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Semester 4 Revision > SBT > Flashcards

SBT Flashcards

1
Q

What is the archetypal NSAID? (1)

A

Aspirin

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2
Q

What are three characteristics of NSAIDs? (3)

A

Analgesic
Anti-pyretic
Anti-inflammatory

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3
Q

What are NSAIDs used to treat? (4)

A

Low grade pain (chronic inflamm. e.g. arthritis)
Bone pain (cancer metastases)
Fever (associated with infections)
Inflammation (to decrease symptoms e.g. oedema, redness, itch)

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4
Q

What is the mechanism of the main therapeutic action of NSAIDS? (1)

A

Inhibition of COX

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5
Q

What does the COX enzyme do? (2)

A

Converts arachidonic acid to prostaglandins + thromboxanes

Inhibition of COX -2 therefore reduces PG/TX inflammatory agents

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6
Q

Where is COX-1 present? (2)

A

In platelets

Constitutively active

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7
Q

What can COX-2 be induced by? (2)

A

IL-1β + TNFα etc.

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8
Q

Do NSAIDs act reversibly or irreversibly on COX? (3)

A

Aspirin acts irreversibly
Others act reversibly
Significant in prophylactic use in CV disease

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9
Q

Why is paracetamol a special case? (6)

A

Not an NSAID
Analgesic with anti-inflamm. effects
Little inhibiton of COX-1/-2 in peripheral tissues
Weakly inhibits COX-3 in CNS
May modulate serotonergic transmission
May inhibit COX-mediated generation of hydroxypeptdies (which stimulate COX activity) from AA metabolism

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10
Q

What are examples of other NSAIDs? (5)

A 
Etodolac
Meloxicam
Ibuprofen
Naproxen
Indomethacin etc.
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11
Q

How do IL-1 and PGE2 cause fever? (5)

A

Bacterial endotoxins produced during infections stimulate macrophages to release IL-1
IL-1β acts on hypothalamus to cause PGE2 release (via COX-2)
Increased PGE2 depresses temp-sensitive neurones
PGE2 elevates set point temp
Onset of fever

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12
Q

How do NSAIDs have an antipyretic action? (4)

A

NSAIDs block PGE2 production
Set point is lowered to normal level
Fever dissipates
NSAIDs have no effect on normal body temp

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13
Q

Why are NSAIDs required for analgesia? (4)

A

PGs sensitise + stimulate nociceptors
Oedema produced by inflamm. also directly activates nociceptive nerve fibres
PGs interact synergistically with other pain producing substances (kinin, 5-HT, histamines)
To produce hyperalgesia (increased sensitivity to pain)

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14
Q

How do NSAIDs have an analgesic action? (5)

A

Block PG production (which breaks cycle -> pain relief
Useful for pain associated with production of inflamm agents (PGs/TXs)
Such as arthritis, toothache, headache)
NSAIDs block PG-mediated vasodilation
COX-1, COX-3, COX-3 inhibition in CNS

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15
Q

How do PGE2 + PGI2 have powerful acute inflammatory effects? (3)

A 
Arteriolar dilation (increased blood flow)
Increase permeability in post-capillary venules
Both processes increase influx of inflamm. mediators into interstitial space
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16
Q

How do NSAIDs have an anti-inflammatory action? ()

A

Inhibition of PGE2/PGI2 reduces redness + swelling
Only provide symptomatic relief
They do not cure underlying cause of inflammation (e.g. in arthritis help but do not cure)
Decreased COX-2-generated PGs (effects develop gradually)

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17
Q

What role does thromboxane A2 have in vascular haemostasis? (2)

A

Platelet aggregation

Vasoconstriction

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18
Q

What effect to NSAIDs have on TXA2 levels? (2)

A

Decrease levels
So increase bleeding time
Could be problematic in childbirth/surgery

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19
Q

What is an example of aspirin being used prophylactically? (1)

A

In disease where platelet aggregation is increased

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20
Q

How can PGs contribute to arthritis? (5)

A

PGs with acute inflamm. effects contribute to swelling + pain
Arteriolar dilation
Increased microvascular permeability
Hyperalgesia
Thus NSAIDs diminish effects but do not treat cause

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21
Q

How do PGs protect gastric mucosa? (2)

