week 10 Flashcards
1
Q
5 signs of inflammation
A
heat, redness, swelling, pain, loss of function
2
Q
what are two key pro-inflammatory mediators
A
prostaglandins & leukotrienes = produce inflammation
3
Q
list the five major groups of anti-flammatory drugs
A
- cyclo-oxygenase inhibitors (NSAIDs)
- glucocorticoids
- antirheumatic drugs (DMARDs) - arthritis
- cytokines modulators & other biological agents (bDMARDs)
- others that do not fit in the above groups (antihistamines & other drugs used to control gout)
4
Q
why inflammatory drugs used so extensively
A
because inflammation is involved in almost all diseases and in some cases can be the cause
5
Q
steroidal define and examples
A
- relates to steroidal hormones and their effects
- steroidal hormones comes from cholesterol
- sex hormones, glucocorticoids, mineralocorticoid
6
Q
are cyclo-oxygenase (COX) inhibitors steroidal?
A
no they are non-sterodial anti-inflammatory drugs (NSAIDS)
7
Q
what are NSAIDs used to treat & are they chemically related
A
minor aches & pains
they are chemically unrelated
8
Q
what 3 properties do NSAIDs carry
A
analgesic (decrease pain), antipyretic (decrease fever) & anti-inflammatory properties
9
Q
examples of NSAIDs
A
e.g., diclofenac (voltaren) & naproxen & ibuprofen & celecoxiib & melocicam, aspirin (irreversible)
10
Q
what is the NSAIDs target
A
an enzyme COX1 = homodimer (two together)
11
Q
the usual product of COX1 & the action it leads to
= this is without the drug interference so normal bodily functions
A
arachidonic is the endogenous substrate
prostaglandin (product) –> toboxon A2 –> platelet activation/aggregation = blood clot/thickening (inflammation)
12
Q
endogenous substrate of COX1 enzyme
A
arachidonic acid
13
Q
affect of the NSAIDs drug e.g., aspirin
A
- aspirin causes irreversible inhibition = cause a covalent bond in the enzyme COX1 preventing the production of prostaglandins = decrease platelet aggregation = thins the blood
14
Q
difference between COX-1 & COX-2
A
- both produce prostaglandins from arachidonic acid
- COX-2 has a side pocket = were able to make drugs cox-2 selective = those drugs have an ending ‘coxib’ & are bulkier
15
Q
mechanism of action of NSAIDs
A
= inhibit synthesis of prostaglandins by inhibiting COX enzymes
16
Q
what is the target of prostaglandins & what specific superfamily
A
G protein-coupled receptors = then the second messengers etc
17
Q
the analgesic effect of NSAIDs
A
= decreased production of prostaglandin: less sensitisation of nocieceptive nerve ending to inflammatory mediators such as bradykinin & 5-hydroxytryptamine (5-HT, serotonin)
18
Q
the anti-inflammatory action due to NSAIDs
A
reduces vasodilation and, indirectly, oedema by decreasing prostaglandin E2 and prostacyclin synthesis
19
Q
the antipyretic effect due to NSAIDs
A
NSAIDs prevents the release of prostaglandins by interleukin-1 in the CNS, where prostaglandins elevate the hypothalamic set point for temperature control. therefore preventing fever
20
Q
difference between COX-1 & COX-2 inhibition in terms of effect
A
1 - impaired gastric protection, antiplatelet effects = gastrointestinal tract
2- more anti-inflammatory action, analgesic action = reduce the risk of gastrointestinal ulceration & upper gastrointestinal bleeding
both - reduction in glomerular filtration & reduction in renal flow
21
Q
route of administration of NSAIDs
A
topical (cream), enteral (via gastrointestinal tract through tube) & parenteral (injection)
22
Q
site of absorption of NSAIDs
A
stomach & small intestine (presence of food & antacids (neutralises stomach acid) delays absorption)
23
Q
distribution of NSAIDs
A
highly bound to plasma protein. wide spread including breast milk & cross placenta
24
Q
metabolism
A
liver
25
distribution of NSAIDs
highly bound to plasma protein (doesn't necessarily mean low VD) . wide spread including breast milk & cross placenta
26
metabolism of NSAIDs
liver
27
excretion NSAIDs
kidney
28
define topical route
application of medication to the surface of the skin or mucous membrane of the eye, ear, nose, mouth, vagina, etc
e.g., gels, lotions
29
define enteral route
administration involves the GIT. methods of administration include oral, sublingual (dissolving the drug under the tongue) & rectal
30
define parenteral administration
introduce drugs to the body by a different route from enteral (GIT). the most frequently used parenteral routes are intravenous route (IV), intramuscular route (IM), and subcutaneous route
