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Semester 4 > SBT - Scientific Basis of Therapeutics > Flashcards

SBT - Scientific Basis of Therapeutics Flashcards

1
Q

What is inflammation

A
  • Bodys defensive response to
    1. Invasion (pathogens that cause disease) (allergens - non disease)
    2. Injury - heat, ultraviolet, chemicals
  • Signs are that there is:
    • Calor (warmth, increased blood flow),
    • Rubor (redness, increased blood flow),
    • Dolor (pain, sensitisation/activation of sensory nerves),
    • Tumour (swelling, increased post ),
    • Functio laesa (loss of function, pain/injury)
  • Inflammation is production by both innate and adaptive immune systems
  • Clinically these are important processes
  • Chronic inflammation - severe tissue damage, e.g. atherosclerosis
  • Acute responses - anaphylaxis, sepsis
  • ## Anti inflammatory drugs are regularly prescribed
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2
Q

Histamine characteristics ?

A
  • Synthesised from histindine amino acid, by histidine decarboxylase
  • Metabolised from imidazole N methyltransferase (IMNT) + diamine oxidase
  • Synthesised and stored, released from
    • Mast cells, which express receptors for IgE, C3a, and C5a on cell surface (connective tissue)
    • Basophils (blood)
    • Neurones in brain
    • Histaminergic cells in gut
  • Pre made, ready to go, in secretory granules that are made up of heparin and acidic proteins
  • Released by allergic reactions (IgE mediated)
  • Production of complement agents C3a, C5a, insect stings, trauma via a rise in [Ca2+]I
  • Release of histamine inhibited by stimulated of beta adrenoreceptors
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3
Q

Histamine receptors characteristics - H1

A
  • Gq/PLC, PIP2 production
  • Generation of DAG + IP3
  • Smooth muscle
  • Endothelium
  • CNS
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4
Q

Histamine receptors characteristics - H2

A
  • Gs/AC, generation of cAMP
  • Stimulation of PKA
  • Parietal cells to increase gastric acid secretion, heat
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5
Q

Histamine receptors characteristics - H3

A
  • Gi, decreases Camp levels

- Neuronal presynaptic terminals

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6
Q

Histamine receptors characteristics - H4

A
  • Gi, decreases in cAMP levels

- Basophils, bone marrow, gut

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7
Q

What are the effects of stimulating the H1 and H2 receptors - Cardiovascular effects

A
  • Dilates the arterioles, causes a fall in the TPR (H1)
  • Increased permeability of post-capillary venules, ¯BV (H1)
  • Increase in heart rate (H2) - in vivo reflex to try to retain BP to normal
  • Generally involved in ¯BP (↓ vascular resistance)
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8
Q

What are the effects of stimulating the H1 and H2 receptors - Non vascular smooth muscle, airways and gut

A
  • Contraction (H1), e.g. bronchoconstriction
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9
Q

What are the effects of stimulating the H1 and H2 receptors -Algesia

A
  • Pain, itching, and sneezing caused by stimulation of sensory nerves (H1)
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10
Q

What are the effects of stimulating the H1 and H2 receptors - Gastric acid

A
  • Increase secretion (H2)
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11
Q

What are the effects of stimulating the H1 and H2 receptors - Associated exocrine secretions

A
  • Increased, due to ­ blood flow
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12
Q

What are the pathological roles of histamine

A
  1. Acute inflammation

2. Stimulating gastric acid secretion

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13
Q

Acute inflammation Triple response:

A
  • Reddening (local vasodilation)
    • Wheal

Flare

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14
Q

What is antidromic impulse

A
  • Antidromic impulse refers to impulse conduction along the nerve fibre in a direction that is opposite of normal direction (orthodromic)
  • It is conduction along the axon away from axon terminal towards the cell body
  • Antidromic impulses in nerve fibres may be produced by electrical stimulation.
  • Antidromic impulses release neuropeptides which case vasodilation distant from the site of irritation → the third phase of inflammation, the flare response
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15
Q

Lewis triple response characteristics

A
  • 3 part response when a line is drawn on the skin , due to a release of histamine from the mast cells
    • Degranulation of mast cells
    • Changes in smooth muscle contractility
    • Stimulation of lymphocytes and granulocytes → neurogenic inflammation
  • Flare: kinin, neurotensin, or substance P, implicated in the chain of biochemical events
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16
Q

describe Dermatographia in the triple response

A
  • Reddening: oedema [↑ vascular permeability induced by substance P (SP) and histamine → ↑leakage of fluid and plasma proteins from capillaries (ie.e, ↑ plasma proteina extravasation)]
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17
Q

H1 antagonists that treat acute inflammation characteristics - 1st gen

A
  • Mepyramine
  • Diphenhydramine
  • Promethazine
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18
Q

H1 antagonists that treat acute inflammation characteristics - 2nd + 3rd gen

A
  • Terfenadine, prodrug which potential cardiac arrhytmia action in high concentration. These are increased with grapefruit juice
  • Grapefruit juice inhibits P450 mediated drug metabolism with liver pathways
    • Fexofenadine, active, non toxic metabolite of terfenadine
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19
Q

H1 antagonists that treat acute inflammation characteristics - Therapeutic and side effects

A
  • Reduce minor inflammatory reactions, like insect bites and hay fever - but there is no significant value in asthma
  • 1st generation drugs are sedative - drowsiness is a major side effect, but sometimes is used as a therapeutic effefct
  • Some, like promethazine are antiemetic = motion sickness
  • Anti muscarinic actions (common in first generation drugs), like atropine like effects of blurred vision, constipation etc.
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20
Q

Gastric problems that can arise because of H2 antagonists

A
  • Archetypal - cimetidine, ranitidine
  • Therapeutic and side effects:
    • Reduces gastric acid secretion in treatment of duodenal and gastric ulcers and Zollinger-Ellison syndrome (duodenum & pancreas tumours increasing gastrin secretion)
    Increase INMT activity so more rapid breakdown of histamine
    Mental confusion, dizziness, tiredness & diarrhoea sometimes as side effects
    Cimetidine, decrease in cytochrome P450 activity so adverse drug interaction potential, gynecomastia
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21
Q

Describe the synthesis of Bradykinin

A

The generation of bradykinin as a result of activation of:

  1. Hageman factor (HF) & production of plasma kallikrein
  2. Production of lysylbradykinin by tissue kallikreins;
  3. Action of cellular proteases in kinin formation
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22
Q

What is the Hageman factor

A

Hageman factor = coagulation factor XII

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23
Q

What are the pharmacological effects of bradykinin

A
  • Potent vasoactive peptides
  • Increase vascular permeability
  • Vasodilation (↓BP)
  • Pain
  • Contraction of smooth muscle (gut and bronchus)
  • Stimulation of arachidonic acid metabolism (initiates phospholipase action)
  • Chemotactic to leukocytes, which defend the body against infections
  • Dry cough
  • Metabolism of bradykinin: kininases (ACE, aminopeptidase P, carboxypeptidase)
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24
Q