A

PGE2/I2 stimulate mucus secretion
+ inhibit gastric acid secretion
+ promote blood flow
Cytoprotective mechanisms

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22
Q

What are the most common adverse reactions to older NSAIDs? (3)

A

Gastric SEs
NSAIDs decrease cytoprotective mechanisms of PGs
Bleeding + ulceration can result

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23
Q

Why might COX-2 selective inhibitors be ‘gastric-friendly’? (1)

A

Suggested that COX-1 is expressed in gut

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24
Q

What other effects can NSAIDs have in GI tract? (8)

A 
NSAIDs = acidic
Decreased mucus production
Decreased HCO3-
Increased acid production
Increased leukotriene production
Increased blood loss
Interfere with tissue healing (COX-2 inhibition)
Nausea, dyspepsia (indigestion) + GI contraction (COX-1 inhibition)
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25
Q

What examples are there of selective COX-2 inhibitors? (4)

A

Celecoxib
Valdecoxib
Etoricoxib (most selective COX-2 inhibitor - no effect on TXA2 in platelets but decreases PGI2 in BVs)
Rofecoxib (withdrawn due to CV effects)

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26
Q

What is diclofenac? (5)

A

NSAID selective for COX-2 but inhibits COX-1 in gut
Ulcers
Take with food
Less effective analgesic
Less inhibition of COX-3 in brain + spinal cord
Anti-gout drug

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27
Q

What can happen in an NSAID overdose? (2)

A

Produce paradoxical hyperexia, stupor + coma
Increased metabolism + metabolic acid production
Reye’s syndrome risk

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28
Q

What is Reye’s syndrome? (2)

A

Brain (cerebral oedema) + liver damage
Can be fatal
When aspirin is used in children with influenza/chicken pox
Aspirin is therefore contraindicated in children

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29
Q

How would you treat aspirin overdose? (2)

A

By alkalinising the urine to help excrete aspirin

+ avert Reye’s syndrome

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30
Q

How can NSAIDs be used to treat pain during menstruation? (3)

A

PGs cause pain + smooth muscle spasm
Mefenamic acid reduces blood loss
NSAIDs may be useful in primary dysmenorrhoea

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31
Q

What effects can NSAIDs have on childbirth? (3)

A 
Delay contractions (as PGs are important in uterine contractions)
Many increase post-partum blood loss as TXA-2 inhibited
NSAIDs delay + retard labour
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32
Q

Why do NSAIDs reduce renal blood flow? (1)

A

Because vasodilatory PGs regulate renal blood flow

Chronic renal injury may result

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33
Q

What affect can concurrent treatment with NSAIDs have on the some anti-hypertensive drugs? (3)

A

Reduced effectiveness
Average BP rise = 2/3mmHg but varies
Low dose aspirin doesn’t seem to interfere with antihypertensive therapy but regular use should be avoided

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34
Q

What effects can inhibition of COX-2 have in kidney? (2)

A

Lowered sodium excretion + increased intravascular vol.

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35
Q

What effects to PGs have on airway smooth muscle? (2)

A

Both constrictor + dilator effects

NSAIDs have no effect on airway tone

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36
Q

Why must NSAIDs be used with caution/avoided in asthma? (2)

A

20% asthma patients wheeze with aspirin/other NSAIDS

Due to hypersensitivity to drugs

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37
Q

What happens to respiratory pharmacology at toxic doses of aspirin? (3)

A

Initially stimulates resp
Action of resp centre uncoupling of oxidative phosphorylation -> medulla stimulated
Resp alkalosis caused by hyperventilation (CO2 washout from lungs)

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38
Q

Patent ductus arteriosus + NSAIDs? (6)

A 
Help to close PDA in neonate if patency is inappropriately mantained by PGE2/PGI2 production
Ibuprofen, indomethacin
Treatment is individualised
Fast breathing/shortness of breath
Sweating while feeding
Tiring very easily
Surgical closure
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39
Q

Why can NSAIDs not be given in 3rd trimester? (1)

A

To avoid premature closure of ducts (avoid PDA)

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40
Q

What are other indications of NSAIDs? (5)

A 
Decrease colonic polyps
Prevent colon cancer
May decrease Alzheimer's risk
Post-operative pain
Renal colic = upper abdominal/groin pain (usually caused by kidney stones)
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41
Q