31
is body concentration the same as plasma concentration
no
32
what are the two steroid hormones
glucocorticoids & mineralocorticoids
33
what are glucocorticoids synthesised from
cholesterol
34
main effects of glucocorticoids
- resistance to stress
- metabolic effects
- anti-inflammatory
- immunosuppressant
35
where are glucocorticoids made
zona fasciculate in the adrenal gland
36
what controls the release of glucocorticoids
hypothalamic and pituitary control = negative feedback
37
the two rhythms influence glucocorticoid release
- circadian rhythm (dark-light sleep)
| - ultradian rhythm (CRH & ACTH)
38
what are the effects of glucocorticoids
anti-inflammatory, immunosuppressant & metabolic effects
39
glucocorticoids effect in inflammation
they are highly effective in controlling inflammation, but largely limited by their adverse effects
40
examples of glucocorticoids
```
hydrocortisone (cortisol)
dexamethasone
betamethasone
triamcinolone
fludrocortisone
```
1. short-acting
2. intermediate acting
3. long acting
= eliminated quite quickly for the most time
41
mechanism of action of glucocorticoids
nuclear effect: they make our bodies synthese more of the protein annexin-1 = inhibits phospholipaseA2 = inhibits the cascade from the top and the arachidonic acid is not synthesised
42
in what ways does glucocorticoids modulate gene transcription
gene active hormones:
- promotes or inhibits synthesis of specific mRNA
- initiation of new protein synthesis (transactivation)
- blocking of protein production (transrepression)
= alters the required time to produce an effect
non genomic rapid actions = vasorelaxation & maybe PGE2 release inhibition
43
what is the target for glucocorticoids
nuclear receptors
44
some examples of NSAIDs adverse effects & understanding why (off or on target??)
```
- nausea, diarrhoea, headache
REMEMBER THIS ONE
- dyspepsia, GI ulceration & bleeding (inhibit COX1, e.g., inhibit platlete aggregation)
- raised liver enzymes (Diclofenac)
- salt & fluid retention
- hypertension
```
45
some examples of corticosteroids adverse effects & understanding why (off or on target??)
- adrenal suppression (if the drug is removed at once so forgets how to signal cortisol it self) = low blood pressure etc
- dyspepsia (indigestion)
- hypokalaemia, hyperglycemia (effects processing of carbs)
- myopathy, msucle weakness & wasting (protein synthesis)
- sodium & water retention, oedema
- hypertension
- fat distribution
- skin atrophy, bruising (due to increase bleed), acne, hirsutism
- diabetes, osteoporosis, fractures
46
what two agonists decrease acid secretion
Prostaglandins E2 and I2 & somatostatin
47
absolute compared to relative conditions
absolute condition is where if u have that condition you should no take the drug, relative is where the doctor is to balance out the risks and benefits
48
what properties does paracetamol have
analgesic & antipyretic properties & very weak anti-inflammatory effects = not suitable substitute for NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis
49
paracetamol mechanism of action
proposed inhibition of COX isoform mainly available at the CNS, however, alternative explanations have been proposed
50
what can acute overdose of paracetamol cause
severe hepatic damage
51
GI adverse effects from paracetamol
low incidence of GI adverse affects
52
what is the autonomic nervous system a division of
PNS
53
what are the two divisions of the Autonomic Nervous System
1. Sympathetic
| 2. Parasympathetic
54
what does the ANS link
link between the CNS & peripheral organs
55
what does the ANS regulate
- contraction & relaxation of vascular & visceral smooth muscle
- all exocrine & certain endocrine secretions
- the heartbeat
- energy metabolism (especially in the liver & skeletal muscle)
56
when is sympathetic action
- fight or flight
- energy expenditure
- both acetylcholine (ACh) & nonadrenaline (NA)
57
when is parasympathetic in action
- rest & digests
- active in resting phase
- conserves energy
- Acetylcholine (ACh) only = transmitter
58
what are the preganglionic nerve fibers & what do they release
They are the fibers they take the message from the CNS. They are myelinated & release ACh from the nerve terminals which is then transfered to the next nerve
59
what does ACh produce
produces an excitatory postynaptic potential (EPSP) in the postganglionic neurons
60