Describe the distribution of 5HT

A
  • Platelets release 5HT, and TXA2
  • The ECL cells of the GI tract, mediates gut movement, diarrhoea,
  • Brain (congition, aggression, mating, feeding, sleep, pain, vomiting, behaviour)
  • Some tumours (e.g. carcinoid) - secrete excess 5HT
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25
Q

What are the inflammatory actions of 5HT

A
  • Stimulates mast cell adhesion and migration
  • 5HT enhances inflammatory reaction of the skin, lungs and gut
  • Promotes inflammation by increasing number of mast cells at the site of tissue injury
  • Might synergise with TXA2 to stimulate platelet activity and vasoconstriction
  • Activation of TXA2 receptors increases 5HT mediated responses in the blood vessels
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26
Q

Prostaglandins, Thromboxanes, Leukotrienes (PTL) - what are they known as

A
  • Eicosanoids
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27
Q

Important of the PTL, eicosanoids

A
  • They are molecules that have powerful inflammatory actions
  • Targets of major anti inflammatory drugs:
    • NSAIDS, glucocorticoids, Lipoxygenase inhibitors, Leukotriene antagonists
  • We need to know how the PTL Eicosanoids are made
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28
Q

How the Prostanoids are made (Prostaglandins and Thromboxanes) - not leukotreines

A
  • Prostanoids are not ‘ready-to-go’ (unlike histamine)
  • Prostanoids are generated from arachidonic acid (AA, poly-unsaturated fatty acid). This is rate-limiting step
  • AAs are produced from phospholipids (PLs) via 1-step/2-step pathways
  • These steps are triggered by many agents, e.g. thrombin on platelets and antigen-antibody reactions on mast cells
  • Bradykinin and adrenaline are known initiators of the cascade and can initiate phospholipase action at the cell membrane.
  • Noradrenaline changes the distribution profiles of eicosanoids
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29
Q

What initiates the formation of prostanoids (prostaglandins and thromboxane)

A
  • Bradykinin + adrenaline
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30
Q

Cyclooxygenases

general action

A
  • Conversion of AA into prostanoids needs COX (cyclooxygenase enzyme)
  • COX1/COX2 are the 2 main isoforms
  • COX are fatty acids that are attached to the endoplasmic membrane
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31
Q

COX 1 actions

A
  • Constitutively active, responsible for the physiological roles of PGs/TXs like the regulation of peripheral vascular resistance
  • Renal blood flow, platelet aggregation, gastric cytoprotection
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32
Q

COX 2 actions

A
  • Needs to be stimulated
  • e.g. by inflammatory cytokines (IL-1), TNFalpha
  • Responsible for role of prostaglandins/TX in inflammatory responses - pain and fever
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33
Q

COX 3 actions

A
  • COX1 variants

- Pain perception of the CNS

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34
Q

Anti-inflammatory lipid mediators - lipoxins and CyPGs

A
  • There is a switch for PG synthesis from pro-inflammatory (PG & LTs) at onset of inflammation to anti-inflammatory lipoxins and 15dPGJ2 (cyPG) during resolution
  • Activation of monocytes is important in their action
    • Lipoxins recruit monocytes to clear inflamed site of necrotic apoptotic neutrophils
  • Regulate activation levels of neutrophils and dampen their damaging effects (↑phagocytosis of neutrophils)
  • By acting in concert with cyPGs,
  • Promote phagocytic clearance of apoptotic cells by macrophages → resolution of inflammation
  • CypG – inhibits macrophage activation→ ↓ uncontrolled tissue damage; ↓NF-kβ activation (helps to ↓ activation of inflammatory genes)
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35
Q

Actions of eicosanoids as local hormones?

A
  • Cells specialise in making particular eicosanoids
    • mast cells: PGD2
    • platelets: TXA2
    • endothelial cells: PGI2, PGE2
  • Act at specific G-protein-coupled receptors
    • PGs subtypes act at DP, FP, IP and EP (EP1, EP2, EP3) receptors
    • TXs at TP receptors
  • LTs : LTB4 at BLT receptors; LTC4, LTD4 & LTE4 at Cys-LT receptors (-chemotactic; bronchoconstrictor & ↑ vascular permeability; oedema, ↑secretion of thick, viscous mucus)
    Exert diverse and often contradictory actions in inflammation
    Subjected to local inactivation
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36
Q

Physiological/Pathological actions of Eicosanoids

A
  • PGs (Lungs, vascular, gut, CNS, kidney, uterus)
    DP receptors: Vasodilatation, ¯ platelet aggregation, bronchoconstriction
    FP receptors: Contraction of myometrial smooth muscle, bronchoconstriction
    IP receptors: Vasodilatation, ¯ platelet aggregation, renin release
    EP1 receptors: Contraction of bronchiole/GIT smooth muscle
    EP2 receptors: Bronchodilation, vasodilatation, relaxation of GIT smooth
    muscle, ­ intestinal fluid secretion
    EP3 receptors : Contraction of intestinal smooth muscle, ­ gastric mucus secretion, ¯ gastric acid secretion, pyrexia
    TXs (vascular/platelets)
    TP receptors: Vasoconstriction, ­ platelet aggregation
    LTs (General inflammation, lungs/vascular in acute allergy responses)
    BLT (1 & 2) receptors: Chemotaxis and proliferation of immune cells, ­adhesion
    CysLT (1 & 2) receptors: Bronchoconstriction, vasodilatation, ­ vascular permeability
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37
Q

Leukotriene receptor antagonists

A
  • Examples: Zafirlukast, montelukast, pranlukast, zileuton
  • Block receptor for cysteinyl LTs (LTC4, LTD4, LTE4, etc)
  • These LTs cause airway oedema, secretion of thick mucus and smooth muscle contraction
  • Receptor blockade is useful in following:
    • Prevention of mild to moderate asthma
    • Early to late bronchoconstrictor effects of allergens
    • Exercise-induced asthma and asthma provoked by NSAIDs
    • Side effects: GI upset, Irritability, Dry mouth, thirst, rashes, oedema
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38
Q

Measurement of effects of mediators that cause bronchospasm

A
  • Comparing SRSA (LTD4, LTC4 , LTE4) with histamine in the lung
  • Effects of LTC4, LTD4 and histamine on the contraction of guinea pig lung strip: a section of peripheral lung tissue
  • Summary of results: Leukotrienes are much more potent than histamine
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39
Q

Poly unsaturated fat intake in disease

A
  • The poly-unsaturated fatty acids (PUFAs; omega-3 essential fatty acids) are of considerable interest because of their (perceived) beneficial effects for our health
  • Substances such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oils play a significant part in inflammation
  • Derivatives of EPA and DHA (resolvins and neuroprotectins, respectively) have anti-inflammatory actions
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40
Q

Poly unsaturated fat acids in inflammation

A
  • Fish oils provide substrates for the generation of alternative eicosanoids
  • Fish oils cause increased proportion of ecosapentanoic acid (EPA) and docosahexaenoid acid (DHA) in inflammatory cells at the expense of AA
  • Less substrate (i.e., AA) is available, therefore there is ↓ production of PGE2, TXB2, LTB4, 5-HETE, LTE4
  • Thus EPA and DHA act as substrates for the generation of alternative eicosanoids
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41
Q

What is the consequence of interaction of EPA with COX/LOX?