What is ulcerative colitis? (1)

A

Inflammation of bowel

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42
Q

What are the aims of treating ulcerative colitis? (3)

A

Reduce symptoms
Induce remission
Maintain remission

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43
Q

What are the 1st line treatment options of ulcerative colitis? (4)

A

Aminosalicylates (sulfasalazine + mesalazine)
Decrease inflamm for mild to moderate ulcerative colitis
ST treatment of flare ups
LT maintenance of remission

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44
Q

What is the MOA for sulfasalazine? (3)

A

Metabolised to 5-aminosalicyclic acid (5-ASA) + sulfapyridine
Reydces synthesis of eicosanoids by blocking activity of cyclooxygenase + lipoxygenase
(May be high in UC)

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45
Q

What are SEs of sulfasalazine? (4)

A

Indigestion, feeling/being sick, abdominal pain, diarrhoea
Dizziness, headache, difficulty sleeping, tinnitus
Coughing, itchy rash
May effect taste, cause sore mouth

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46
Q

What is gout? (5)

A

Type of athrtitis
Where uric acid crystals accumulate in joints
Irritate joint tissues
Causing painful inflamm
High levels of uric acid in blood = hyperuricemia

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47
Q

What do (harmless) low levels of uric acid? (2)

A

Prevent damage to BV linings

Passed out with urine + faeces

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48
Q

What anti-gout drugs are there? (3)

A

Naproxen
Diclofenac
Indomethacin

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49
Q

What is the MOA of naproxen? (3)

A

Inhibits COX-1/-2 levels which lowers PG levels
Exhibits analgesic, anti-pyretic + anti-inflammatory activity
Inhibits platelet agg (inhibits platelet TXA2)

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50
Q

What are the SEs of naproxen? (2)

A

Dizziness, nausea, indigestion, blurred vision, diarrhoea, abnormal liver function test, water retention, ringing in ears, hives
Relatively risk neutral for CV events

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51
Q

Why does aspirin cause bleeding + ulceration of GI tract if taken on empty stomach? (3)

A

NSAIDS decrease gastroprotective mechanisms of gut e.g. mucus secretion stim, gastric acid secretion inhibition + promotion of blood flow

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52
Q

Name 3 important chemical mediators of inflammation that are collectively referred to as eicosanoids (3)

A

Prostaglandins
Leukotrienes
Thromboxanes

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53
Q

How does aspirin mediate its antipyretic effects? (5)

A

During infections, bacterial endotoxins stimulate macrophages to produce IL-1
IL-1β acts on hypothalamus + PGE2 is released via COX-2 (which is now irreversibly acetylated by aspirin)
Decrease in PGE2 cause set point to lower (from its heightened state during fever)
Fever dissipates

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54
Q

List 4 uses of NSAIDs (4)

A

Anti-inflammatory drug (reduce inflammation associated with RA)
Decrease risk of ischaemic heart diseases/thrombus
Antipyretic drug (reduce fevers)
Analgesic (e.g. headache/toothache)

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55
Q

What are corticosteroids subdivided into and where are they both synthesised/released from? (3)

A

Glucocorticoids e.g. cortisol
Mineralocorticoids e.g. aldosterone
From adrenal cortex

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56
Q

What are the main functions of glucocorticoids? (2)

A

Carb + protein metabolism

Potent anti-inflammatory/immunosuppressant

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57
Q

What is the main function of mineralocorticoids? (1)

A

Controls H2O + electrolyte levels in the kidney

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58
Q

How is cortisol release controlled? (3)

A

Stress causes the release of corticotrophin releasing hormone (CRH) by the PVN of the hypothalamus
CRH stimulates ant. pit. to secrete ACTH
Adrenocorticotropin hormone increase glucocorticoid secretion

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59
Q

What are the functions of cortisol? (6)

A 
Promotes normal metabolism
Favours immediate use of glucose
Maintains blood sugar levels + BP
Provides resistance to stress
Acts as anti-inflamm. agent
Role in regulation of fluid balance in body
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60
Q

How is the release of aldosterone controlled? (7)

A

Via RAAS system (+ ACTH)
Juxtaglomerular apparatus senses low BP/blood flow
In response, glomerulus releases renin hormone into blood stream
Renin converts inactive angiotensinogen to angiotensin I in liver
ACE converts angiotensin I into angiotensin II in lungs
Angiotensin II:
- constricts BVs to increase BP
- stimulates adrenal glands to release aldosterone (stimulates resorption of Na+ and thus water, increasing blood vol.)