what does the ACh activate to produce the EPSP
by activating nicotinic receptors
61
what does sympathetic postganglionic release
mainly noradrenaline (vasoconstriction = increase blood pressure)
62
what does parasympathetic postganglionic release
acetylcholine
63
sympathetic fibre lenghts
1st is very short & second is long
64
parasympathetic fibre lengths
1st long & second shorter
65
what are the ganglions next to in sympathetic nervous system
the spinal cord
66
what are the ganglions closer to in the parasympathetic nervous system
the effector organ (e.g. heart & lungs)
67
what is released by presynaptic neurons
acetylcholine
68
what does acetylcholine crossing the synaptic cleft activate
ligand gated ion channel known as nicotinic receptors
69
what does activation of adrenoceptors do
lead to an action potential
70
what does the action potential do
takes the message to the effector organ
71
in the parasympathetic system what does the release of acetylcholine do in the postsynaptic neurons
activates muscarinic receptors
72
what type of receptor are muscarinic
GPCR
73
in the sympathetic system what does the release of acetylcholine do in the postsynaptic neurons
noradrenaline is released
74
what is receptor is activated by the release of noradrenaline
adrenoceptor
75
whats the difference between a ligand-gated ion channel or voltage ion channel
the receptor ion channel will have an endogenous agonist
76
how many units is the nicotinic acetylcholine receptor/structure
it has 5 units that come together and form a core
77
how is the nicotinic acetylcholine receptor opened
two acetylcholine ligands bind to the receptor
78
location of nicotinic acetylcholine receptor muscle & ganglion examples
skeletal neuromuscular junction & autonomic glanglia: mainly postsynaptic
79
response of nicotinic acetylcholine receptor opening
excitatory: increased cation permeability (mainly sodium & potassium)
80
example of a cholinergic receptors & there systems
1. nicotinic receptor = both
| 2. muscarinic receptors (5 subtypes) = mostly parasympathetic
81
what are the main three subtypes of muscarinic receptors
M1: CNS & gastric parietal cells
M2: heart
M3: smooth muscle & glands
= not very selective
82
what type of receptor is muscarinic receptor
metabotropic receptor = GPCR
83
what is ScfV16
added to the structure to help stabilise tertiary complexes
84
what are cholingeric receptors associated with
acetylcholine
85
what are adrenoceptors associated with
sympathetic nervous system binds to adrenaline or nonadrenilie endonouse
86
main areas of adrenoceptors x5
```
α1 (postsynaptic): vascular smooth
muscles
• α2 (presynaptic): vascular smooth
muscles and CNS
• β1: heart, intestinal smooth muscle
• β2: bronchial, vascular and uterine
smooth muscles
• β3: plasma membrane of adipocytes
```
87
adrenoreceptor: what does alpha 1 couple with
Gq
| - more selective to NA (more potent)
88
adrenoreceptor: what does alpha 2 couple with
Gi
| - a lot more selective to NA
89
adrenoreceptor: what does beta 1 couple with
Gs
| - more selective to NA
90
adrenoreceptor: what does beta 2 couple with
Gs
| - more selective to A
91
adrenoceptor: what does beta 3 couple with
Gs
| - the same selectivity between NA & A
92
how to know if it is a target on the diagram
it will have a T on the end standing for transferase and also will cause a change in ligand
93
when is acetycholine in vesicles released in the synapse
when intracellular calcium decreases
94
what are the 3 possibilities when acetycholine crosses the synapse
1. binds to postsynaptic receptors
- muscarinic
- nicotinic
2. bind to pre-synaptic receptors = most cause neg feedback which decreases acetycholine
3. degraded by enzyme acetylcholinsterase
95
what do cholinomimetirc activate (aka muscarinic agonist)
directly activates muscarinic receptors, usually producing excitatory effects
96
explain main affect of M1 receptor
CNS excitation (improve cognition?), gastric secretion
"neural"
- Gq
97
explain main affect of M2 receptor
cardiac inhibition, neural inhibition, central muscarinic effect (e.g., tremor hypothermia)
"cardiac"
Gi - in heart decreases rate & force of atrial contraction
98
explain main affect of M3 receptor
gastric & salivary secretion, GI smooth muscle contraction, ocular accommodation, & vasodilation
"glandular/smooth muscle"
Gq
99
how does the indirect affect work aka use of Anticholinesterases