A

Consequence of interaction of EPA with COX/LOX:
↑ LTB5, LTE4, 5-HPETE - eicosanoids of different structure to those generated from AA

LTB5 is 10-100 less chemotactic to neutrophils

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42
Q

Anti-inflammatory metabolites of EPA and DHA

A
  • A novel group of mediators have also been identified from COX-mediated action on EPA and DHA.
  • E-series resolvins (resolvin D1-D4; EPA-derived mediators) have anti-inflammatory actions.
  • Docosatrienes and neuroprotectins (D-series resolvins; DHA-derived mediators) also have anti-inflammatory effects.
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43
Q

Mechanism of action of PUFAs (EPA and DHA)

A
  • Overall, specialized counter-regulatory lipid mediators (lipoxins, resolvins, protectins and cyPG) initiate the resolution of inflammation in vivo and in vitro animal models.
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44
Q

Which enzymes are responsible for the formation of leukotrienes?

A
  • Lipoxygenase is the enzyme that is responsible for leukotreines
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45
Q

What are the effects of Bradykinin on vascular smooth muscle cells

A
  1. Increases vascular permeability
  2. Vasodilation
  3. Contraction of gut + bronchial smooth muscle cells
  4. Causes secretion of TXA2, which will increases platelet aggregation
  5. TXA2 also causes contraction of smooth muscle cells - vasoconstriction
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46
Q

What are the effects of 5HT serotonin on vascular smooth muscle cells

A
  1. Promotes TXA2 - promotes platelet aggregation
  2. Release from endothelial cells
  3. Promotes mast cell number @ inflammatory sites, etc.
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47
Q

Prostaglandins have protective effects on the gut. Which prostaglandin mediates protective effects, the receptor it interacts with and the types of effects that it modulates in the gut?

modulation of action of other agents

A
  • PGE2, EP3 receptors.
  • It negatively regulates the behaviour of the parietal cells + causes gastro protection
  • Increases:
    • Mucus secretion
    • Blood flow
    • Bicarbonate secretion, therefore there is neutralisation of Ach
    • Gastrin mediated acid secretion in the gut
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48
Q

What is asprin?

A
  • Archetypal NSAID (ASA)
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49
Q

What are NSAIDs (Non Steroidal Anti Inflammatory Drugs)

A
  1. Analgesic (pain prevention)
  2. Anti Pyretic (lowering raised temperature, fever)
  3. Anti Inflammatory (decreased immune response)
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50
Q

What are NSAIDs used to treat

A
  • Low grade pain (chronic inflammation like arthritis)
  • Bone pain (cancer metastases)
  • Fever (associated with infections)
  • Inflammation (fall in symptoms: oedema, redness, itch)
  • Responses are dependent on inhibitory profiles, on different COXs.
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51
Q

What are the pharmacological mechanisms of NSAIDs

A
  • The main therapeutic action, is by inhibition of COX.
    1. Converts AA –> PG + TXs.
    2. COX 1 (constitutively active, platelets)
    3. COX 2 (inducible enzyme e.g. by IL-1B & TNFa)
    4. Inhibition of COX-2 reduces PG/TXs inflammatory agents
  • Asprin acts irreversibly on COX
  • Others can act reversibly & this is significant in its use as a prophylactic in cardiovascular disease
  • Older generation NSAIDs, inhibit both COX-1 and COX-2
  • Newer COX-2 selective agents could act as “super asprins” + paracetamol is a special case.
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52
Q

What are the pharmacological mechanisms of NSAIDs - what is the action of COX (which NSAIDs will inhibit)

A
  1. Converts AA –> PG + TXs.
  2. COX 1 (constitutively active, platelets)
  3. COX 2 (inducible enzyme e.g. by IL-1B & TNFa)
  4. Inhibition of COX-2 reduces PG/TXs inflammatory agents
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53
Q

Paracetamol is not an NSAID: what is paracetamol?

A
  • Paracetamol is an analgesic that does not have anti-inflammatory effects
  • Little inhibition of COX 1 / COX 2 in peripheral tissue
  • Weakly inhibits COX 3 in the CNS - this does not explain its effects though.
  • Might modulate serotonergic neurotransmission
  • Inhibits COX mediated generation of hydroxypeptides from AA metabolis
  • Hydroxypeptides, stimulate COX activity
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54
Q

Describe Antipyretic Action

A
  • There are bacterial endotoxins that are produced during infections stimulate macrophages, to release Interleukin-1 (IL1)
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55
Q

Describe the action of IL-1B

A
  • Acts on the hypothalamus, to cause PGE2 release
    • Via COX2
  • Increase in PGE2 depresses temperature sensitive neurones
  • PGE2 elevates set point temperature which leads to the onset of a fever
  • NSAIDs will block PGE2 production, which means that set point is lowered back to normal value + fever dissipates
  • But NSAIDs will have no effect on normal body temperature
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56
Q

What do NSAIDs do to PGE2 production

A
  • NSAIDs block PGE2 production = fever dissipation

- This means set point lowered to normal value

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57
Q

Analgesic action of NSAIDs

A
  • Prostaglandins sensitise + stimulate the nociceptors
  • Oedema is produced by inflammation + also directly activates nociceptive nerve fibres
  • PGs interact synergistically with other pain producing substances
    • Kinins
    • 5HT
    • Histamine
  • To produce hyperalgesia, which is increased sensitivity to pain relief
  • Useful for pain that is associated with the production of inflammatory agents, like PGs/TXs:
    • Arthritis, toothache, headache
    • This is because NSAIDs inhibit PGs mediated vasodilatation
    ○ COX1, COX2, + COX2 inhibition in CNS
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58
Q

What happens when there is blockade of PG production?

A
  • Breakage of this cycle

Leads to pain relief

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59
Q

Give examples of inflammatory agents

A
  • PGs

- TXs

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60
Q

Anti-inflammatory action

- PGE2 + PGI2 have powerful acute inflammatory effects - Explain how

A
  • Arteriolar dilatation, so increased blood flow
  • Increased permeability in post capillary venules
  • Both of these processes increase the influx of inflammatory mediators, into interstitial space
  • Inhibition of their formation, reduces redness and swelling
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61
Q

Why do NSAIDs only provide symptomatic relief

A
  • NSAIDs do not cure the underlying cause of inflammation - they help; but do not cure arthritis
  • Fall in COX2 generated PGs - the effects develop gradually
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62
Q

Describe systems pharmacology of NSAIDS : Action on the Cardiovascular System

A
  • TXA2- major role in vascular haemostasis - platelet aggregation, vasoconstriction
  • NSAIDs decrease TXA2 - COX 1 product levels, and so increase bleeding time
    • This could be problematic in surgery or childbirth
  • Where platelet aggregation is increased in disease, aspirin has a role in prophylactic treatment.
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63
Q

Describe how thrombo resistance is conferred by endothelial mediators: step 1

A
  • Prevention of platelet aggregation in the vessel lumen
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64
Q