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61
Q

What are the metabolic actions of glucocorticoids? (3)

A

Breakdown of proteins + fats (muscle wasting etc.)
Decreased glucose usage + increased gluconeogenesis
Tendency to hyperglycaemia + increased glycogen storage

62
Q

What role do glucocorticoids have in hormonal regulation? (1)

A

-ve feedback on both hypothalamus + ant. pit.

63
Q

What effect do glucocorticoids have on cardiovascular system? (2)

A

Decrease in microvascular permeability + vasodilation (hallmarks of inflamm)

64
Q

What effect do glucocorticoids have on the CNS? (2)

A

Mood changes

Linked with changes in memory/stress

65
Q

What are the anti-inflammatory effects of glucocorticoids? (3)

A

Decreased microvascular fluid exudation (reduces influx of cells to inflamm area)
Decreased inflamm mediators + cytokines (decreased expression of COX-2, reduced eicosanoids + decreased levels of cytokines/complement)

66
Q

Where are glucocorticoid receptors found? (1)

A

Intra-cellularly in almost all tissues
UnboundR is usually sequestered in cytoplasm of target cell bound to heat-shock protein (HSP) complex which stabilise tehm

67
Q

How do glucocorticoids interact with their receptors? (4)

A

Enter cells through passive diffusion + form complex with receptor protein
Complex undergoes irreversible activation + enters cell nucleus where it binds to DNA
Leads to biological effects of glucocorticoids e.g. increased hepatic gluconeogenesis, increased lipolysis etc.
HSPs are uncoupled + then recycled

68
Q

How do glucocorticoids switch gene expression on + off? (4)

A

Interaction of steroid/receptor with promoter region - occupancy of GREs (glucocorticoid response elements) turn off/on certain genes
Steroid/receptor complexes prevent gene activation by other TFs involved in switching on COX-2/cytokines (e.g.NFkappaB)
Induction of inhibitor kappaBalpha which leads to:
- increased expression of anti-inflamm proteins (increased lipocortin which decreases AA + eicosanoids)
- decreased expression of pro-inflamm proteins (cytokines)

69
Q

What are glucocorticoids used for therapeutically? (3)

A

Adrenal insufficiency/failure (e.g. Addisons) = drug-induced or congenital
- combo treatment of GCs + MCs
Inflammation (e.g. asthma, rhinitis, skin disorder, sports injuries, cerebral oedema in patients with brain tumours)
Immunosuppression (inhibit graft vs host reaction in tissue transplantation)

70
Q

Examples of therapeutic glucocorticoids (5)

A 
Hydrocortisone
Prednisolone
Dexamethasone
Betamethasone
Beclomethasone
71
Q

Comparing effects of NSAIDs + glucocorticoids on eicosanoid biosynthesis (3)

A

Glucorticoids reduce expression of COX-2 + NSAIDs decrease activity of COX-2
Glucocorticoids also prevent PLA2 expression meaning membrane lipids cannot be hydrolysed to arachidonate

72
Q

What is the endogenous mineralocorticoid? (1)

A

Aldosterone

73
Q

How does aldosterone increase Na+ retention? (5)

A

In distal tubules of kidney
Stimulates Na/H exchanger via aldosterone receptors
Enters cells + upregulates Na+ permeable ENaCs in cell membrane
Enters cells + stimulates upregulation of basolateral Na/K ATPase pump
Water retention, loss of K+ and H+ as result

74
Q

What are therapeutic uses of mineralocorticoids? ()

A

Adrenal insufficiency e.g. Addison’s disease
Electrolye disorder e.g. cerebral salt-wasting
Orthostatic hypotension (postural hypotension) -> failure of baroreceptor reflex

75
Q

Example of a mineralocorticoid (1)

A

Fludocortisone

76
Q

What are the SEs of corticosteroids?