in increase affect by increasing aachetylcholine in the synapse - done by inhibiting the enzyme that breaks it down
100
example of irreversible indirectly acting cholinomimetics
• Toxic – Topic malathion (head lice) • Organophosphate insecticides and
warfare agents
101
example of reversible indirectly acting cholinomimetics
```
Indications: Myasthenia gravis and
Alzheimer's
• Similar effects to muscarinic agonists
in addition to a potentiation of the
transmission in the neuromuscular
junction
```
102
why irreversible toxic
continuously activating the parasympathetic system = strong imbalance
103
what are anticholinergics / antimuscarinics
cholinergic receptors antagonist = decreasing response cause not blocking all
104
two types of anticholinergics / antimuscarinics
1. n (nicotinic) ACh = not clinically useful for ANS because they block both systems
- muscle relaxants act on the neuromuscular junction
e. g., pancuronium
2. m (muscarinic) ACh receptors antagonists = they complete & block the action of ACh at the muscarinic receptors = decrease contraction/movement = decrease cramps
- e.g., hyoscine (scopolamine) butylbromide (buscopan) or hydrobromide (travacalm), atropine & tiotropium (spiriva - COPD)
105
what targets are involved in acetylcholine synthesis
ChAT = enzyme or transporter
106
what synthesises noradrenaline in the vesicle & what is released with it
dopamine & released with increasing calcium levels
107
what are the three paths of noradrenaline & in path 2 what is the difference between Alpha-2 & Beta-2
1. cross the synaptic cleft & activate post-synaptic alpha/beta adrenergic receptors (GPCR)
2. bind to pre-synaptic receptors which modulate noradrenaline release.
Alpha-2 = provides negative feedback decreasing noradrenaline release
Beta- 2 = does the opposite
3. return to the inside of the pre-synaptic neuron by using transporters called NET (noradrenaline transporter). in the cytoplasm, it may return to the besicle or be defraded by monoamine oxidase (MAO) enzymes
108
what is the name of the adrenoreceptor agonists
symoathomimetics
109
what does symoathomimetics do
= Partially or completely mimics the
actions of noradrenaline (NA) and
adrenaline (A)
110
explain the two types of symoathomimetics - indirect & directly
directly - agonist binds to alpha &/or beta receptors
indirectly (act on transporter or enzymes) - Facilitate the release of NA, block
NA reuptake or inhibit metabolism by
MAO or COMT
111
the four type of direct receptors for sympathomimetics
alpha 1 (Gq) - vasoconstriction = relaxation of Gi smooth muscle, salivary secretion & hepatic glycogenolysis
alpha 2 (Gi) - inhibition of transmitter release = vascular smooth muscle contraction & inhibition of insulin release
beta 1 (Gs) - increased cardiac rate & force
beta 2 (Gs) - bronchodilation = vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis, muscle tremor
beta 3 (Gs) - lypolisis & thermogenesis, & bladder detrusor muscle relaxation (relax bladder wall allowing urine storage)
112
example of 𝛼/β-adrenoceptor agonist
Anaphylactic shock, cardiac arrest - adrenaline epipen
113
example of β2-adrenoceptor agonist
• Asthma relievers
| - Salbutamol
114
example of Selective 𝛼1-adrenoceptor agonist
• Decongestants
- Phenylephrine
- Oxymetazoline
115
example of Selective 𝛼2-adrenoceptor agonist
• Antihypertensive
- Clonidine
- causes increase which signals it to stop = negative feedback
116
the three type of indirect receptors for sympathomimetics
1. Inhibits the reuptake of noradrenaline
(Block NET)
• Stimulants
- Cocaine
- Tricyclic antidepressants (e.g. imipramine)
2. Increase noradrenaline release
• Stimulants
- Amphetamines (used in ADHD) – also affect
serotonin and dopamine release
3.Monoamine Oxidase (MAO) inhibitors
117
role of adrenoceptor antagonists
Block the effects of noradrenaline and
adrenaline. Most are selective to 𝛼𝛼 or
β receptors (even subtype selective).
118
examples of role of adrenoceptor antagonists
Selective 𝛼𝛼1 antagonists
• Antihypertensive
- Prazosin
Selective 𝛼𝛼1A antagonists
• Treat benign prostatic hypertrophy
- Tamsulosin
Non-Selective β-blockers (blocks β1 and β2)
• Treat hypertension, angina,
tachyarrhythmias, myocardial infarction,
migraine prophylaxis, essential tremor, etc
- Propranolol
Selective β1-
blocker (cardioselective)
• Treat cardiovascular conditions as above
- Atenolol, metoprolol
Non-Selective β-blockers (blocks 𝛼𝛼 and β)
• Treat hypertension and heart failure
- Caverdilol