Describe how thrombo resistance is conferred by endothelial mediators: step 2

A
  • When there is increased platelet aggregation, there is a fall in blood loss because of haemostasis
  • Damaged endothelium will cause an increase in collagen and also Von Willebrand Factor (vWF)
  • Inappropriate platelet aggregation will lead to thrombus + ischaemia heart disease
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65
Q

Why is aspirin beneficial in cardiovascular disorders - Inducible COX-2

A
  • Endothelial cells produce PGI2 and COX

- Anti aggregator vasodilator

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66
Q

Why is aspirin beneficial in cardiovascular disorders - Constitutively active COX-1

A
  • Platelet produces COX enzyme
  • Which then makes TXA2
  • This is a pro aggregatory vasoconstrictor
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67
Q

Why is asprin beneficial in cardiovascular disease - Inducible COX-2

A
  • Anti- aggregatory vasodilator
  • Plus low doses of aspirin
  • Endothelial cell cannot produce PGI2 because COX inhibited.
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68
Q

Why is asprin beneficial in cardiovascular disease - Constitutively active COX-1

A
  • Pro aggregator vasoconstrictor

- TXA2 cannot be produced because COX inhibited

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69
Q

Why is aspirin beneficial in cardiovascular disorders, over time [Inducible COX-2]

A
  • New protein synthesis

- New COX, recovery

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70
Q

Why is aspirin beneficial in cardiovascular disorders, over time [Constitutively active COX-155]

A
  • No protein synthesis in platelets - no new COX, no recovery
  • Platelets cannot synthesise more COX
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71
Q

Skeletal action of PGs

A
  • PGs with acute inflammatory effects contribute to swelling and pain in arthritis - joint pains
    • Arteriolar dilatation
    • Increased microvascular permeability
    • Hyperalgesia - increased sensitivity to pain
  • NSAIDs thus diminish these effects but do not treat the cause
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72
Q

GI tract action of PGs

A
  • PGs (PGE2/PGI2) important in protecting the gastric mucosa.
    1. Stimulate mucus secretion
    2. Inhibit gastric acid secretion
  • NSAIDs decrease these cytoprotective mechanisms - bleeding and ulceration can result
  • Gastric side effects are the most common adverse reactions to older NSAIDs
  • COX 2 selective inhibitors might be gastric friendly - as it is suggested that COX 1 is expressed in the gut
  • NSAIDs = acidic
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73
Q

List the effects of NSAIDs on the GI tract

A
  • Decreased: mucus secretion, HCO3-
  • Increased: acid secretion, LT production, blood loss
  • Interefere with tissue healing (COX-2 inhibition)
  • Nausea, dyspepsia, GI contraction (COX-1 inhibition)
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74
Q

Give examples of some COX2 selective agents

A
  • Celecoxib
  • Valdecoxib
  • Etoricoxib [most selective COX 2 inhibitors]
  • Rofecoxib
    • These are withdrawn due to CV effects - not suitable for RA / osteoarthritis
    • Use melaxicam, etodolac instead
  • COX-2 + NSAID = ulcer
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75
Q

What causes ulcers

A
  • COX 2 + NSAID
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76
Q

Describe the action of Diclofenac (NSAID)

A
  • Selective for COX2
  • Inhibits COX 1 in GIT –> ulcers
  • Less effective analgesics will have less inhibition of COX 3 in brain + spinal cord
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77
Q

CNS actions of NSAIDs

A
  • NSAIDs inhibit pyrexia - therapeutic use
  • In overdose, NSAIDs produce paradoxial hyperpyrexia, stupor + coma
    • Increase in metabolism + metabolic acid production
  • Risk of Reyes syndrome (brain and liver damage), when used in children with influenza / chicken pox
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78
Q

What is the mechanism of Reyes syndrome

A
  • This is why Aspirin is contraindicated in children. And Acetaminophen should be used instead
    • Can alkalinize urine to help excretion of aspirin
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79
Q

Describe features of the genital tract involving PGs

A
  • PGs cause pain + smooth muscle spasm during menstruation, NSAIDs are used as a treatment
    • Mefanamic acid reduces blood loss
    • NSAIDs might be useful in primary dysmenorrhoea
  • PGs (PGE2 + PGF2a) - important in uterine contractions in childbirth, thus NSAIDs delay contractions
  • Lots of NSAIDs increase post partum blood loss, because TXA2 production prevented
  • NSAIDs delay + retard labour
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80
Q

Describe the characteristics of the kidney and how it works

A
  • Vasodilator PGs - (E2/I2) regulation of renal blood flow
  • NSAIDs thus reduce renal blood flow
  • Chronic renal injury might result.
  • Effectiveness of some antihypertensive drugs is reduced by concurrent treatment with NSAIDs
  • Inhibition of COX2, decrease in sodium excretion and increased intravascular volume
  • Average blood pressure rise = 3/2 mmHg but varies
  • Low dose aspirin does not seem to interfere with antihypertensive therapy but regular use should be avoided
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81
Q

Respiratory effects of PGs

A
  • PGs (PGD2, PGF2a) have both constrictor + dilatator effects on airway smooth muscle - but NSAIDs have no effect on normal airway tone
  • But NSAIDs must be avoided or used with caution in asthma
    • Ca 20% asthma patients wheeze when given asprin, or other NSAIDs because they are hypersensitive to these drugs
  • @ toxic doses, aspirin initially stimulates respiration
    • Actions of respiratory centre & uncoupling of oxidative phosphorylation - medulla stimulation
    • Respiratory alkalosis caused by hyperventilation (Co2 ==> washout from lungs )
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82
Q

What are the other indications of NSAIDs

A
  • Helps to achieve closure of patent ductus arteriosus in neonate
  • If patency is inappropriately maintained by PGE2, PGI2 production (indomethacin, ibuprofen)
    • Low birth weight infants
    • Treatment is individualised
    • May close by age 1
  • Fast breathing / shortness of breath
  • Sweating while feeding
  • Tiring very easily
  • Surgical closure
  • Do not give NSAIDs by 3rd trimester to avoid premature closure of ductus
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83
Q

Give the other indications of NSAIDs

A
  • Decrease colonic polyps & prevents colon cancer
  • May decrease Alzheimers disease risk
  • Post operative pain releif
  • Renal colic - upper part of abdominal pain/groin usually caused by kidney stones
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84
Q

Aims of treatment of ulcerative colitis - Ø Ulcerative colitis = inflammation of bowel

A
  • Reduce symptoms, known as inducing remission (a period without symptoms)
  • Maintain remission
  • First line treatment options:
    Ø Aminosalicylates
    Ø Sulfasalazine
    Ø Mesalazine
  • Decreased inflammation for mild or moderate ulcerative colitis
  • Short-term treatment of flareups
  • Useful in the long term to maintain remission
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85
Q

What is the mechanism of action of sulfasalazine?

A
  • Metabolised to 5-aminosalicylic acid (5-ASA) & sulfapyridine
  • Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase
  • Cyclooxygenase and lipoxygenase activities are high in ulcerative colitis
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86
Q

What are the side effects sulfasalazine?