A

Cushing’s-like syndrome
Euphoria (but also depressive/psychotic symptoms)
Buffalo hump
Poor wound healing
Opportunistic infection
Osteoporosis
Gastric ulceration (generation of gastro-protective PGs inhibited)
Behavioural/reproductive problems
Prolonged HPA suppression after cessation of therapy

77
Q

Summarise corticosteroid drug use (2)

A

Useful drugs with wide-ranging action

+ thus expected penalty of wide-ranging SEs

78
Q

What are antibiotics? (1)

A

Antimicrobials that target bacteria

79
Q

How are antibiotics used? (5)

A 
20-50% questionable use
30% of hosp drug budget
In ICU, 50% patients are on antibiotics
50mill prescriptions per year
80% of human use is in community (50% resp infections, 15% UTIs)
80
Q

Where are antibiotics derived from? (5)

A

Natural products of fungi + bacteria
- natural antagonism gives them selective advantage
- kill/inhibit growth of other organisms
Most derived from natural products by fermentation the modified chemically to enhance pharm properties + antimicrobial effect
Some are totally synthetic (e.g. newer sulphonamides)

81
Q

Examples of pre-science anti-infectives (4)

A 
Used poultices (moulds, moss etc) to treat sepsis from wound infections - active ingredients of intro of microbial antagonism
Hysopp plant (often colonised by Penicillium notatum) = herbal remedy
Cinchona bark (contains quinine) as malaria treatment
Mercury used to treat syphilis, often toxic to patient
82
Q

What is meant by selective toxicity of antibiotics? (4)

A

Due to diffs in structure + metabolic pathways b/w host + pathogen
Harm microorganisms, not host
Target specific to microbe if poss
Difficult to find targets with anti-virals as viruses live inside host cells + anti-protosoals (eukaryotic)

83
Q

What is meant by therapeutic margin of antibiotics? (5)

A

Want to give MIC (min. inhibition conc.) - defines active dose
Want to achieve MIC long enough for microorganism to respond + die
Active dose vs toxic effect
If toxic dose is low + active dose is high = narrow therapeutic margin
- e.g. aminoglycosides, vancomycine (ototoxic/nephrotoxic)
All drugs have some adverse effects

84
Q

Why is it important to understand the MOA of an antibiotic + the organism you are targeting? (2)

A

To decide its clinical utility

Can’t understand antibiotic unless you understand target organism + why/why not it’s susceptible to antibiotic

85
Q

Why is maintenance of normal flora important? (2)

A

Creates environments where pathogens don’t tend to grow as they are being suppressed by commensal organisms

86
Q

What effect can microorganisms have on normal flora? ()

A

Damages normal flora

Can get overgrowth of organisms that are normally maintained at low levels

87
Q

What is antibiotic associated colitis/pseudomembranous colitis? (4)

A

Antibiotics (e.g. clindamycin, broad-spectrum lactams, fluoroquinolones) can disturb normal gut flora
Leads to overgrowth of Clostridium difficile (also candida/which expresses virulence determinants
Highly inflamed gut, large mucus production, can’t absorb water, diarrhoea, pseudomembranes
Serious hospital cross-infection risks (carriage rate up to 70%)

88
Q

In what % of population is C.difficile part of normal flora? (1)

A

3%

89
Q

How does immunosuppression affect choice of antibiotic? (2)

A

In healthy immune response, antibiotics act in combo with out own defence mechanisms to achieve bacterial clearance + cure
If immunocompromised it is difficult to treat same infection so need to use diff drugs/admin route/combos

90
Q

How are antibiotics classified? (3)

A

Type of activity
Structure
Target site for activity

91
Q

What do bacteriCIDAL drugs do? (3)

A

Kill bacteria
Used when host defence mechanisms are impaired or in life threatening illnesses (e.g. meningitis)
Required in endocarditis, kidney infection
Can be -static for one + -cidal for another, dose also makes a difference

92
Q

What do bacterioSTATIC drugs do? (3)

A 
Inhibit bacteria (prevent from growing + immune system clears bacteria e.g. tetracylins)
Used when host defence system mechanisms are intact
Used in many infectious diseases
93
Q

How are drugs classified by spectrum of activity? (2)

A 
Broad spectrum antibiotics
- effective against many types e.g. cefotaxime
Narrow spectrum antibiotics
- effective against v few types
e.g. penicillin G
94
Q

1st-3rd generation cephalosporins + refinement of antibiotic activity? ()

