, such as prednisolone 30mg for 1-2weeks
First line of treatment for COPD ?
Short acting beta agonist/short acting antimuscarinic agent.
Salbutamol is an example of a short acting beta agonist.
Are glucocorticoids effective at treating COPD
NO
As in smokers HDAC activity is inhibited
explaining the lack of effect glucocorticoids have
Additional treatments for COPD patients ?
1) Immunised against influenza
2) Antibacterial treatments
3) Oxygen administration
- However be cautious for potential co2 retention
- only 24% o2 is administered
4) Administration of mucolytic drugs ro reduce plegm production
What type of nerve stimulation, leads to sneezing and itching ?
Afferent nerve stimulation.
What are the 4 types of histamine receptors ?
H1,H2,H3,H4