A
  • Indigestion, feeling or being sick, abdominal pain, diarrhoea
  • Dizziness, headache, difficultly sleeping, tinnitus
  • Coughing: itchy rash, may affect your taste and cause sore mouth
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87
Q

What are the anti-inflammatory agents for gout

A
  • Gout (a type of arthritis) accumulation of uric acid crystals in joints
  • Painful inflammation caused by buildup of uric acid in the joints
  • Uric acid (from purines) is in the blood & is harmless at low levels
  • Uric acid prevents damage to blood vessel linings
  • Passed out with the urine and faeces
  • High level of uric acid in the blood (hyperuricemia) cause tiny grit-like crystals to collect in the joints which irritate the joint tissues, causing inflammation, and pain
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88
Q

Examples of anti-gout drugs

A

Ø Naprozen, Diclofenac, and Indomethacin

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89
Q

What is the mode of action of naproxen

A
  • Inhibits COX1/COX2 levels which lowers PG levels - targets mediators engaged at the onset of inflammation
  • Exhibits analgesic, anti inflammatory and antipyretic activity
  • Inhibits platelet aggregation (inhibits platelet TXA2)
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90
Q

What are the side effects of naproxen

A
  • Dizziness, nausea, indigestion, blurred vision, diarrhoea, abnormal liver function, water retention, ringing in the ears, hives
  • Relatively risk neutral for CV events (heart attacks are rare)
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91
Q

Corticosteriod characteristics

A
  • Can either be 1. Glucocorticoids (cortisol) 2. Mineralocorticoids (aldesterone)
  • Both are synthesised, and released from the adrenal cortex - they are often termed the “salt + sugar” hormones
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92
Q

Glucocorticoid characteristics

A
  • “sugar” hormone - carbohydrates + protein metabolism

- Potent anti inflammatory / immunosuppressant

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93
Q

Mineralocorticoids characteristics

A
  • “salt” hormone - controls H20 and electrolyte in the kidney
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94
Q

What are the effects of glucocorticoids?

- Metabolic actions

A
  • Breakdown of protein + fats (muscle wasting etc. )
  • Decreased glucose usage + increased gluconegenesis
  • Tendency to hyperglycaemia + increased glycogen storage
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95
Q

What are the effects of glucocorticoids?

- Metabolic actions

A
  • Breakdown of protein + fats (muscle wasting etc. )
  • Decreased glucose usage + increased gluconegenesis
  • Tendency to hyperglycaemia + increased glycogen storage
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96
Q

What are the effects of glucocorticoids?

- Hormonal regulation

A
  • Negative feedback on both the hypothalamus and pituitary gland
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97
Q

What are the effects of glucocorticoids?

- Cardiovascular system

A
  • Decrease in both microvascular permeability + vasodilation
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98
Q

What are the effects of glucocorticoids?

- CNS

A
  • Mood changes

- Linked with changes in memory / stress

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99
Q

Describe the anti- inflammatory effects of glucocorticoids

A
  1. Decreased microvascular fluid exudation
    (- Reduces the influx of cells to areas of inflammation)
  2. Decreased inflammatory mediators + cytokines
    (- Decreased expression of COX-2
    - Reduced levels of eicosanoids
    - Decreased levels of cytokines + complement levels )
  3. Decreased function of inflammatory effector cells
    - Inhibition of cell migration + mediator release
    - Reduced clonal expansion of T and B cells
    - Reduction in chronic inflammatory events
    - NB healing and repair inhibited
    (- Inhibition of cell migration + mediator release
    - Reduced clonal expansion of T and B cells
    - Reduction in chronic inflammatory events
    - NB healing and repair inhibited)
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100
Q

What are the cellular mechanisms of glucocorticoids?

A
  1. Glucocorticoid enters the cell membrane
  2. Glucocorticoid binds to receptor (GCR) + dissociates HSP
  3. Glucocorticoid / GCR complex translocated to nucleus
  4. Expression of genes can be both increased or decreased
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101
Q

How can glucocorticoids switch gene expression on, or off? (1 via Interaction of steroid receptor with promoter regions)

A
  • These gene promoters have: glucocorticoid response elements (GREs)
  • Occupancy @ GREs will turn on or off certain genes
  • This leads to increased expression of anti inflammatory proteins
    ○ Increased lipocortin which will decreased arachidonic acid and decreased eicosanoids
  • Decreased expression of pro-inflammatory proteins
  • Decreased cytokine production
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102
Q

How can glucocorticoids switch gene expression on, or off? (2 via Steroid / receptor complexes prevent gene activation by other transcription factors)

A
  • AP-1
  • NFkB
  • Transcription factors involved in switching on COX-2, cytokines
  • This leads to increased expression of anti inflammatory proteins
    ○ Increased lipocortin which will decreased arachidonic acid and decreased eicosanoids
  • Decreased expression of pro-inflammatory proteins
  • Decreased cytokine production
103
Q

What turns on/ off the occupancy for certain genes

A
  • The occupancy at GREs will turn off / on certain genes
104
Q

What are the therapeutic uses of glucocorticoids:

Adrenal insufficieny

A
  • Hydrocortisone, prednisolone, dexmethasone, betamethasone
    1. Adrenal insufficiency or failure - Addisons disease
  • This can be congenital, or drug induced
  • Treatment will need combined GC and MC
105
Q

What are the therapeutic uses of glucocorticoids:

Treatment of inflammation

A
  • Hydrocortisone, prednisolone, dexmethasone, betamethasone

- Asthma, rhinitis, skin disorders, sports injuries, reduction of cerebral oedema in patients that have brain tumours

106
Q

What are the therapeutic uses of glucocorticoids:

Immuno suppression

A
  • Hydrocortisone, prednisolone, dexmethasone, betamethasone

- Inhibit graft v host reaction in tissue transplantation

107
Q

Describe the characteristics of mineralocorticoids

A
  • Endogenous mineralocorticoid - aldesterone
  • Secretion is controlled by renin angiotensin system, and ACTH
  • Increases Na+ retention in the distal tubules of the kidney
    1. Stimulates Na+/H+ exchanger via aldosterone receptors
    2. Enters cells + upregulates Na+ permeable ENaC channels in cell membrane
    3. Enters cells + stimulates upregulation of the basolateral Na+/K+ ATPase pump
    4. Also causes H20 retention, and loss of K+ and H+
108
Q

Where are mineralocorticoid receptors found

A

Only in a few tissues, kidney, colon, bladder

109
Q

What happens when there is low Na+ plasma levels

A
  • Increase aldosterone

- By directly activating adrenal gland + stimulating RAA system to produce Ang2

110
Q

Side effects of corticosteroids - Cushings like syndrome

A 
Euphoria 
Buffalo hump 
Hypertension
Skin thinning 
Thin arms + legs - muscle wasting 
Benign intracranial hypertension 
Cataracts 
Moon face, with red plethoric cheeks 
Increased abdominal fat 
Avascular necrosis of femoral head 
Easy bruising 
Poor wound healing
111
Q

What are side effects of glucocorticoids

A
  • Cushings syndrome
  • Opportunistic infection
  • Osteoporosis
  • Gastric ulceration
  • Growth suppression
  • Behavioural / reproductive problems
  • Prolonged HPA suppression after cessation of therapy
  • Useful drugs with wide ranging actions + thus expected penalty with wide ranging side effects
112
Q

The principles of selective toxicity

A
  • Differences between biochemistry of host tissues + infectious agents
  • Differences between normal, and cancer cells
    • Or metabolic pathways
    ○ Between normal cells and cells
    ○ Or metabolic pathways between normal and tumouric cells or invading species
  • A high degree of discrimination = ratio of therapeutic to toxic effects must be wide
  • Magic bullet
  • Selectively target a disease-causing organism
  • Basis of chemotherapy
113
Q

Common characteristics of cancer cells?