A

E.coli, Strep.pneumoniae, Staph.aureus
1st gen = v effective at killing gram+ (S.a + S.p) but not effective at killing E.coli
2nd gen = better distribution of bactericidal activity
3rd gen = v effective at killing E.coli + S.p but not S.a

95
Q

In which drugs is the beta-lactam ring present + why is it important? (3)

A

Cephalosporins + penicillins
Confers antimicrobial properties to antibiotics containing this structure
(Rest of structure confers the pharm properties of the antibiotic)

96
Q

What are common bacterial targets of antibiotics? (4)

A

Cell wall synthesis
Protein synthesis (50s + 30s)
Folic acid metabolism
Cell membrane

97
Q

Which antibiotics inhibit cell wall synthesis? (3)

A

Penicillins, cephalosporins
Vancomycin (but usually reserved for treating MRSA)
Human cells do not have cell wall, so specific to bacteria

98
Q

Which antibiotics inhibit protein synthesis? (4)

A 
50s inhibitors (erythromycin)
30s inhibitors (tetracyline, gentamicin)
99
Q

How can synthesis of DNA be targeted by antibiotics? (2)

A

Quinolones inhibit DNA gyrase (which unwinds + then rewinds bacterial DNA during replication)
Selective target as human equivalent enzyme is different

100
Q

What is rifampcin used for? (3)

A

To treat TB
Reduce carriage rates in pop. after exposure to e.g. meningitis outbreak
Blocks RNA polymerase enzyme + therefore ability of bacteria to produce mRNA

101
Q

How do polymyxins work? (2)

A

Target bacteria cell membrane

Very toxic as very little diff b/w human + bacterial membranes

102
Q

How can folic acid synthesis be targeted by antibiotics? (3)

A

E.g. trimethoprim, sulfonamides (often used in combo)
Inhibit bacterial enzymes used in folic acid metabolism (enzymes absent/in low levels in humans)
Bacteriastatic

103
Q

Gram +ve bacteria (4)

A

Inner membrane
Large peptidoglycan structure synthesised by enzymes that are released across membrane + sit on membrane surface
Beta lactams inhibit synthesis of cell wall
Cell wall very porous so antibiotics can v quickly + easily get to site where they can inhibit enzymes

104
Q

Gram -ve bacteria (3)

A

Have smaller peptidoglycan layer but have outer membrane in addition
Outer membrane is impermeable (except through porins = selective transporters)
Porins define specificity of what can enter bacterium

105
Q

Are gram +ve or gram -ve bacteria easier to treat? (2)

A

Gram -ve - don’t respond to a lot of antibiotics

Antibiotic has to pass through porin, through peptidoglycan + into peri-plasmic space before it can have its effect

106
Q

Why might an antibiotic inhibit cell wall synthesis well in one organism but not in another? (1)

A

Because the peptidoglycan enzymes are different in different organisms

107
Q

How is peptidoglycan synthesised? (4)

A

Precursor dimers in bacterial cytoplasm
Incorpotate terminal D-alanines
Lipid transporters flip precursors across membrane into peri-plasmic space onto outer membrane of gram +ve
Polymerised into longer side chain by cross linking

108
Q

How do different antibiotics inhibit bacterial cell wall synthesis? ()

A

Cycloserine = inhibits reactions involved in incorporation of alanine into cell wall precursor
Bacitracin targets lipid carrier
Vancomycin binds + recognises terminal D-ala-D-ala region, preventing chain polymerisation by cross-linking

109
Q

How does cycloserine work to inhibit bacterial cell wall synthesis? (1)

A

Inhibits reactions involved in incorporation of alanine into cell wall precursor

110
Q

How does bacitracin work to inhibit bacterial cell wall synthesis? (1)

A

Targets lipid carrier

111
Q

How does vancomycin work to inhibit bacterial cell wall synthesis? (3)

A

Binds + recognises terminal D-ala-D-ala region, preventing chain polymerisation by cross-linking
Also blocks enzymes that polymerise the peptidoglycan
V potent inhibitor

112
Q

How does penicillin/cephalosporins work to inhibit bacterial cell wall synthesis? (3)

A 
Inhibit PBPs (penicillin-binding proteins) = competitive inhibitors
PBPs = transpeptidases + carboxypeptidases cross link structures by cleaving of final D-ala
Pen/ceph stop recognition + cleaving of final D-ala so no cross linking
113
Q