A
  • Uncontrolled cell proliferation
  • Cells become invasive
  • Metastasis
  • Change in cell morphology in some, but not all of the cells
Diagnosis= 
	• Social stigma 
	• Myths 
Side effects of chemotherapy=
	• Many and varied 
	• But hair loss is a loss is a major concern for patients

Successful treatment also requires psychological and social support

114
Q

What are the principles of cancer treatment

A
  • These drugs can be given singly
  • Combination therapy
    • 2-6 drugs
    • Watch out for toxicity
    ○ e.g. myelosuppression
  • Criteria for choosing drug combinations
    • Drugs that are active when used alone
    • Drugs with different mechanism of action
    • Drugs with different toxicity profiles
    • Use the drugs at doses close to their maximum tolerated levels
115
Q

What are the characteristics of cytotoxic drugs

A
  • Active against cycling / proliferating cells
  • Phase specific drugs = affect only certain parts of the cell cycle
  • Cycle specific drugs = affect cycling cells throughout the cell cycle
  • Affect DNA synthesis

They have less activity against non dividing cells - resting cells

Considerations

1. Does the drug require hepatic metabolic activation - e.g. cyclophosphamide
2. Is the patient nil by mouth etc.
116
Q

What are antibiotics

A
  • Natural products of fungi + bacteria. Soil dwellers.
  • Natural antagonism + selective advantage
  • Kill / inhibit the growth of other microorganisms
  • Most are derived from natural products by fermentation.
  • Then they get chemically modified.
    • Increases their pharmacological properties + their antimicrobial effect
  • Some are totally synthetic - like newer sulphonamides
117
Q

Principles of antibiotics and therapeutic agents

- Selective toxicity
A
  • Because of the differences in structure + metabolic pathways between the host and pathogen
  • Harm micro organisms, not the host
  • Target in microbe, not the host if possible
  • Difficult for viruses (intracellular), fungi and parasites
  • Variation between microbes
118
Q

Principles of antibiotics and therapeutic agents :

- Therapeutic Margin
A
  • Active dose vs. toxic effect
  • Narrow for toxic drugs
    • Aminoglycosides (ototoxic)
    • Vancomycin (nephrotoxic)
  • “no safe drug”
  • Understanding the mode of action leads to clinical utility.
119
Q

What happens when there is loss of flora

A
  • There will be bacterial or pathogen overgrowth. e.g.
    • Antibiotic Associated Coilitis
    • Clindamycine, broad spectrum lactams, fluoroquinolones
    • Pseudomembranous colitis
  • Clostridium difficile = part of normal flora of 3% of the population
  • Candida, staphylococcus
  • But also found without the presence of pathogens
  • Cytotoxins
  • There are ulcerations - infallamtion to produce fibrinous coating
  • Severe diarrhoea
  • Serious hospital cross infection risks - carriage rate is up to 70%
  • Treatable with antibiotics
120
Q

Compare bactericidal vs. bacteriostatic

- Bactericidal

A
  • Kill bacteria
  • Used when the host defence mechanisms are impaired
  • Needed in endocarditis, kidney infection
121
Q

Compare bactericidal vs. bacteriostatic

- Bacteriostatic

A
  • Inhibit bacteria
  • Used when the host defence mechanisms are intact
  • Used in many infectious disease
122
Q

What is the spectrum of activity of antibiotics - Broad spectrum antibiotics

A
  • Effective against many types like cefotaxime
123
Q

What is the spectrum of activity of antibiotics - Narrow spectrum antibiotics

A
  • Effective against very few types

- Like penicillin G

124
Q

Classification of antibiotics

- Molecular structure

A
  • Structure mimics of natural substrates of enzymes, e.g. lactams
  • There are penicillins and cephalosporins
125
Q

What is the active structure in penicillin

A
  • The Beta lactam ring is the active structure in penicillin
126
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Cell wall synthesis \

A
  • Cycloserine
  • Vancomycine
  • Teichoplanin
  • Bacitracin
  • Penicillins
  • Cephalosphorins
  • Monobactams
  • Carbapenems
127
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Folic acid metabolism

A
  • Trimethoprim

- Sulfonamides

128
Q

What are the different bacterial targets for current antibiotics that are used in clinic - DNA gyrase + DNA directed RNA polymerase

A
  • Quinilones
129
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Protein synthesis (50S inhibitors)

A
  • Eryhthromycine - macrolides
  • Chroamphenicol
  • Clindamycin
130
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Protein synthesis (30S inhibitors)

A
  • Tetracycline
  • Spectinomycin
  • Streptomycin
  • Gentamycin
  • Tobramycin (aminoglycosides)
  • Amikacin
131
Q

Describe cell wall inhibitors (Gram positive)

A
  • Lipoteichoic acids, traversing wall and anchored in membrane
132
Q

Describe cell wall inhibitors (Gram negative)

A
  • Polysaccharide O antigen

- There is a porin and lipid A

133
Q

How would you treat bacterial infections

A
  1. Antibiotics
  2. Surgery - drainage of abscess
  3. Immunological (rare) - use of antitoxin in tetanus
134
Q

When do we use antibiotics

A
  • Treatments of bacterial infections
  • Prophylaxis - close contacts of transmissible infections, fall in carriage rates (increase in 80% of outbreaks)
  • Prevention of infection - like meningitis or tuberculosis
  • Perioperative cover for gut surgery
  • People with increased susceptibilty to infection
  • Inappropriate use - viral sore throat - patient pressure
135
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Penicillins
- Basic penicillins

A
  • Benzyl penicillin
  • Penicillin V
    • Active against streptocci, pneumococci, meningococci, treopnemes
    • Most strains of Staphylococcus Aureus are resistant
136
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Penicillins
Anti staphylococcal penicillins

A
  • Flucloxacillin
137
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Penicillins

A
  • Ampicillin
    • Spectrum of activity is similar to basic penicillins but also includes some gram negative organisms + also enterococci
138
Q

Antibiotics and how they work. Give examples of bacteria that they work against.
Broader spectrum penicillins

A
  • Ampicillin
    • Spectrum of activity is similar to basic penicillins but also includes some gram negative organisms + also enterococci
139
Q

Antibiotics and how they work. Give examples of bacteria that they work against.
Anti pseudomonal penicillins

A
  • Piperacillin
140
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Cephalosporins : what is Cefalexin

A
  • Oral agent that is primarily used to treat UTIs
141
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Cephalosporins : what is Cefuroxime

A
  • Parenteral 2nd gen agent with good activity against many gram, and gram negative
142
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Cephalosporins : what is Cefotaxime

A
  • Parental 3rd generation agent with greater activity against many gram negative and retaining anti gram activity
143
Q

Antibiotics and how they work. Give examples of bacteria that they work against.

BETA-LACTAMS, Cephalosporins : what is Ceftazidime

A
  • Parenteral 3rd generation agent with a spectrum of activity extended to pseudomonas aeruginosa
144
Q

What are the characteristics of aminoglycosides

A
  • Gentamicin
  • Aminkacin
  • Streptomycin
  • These cannot be absorbed from the gut - must be given parenterally
  • They are active predominantly against gram negative bacteria, including pseudomonas aeruginosa
  • These agents are nephrotoxic + ototoxic & serum levels must be monitored
145
Q

What are the characteristics of macrolides

A
  • Like eryhromycin
  • Used to treat Gram positive infections, especially in those allergic beta lactams
  • Also active against 1. Mycoplasma pneumoniae and 2. Legionella Pneumophilia
146
Q

What are the characteristics of Glycopeptides

A
  • Vancomycin + Teicoplanin
  • Active only against Gram positive organisms
  • Parenteral only
  • Usually reserved for situation when other agents cannot be used - e.g. against MRSA
147
Q

What are the characteristics of Tetracyclines

A
  • Oxytetracycline
  • Deoxycycline
  • Broad spectrum, bacteriostatic, used mainly for treating chlamydia
  • Mycoplasma pneumoniae
  • Acne
148
Q

What are the characteristics of Quinolones

A
  • Ciprofloxaxin
  • Moxifloxacin
  • Older drugs like ciprofloxacin active mostly against gram negatives - useful for complicated UTIs, and gastro intestinal infections
  • Newer agents have better anti gram positive activity
    • Useful for some respiratory tract infections.
149
Q

Other agents that can be used for antibiotics : Trimethoprim

A
  • Useful for UTIs

- Combined with sulphamethoxazole, as co trimoxazole

150
Q

Other agents that can be used for antibiotics : Metronidazole

A
  • Active against anaerobic bacteria and some parasites
151
Q

Other agents that can be used for antibiotics : Chloramphenicol

A
  • Broad spectrum
  • Used rarely systematically because of side effects
  • Commonly used topically for eye infections
152
Q

Other agents that can be used for antibiotics : Fusidic acid

A
  • Narrow spectrum, used in combination to treat Stapylococcal infections only - topical use
153
Q

Other agents that can be used for antibiotics : Linezolid

A
  • An oxazolidinone
  • Blocks protein synthesis
  • The newest antibiotic reserved for multi resistant gram positive infections
154
Q

What are “superbugs”

A
  • Drug resistant bacteria. They are not more pathogenic.

- We just have fewer antibiotic options for treatment

155
Q

What are the paths to resistance :

1. Directed @ antibiotic itself

A
  • Degrading the drug

- Modifying the drug

156
Q

What are the paths to resistance :

2. Altered target

A
  • Antibiotic will no longer bind
157
Q

What are the paths to resistance :

3. Altered trasport

A
  • Actively pumping drug out - efflux pump

- Porins are no longer influx drug

158
Q

What are the 3 mechanisms of resistance

A
  1. Genetic mechanisms
  2. Non genetic mechanisms (growth phases)
  3. Natural resistance
159
Q

What is natural resistance (as opposed to acquired)

A
  • Drug must reach the target. There are natural barriers, porins and export pump
  • Gram positive peptidoglycan - highly porus, no barrier to diffusion
  • Gram negatives outer membrane - barrier, resistance advantage
  • Porins, single mutation, multiple resistance
160
Q

Genetic mechanisms of resistance

A
  • Can be chromosome mediated or plasmid mediated
  • Chromosome mediated:
    • Due to spontaneous mutation - in the target molecule, in the drug uptake system
    • Mutants are selected + they are not induced
  • Plasmid mediated
    • Common in gram negative rods
    • Transferred via conjugation
    • Multidrug resistance
161
Q

Give a summary of gene transfer in bacteria

A
  • Mechanism for genetic heterogeneity + evolution
  • Rapid, cross species
  • Virulence (toxins), drug resistance, antigens (immune evasion)
162
Q

Resistance to beta lactams

- Gram positive

A
  • Beta lactamase: Penicillinase

- Alteration of transpeptidase enzyme (PBP)

163
Q

Resistance to beta lactams

- Gram negative

A
  • Beta lactamase: Penicillinase

- Alteration of porins

164
Q

What is the action of penicillinase

A
  • Destroys the active part of penicillin molecule
165
Q

Describe augmentin

A
  • Clavulanic acid + amoxycillin
  • Binds to + inactivates beta lactamases
  • No antibacterial activity of its own
166
Q

Give a summary of the genetic mechanisms of resistance

A
  • There is production of drug inactivating enzymes, and modification of target structures. Then there is alteration of membrane permeability.
167
Q

What are the difficulties of developing a safe anti-viral agent

A
  • Viruses, use cellular receptors to be able to get inside cells
  • Obligate intracellular parasites
  • Must replicate, once inside the cells and take over host cells biochemistry
  • High mutation rate = quasispecies
  • Latency common (Herpes viruses)
  • ## Genetic integration (HIV and HBV)
168
Q

Targetting of virus specific enzymes

A
  • Discovery of virally encoded enzymes, sufficiently different from human counterparts
  • Thymidine kinase of herpes virus
  • Protease enzyme of HIV
  • Reverse transcriptase of HIV
  • DNA polymerase of HBV
169
Q

How to use anti-viral antigens 1

A
  • Choice = virus / virus family specific
  • Some agents have broad activity, not easy to do sensitivity testing in real time
  • Can be used therapeutically or prophylactically
  • Safety profile: could have side effects + interactions
  • Expensive e.g. HIV treatment
170
Q

How to use anti-viral agents 2

A
  • Treatment of acute infection, influenza (oseltaminivir), chickenpox, aciclovir
  • Treatment of chronic infection - HCV, HBV, HIV, numerous diff agents
  • Post exposure prophylaxis + preventing infection - HIV (PEP)
  • Post exposure prophylaxis + allowing infection - VZV (Aciclovir)
  • Pre exposure prophylaxis - HIV (PREP)
  • Prophylaxis for reactivated infection, e.g. in transplantation, CMV (ganciclovir, foscarnet)
171
Q

Why is aciclovir so effective + safe

A
  • HSV thymidine kinase (TK) has 100x affinity for ACV, compared with cellular phopshokinases
  • ACICLOVAR TRIPHOSPHATE has 30x affinity for HSV DNA polymerase compared with cellular DNA polymerase
  • Aciclovar triphosphate is a highly polar compound - difficult to leave or enter cells, but aciclovir is easily taken into cells, prior to phosphorylation
  • DNA chain terminator
172
Q