What is an example of an antibiotic’s structure mimicking natural substrates for bacterial enzymes? (1)

A

Similarity of molecular backbone in D-ala-D-ala + penicillin

114
Q

What action do beta-lactams have on PBP in gram -ve bacteria? (5)

A

Penicillin with beta lactam has to enter through porin + bind to PBP to inhibit it
Then precursors build up
This induces autolysis
Peptidoglycan structure is disrupted + bacteria die
Pen + ceph are bacteriacidal

115
Q

Why can’t we treat some organisms with penicillin/cephalosporins? (2)

A

Some organisms do not have peptidoglycan so have to choose a different target
For example - DNA synthesis (e.g. erythromycin)

116
Q

How else might we treat bacterial infections? (4)

A

Surgery e.g. drainage of absces to remove necrotic tissue/pus
Have to re-establish vascularity so we can get MIC to site which requires their action
Immunologically (rare)
E.g. in tetanus the bacteria releases tetanus toxin which can be neutralised with an anti-toxin

117
Q

How might we use antibiotics as prophylaxis? (3)

A

Decrease carriage rates + prevent infection (e.g. of TB/meningitis)
Peri-operative cover prior to gut surgery
People with increased susceptibility to infection (e.g. CF are given LT antibiotics)

118
Q

What routes of admin are there for antibiotics? (3)

A

Community infections often treated orally
Serious infections - often unable to take oral (vomiting, unconscious, poor gut absorption due to trauma) so IV (rapid delivery, high blood conc)
Topical (conjuctivitis, superficial skin infections, burns) - antiseptic creams, heavy metal ointments

119
Q

When do we give antibiotics in combo? (4)

A

Before an organism is identified in life-threatening infections (e.g. septicaemia, endocarditis)
In polymicrobial infections
Sometimes have synergistic effect (e.g. penicillin + gentamicin)
To give less toxic dose of an individual drug e.g. penicillin + gentamicin (narrow therapeutic window)
To reduce antibiotic resistance (e.g. TB 4-drug treatment)

120
Q

What is empirical therapy (antibiotics)? (3)

A

‘Best guess’
Antimicrobials are commonly started before lab results are available
E.g. acute bacterial meningitis, paramedic IM penicillin for suspected meningitis, STIs (chlamydia + gonorrhoea)

121
Q

Which antibiotic + why? (10)

A 
Spectrum of activity (cidal/static)
Toxicity
Excretion
Patient age (renal capacity)
Route of admin (oral, IM, IV, topical)
Clinical condition
Type of bacteria
Sensitivity of bacteria (consider synergy, resistance mechanisms)
Cost
Distribution in body
122
Q

Distribution of antibiotic in body relative to distribution of bacteria ()

A

Some not absorbed from gut (vancamycin can be used to treat gut infections but usually reserved for MRSA_
Many do not cross BBB
Some do not penetrate abseces
Few accumulate inside cells e.g. TB

123
Q

What treatment would you choose for stage 1 therapy? (3)

A

0-2 days
Unstable, don’t know where/what pathogen is
Treat empirically with cidal + broad spectrum antibiotic e.g. 3rd gen cephalosporin

124
Q

What treatment would you choose for stage 2 therapy? (4)

A

2-7 days
Stabilised + better idea of what organism is
Can rationalise therapy away from empirical treatment towards more narrow spectrum antibiotic (monotherapy)
IV if you have to (risk of hospital acquired infections), oral if you can

125
Q

What treatment would you choose for stage 3 therapy? (3)

A

7-10 days
Stable
Oral therapy is common

126
Q

Reasons for failure of antibiotic therapy - drug (4)

A

Inappropriate drug/route of admin
Poor tissue penetration
Inadequate MIC
Increased excretion

127
Q

Reasons for failure of antibiotic therapy - host (5)

A 
Immunocompromised host
Undrained pus
Poor circulation/damaged tissue
Unusual site for pathogen
Retained infected body e.g. catheter
128
Q

Reasons for failure of antibiotic therapy - bacteria (4)

A

Natural or acquired resistance
Dormant (non-growing bacteria)
Dual infections
Biofilms e.g. endocarditis

129
Q

Reasons for failure of antibiotic therapy - lab (1)

A

Errors of equivocal tests

130
Q

What is inflammation the body’s defence mechanism to? (2)

A

Invasion - pathogens + allergens

Injury - heat, UV, chemicals

131
Q

What are the cardinal signs of inflammation? (5)

A

Calor - increased blood flow
Rubor - increased blood flow
Dolor - sensitisation/activation of sensory nerves
Tumour - increased post-capillary venule permeability
Function lasea - pain/injury

132
Q

Which immune system produces inflammation? (1)

A

Both innate + adaptive immune systems

133
Q

What can occur as a result of chronic + acute inflammation? (2)

A

Chronic - severe tissue damage e.g. athersclerosis

Acute - e.g. anaphylaxia, sepsis

134
Q

Brief description of inflammation (5)

A

Beginning of injury of process to injury resolution can last hours/up to 5 days usually
Recognition of agent causing injury leads to mediator release which usually lasts for whole length of inflamm. reaction
Some inflammatory mediators will compromise permeability of endothelial cells which fall apart + exudate (leak out of components in capillary bed)
Chemoattractants cause cell accumulation e.g. macrophages, neutrophils
Redness + fever = systemic effects
Repair/healing

135
Q

What are local hormones? (5)

A

Chemical mediators that orchestrate complex response + many signs of inflammation
Produced in response to wide range of stimuli
Synthesised/released only when required
Local release for local action
Inactivated locally to minimise systemic effects

136
Q

Where is histamine synthesised, stored + released from? (4)

A

Mast cells (express receptors for IgE, C3a + C5a on cell surface)
Basophils
Neurones in brain
Histaminergic cells in gut

137
Q

Describe the secretory granules histamine is found in (2)

A

Pre-made, composed of heparin + acidic proteins

Allow histamine to be maintained in ionic form

138
Q

In what circumstances might histamine be released? (5)

A 
Allergic reactions (IgE-mediated)
Production of complement agents C3a + C3b
Insect stings
Trauma
Through a rise in intracellular calcium
139
Q

Stimulation of which receptors, inhibits histamine release (1)

A

β-adrenoceptors

140
Q

How is histamine synthesised? (2)

A

From histidine amino acid

By histidine decarboxylase

141
Q

How is histamine metabolised? (2)

A

By imidazole-N-methyltransferase (INMT) + diamine oxidase

142
Q

What type of receptors are H1-H4? (2)

A

GPCR which produce physiological effects by activating secondary messenger systems

143
Q

Describe the H1 receptor (6)

A

Gq
Activates PLC which hydrolyses PIP2 to DAG + IP3
Systemic vasodilation, bronchoconstriction, CNS

144
Q

Describe the H2 receptor (5)

A

Gs
Activates AC, generation of cAMP, stimulation of PKA
Parietal cells to increase gastric secretion, heart

145
Q

Describe H3 + H4 (3)

A

Gi, decrease in cAMP
H3 - neuronal presynaptic terminals
H4 - basophils, bone marrow, gut

146
Q

What occurs as a result of stimulation of H1 + H2? (1)

A

Many actions of histamine-mediated inflammation

147
Q

What are the cardiovascular effects of stimulation of histamine receptors? (4)

A

Dilates arterioles, decreased TPR (H1)
Increased permeability of post-cap venules, decrease in BV (H1)
Increase in HR (H2) - in vivo reflex to retain normal BP
Generally involved in lowering BP (lowering vasc. resistance)

148
Q

What are the non-vascular smooth muscle effects of stimulation of histamine receptors? (4)

A

Contraction (H1) e.g. bronchoconstriction

149
Q

What are the algesia effects of stimulation of the histamine receptors? (3)

A

Pain, itching, sneezing caused by stimulation sensory nerves (H1)

150
Q

What are the GI effects of stimulation of the histamine receptors? (3)

A

Increased secretion (H2)

151
Q

Why are associated exocrine secretions increased upon stimulation of H1 + H2 receptors? (1)

A

Due to the increased blood flow

152
Q

What are the most important clinical roles of histamine + which receptors mediate these effects? (2)

A 
Acute inflammation (H1 effects)
Stimulating gastric acid secretion (H2 effects)

Semester 4 Revision (15 decks)

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