Characteristics of Aciclovir

A
  • Herpes simplex: treatment of encephalitis, genital infection, suppressive therapy for recurrent genital herpes
  • Varicella zoster virus: chickenpox, shingles treatments
  • CMV - prophylaxis
  • Shingles = zoster
173
Q

Characteristics of Ganciclovir

A
  • CMV:
    • Treatment of reactivated infection, in organ transplant recipients
    • Treatment of congenital infection in newborn
    • Prophylaxis in organ transplant recipients = mismatch
174
Q

Valaciclovir characteristics

A
  • Prodrug. Valine ester of aciclovir
  • Used to treat varicella - zoster infections in the immune compromised or anti CMV prophylaxis in transplant patients
  • Better bioavailability
175
Q

Valganciclovir characteristics

A
  • Prodrug - also an ester of Ganciclovir

- Used for the treatment + prophylaxis of CMV infection

176
Q

Give examples of some other anti-herpes virus agents

- Foscarnet

A
  • Used for CMS infection in the immunocompromised
    • Pneumonia in solid organ and bone marrow transplants
    • May be used because of ganciclovir resistance or toxicity profile
    • Renal toxicity - so usually not used for renal transplant patients, with CMV reactivation unless resistance to Ganciclovir
177
Q

Give examples of some other anti-herpes virus agents

- Cidofovir

A
  • Drug active against CMV

- But much more nephrotoxic

178
Q

Resistance to anti-virals in Herpes viruses

A
  • 2 main mechanisms: thymidine kinase mutants
  • DNA polymerase mutants
  • If occurs in TK, drugs not needing phosphorylation are still effective - e.g. Foscarnet, Cidofovir
  • If occurs in DNA polymerase, all drugs rendered less effective
  • Very rare in immune competent patients
179
Q

What are the characteristics of influenza

A
  • Can cause epidemics - killed half of world population.
  • AMANTIDINE
    • Inhibits the virus uncoating by blocking the influenza encoded M2 protein, when inside cells and assembly of haemagluttinin
    • This is now rarely used
  • ZANAMIVIR + OSELTAMIVIR
    • Inhibits virus release from inhibition of neuraminidase
    • Oseltamivir - oral.
    • Zanamivir - inhaled or IV, less likely for resistance to develop
180
Q

Treatment of viral hepatitis

A
  • Hepatitis B + C: chronic infection common, up to 70% of those infected with HCV
  • With HBV varies depending on when infected
  • Chronic infection - cirrhosis, hepatocellular carcinoma
181
Q

Treatment of Hep C

A
  • Curable in some, the response is influenced by viral genotype and host genotype
  • Treatment with pegylated interferon + ribavirin
  • Rapidly advancing field, with specific antivirals - e.g. Telaprevir + Brocepevir and others
  • Possible interferon gene treatments
182
Q

Treatment of Hep B

A
  • Hep B = pegylated interferon alfa.
    • Specific antivirals: lamivudine, tenofovir, entecavir, adefovir
    • Used singly or in combination
    • Complicated, especially if co-infection
183
Q

What are the characteristics of HIV infection

A
  1. Binding of GP120, to CD4 receptor + CCR5 co receptor
  2. Penetration and uncoating
  3. RNA genome is then reverse transcribed into a DNA proviruse which is integrated into the cell genome
  4. Synthesis + maturation of virus progency
  5. Opportunity for antivirals
184
Q

Describe anti retrovirals

A
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Nucleotide reverse transcriptase inhibitors (NtRTI)
  • Non nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • CCR5 inhibitors
  • Integrase inhibitors
185
Q

Anti- HIV therapy

A
  • Complicated, there are rapidly evolving field with new drug development
  • Needs specialist approach as many side effects and interactions
  • Combination approach - reduces the risk of resistance
  • Multiple viral enzymes targets (reverse transcriptase, protease, integrase, viral receptor binding proteins)
  • Adherence to treatment is essential
  • Use 3-5 drugs, which can be combined in one pill and once a day tablets are best
186
Q

Describe what happens when there is resistance to antivirals

A
  • There is selection pressure and mutation frequency. Increased mutation rates seen in HIV (MCV)
  • The viruses form quasispecies
    • (“molecular swarm” of related sequences, clustered around a master sequence)
  • Error rate in copying RNA viral genome is 1 base per 1 4-5 incorporations
  • Error rate is 10k fold higher than DNA polymerase enzymes. This is because there is no proof reading capacity
  • HIV = 10 9-10 viruses produced daily. All possible viral variants would be produced
  • Capable of adapting really fast to changes in the environment, their genome size is smaller than DNA viruses.. There could be loss of fitness
187
Q

What are the characteristics of cytotoxic drugs -

A
  • Active against cycling / proliferating cells
  • Phase specific drugs = affect only certain parts of the cell cycle
  • Cycle specific drugs = affect cycling cells throughout the cell cycle
  • Affect DNA synthesis

Ø They have less activity against non dividing cells - resting cells.
Ø Because these drugs rely on targeting the cycling cells = then you could miss these resting cells.
• This is why there can be remission as drug is not hitting cells at G0 phase.

188
Q

What considerations should we take in use of cytotoxic drugs?

A
  1. Does the drug require hepatic metabolic activation - e.g. cyclophosphamide
    Ø Need whole animal to metabolise it
    Ø Insert cp450 in cell type of interest
  2. Is the patient nil by mouth etc.
189
Q

examples of - Antimetabolites : act on S phase

A

Ø 5 fluoroacid
Ø Methotrexate
Ø Mercaptopurine
Ø Cyatabine

190
Q

examples of Ø Cycle specific drugs : act on G1 late phase

A
  • Alkylating agents
  • Chemotoxic antibiotics
  • Cytotoxic throughout the cell cycle
  • Do not affect resting (non cycling) cells that are in G0
191
Q

examples of Ø Mitotic inhibitors : act @ M phase

A
  • Mitotic inhibitors
  • Vincristine
  • Vinblastine
  • Etoposide
192
Q

Alkylating agents mode of action

A
  • Intercalate into the DNA
    • Formation of new reactive species= which alkylates into the DNA sites
    • Base paring is altered - then there is cross linkage
    ○ End result = decrease in levels of cell proliferation which is good for the host
    • They also alkylate biomolecules, lie proteins and lipids
    ○ Wide ranging and negative effects on tumour cells
193
Q

The selectivity of cytotoxic drugs

A
  • Overall, their activity = marginal @ best
  • Therapeutic index = 1.
    • This means concentration that causes toxicity = concentration that causes cancer cell death
  • You want the therapeutic index of chemotherapy to be wide; not narrow
    • Wide and varied side effects

Ø All dividing cells affected => massive side effects
Ø Some degree of selectivity,
• e.g. malignant tumours (tumours that display uncontrolled growth and invasion/metastasis)

Ø The side effects of the drugs, are related to their mode of action
• Gut, bone marrow, reproductive and endocrine systems are affected.

194
Q

What does a therapeutic index of 1 mean

A

• This means concentration that causes toxicity = concentration that causes cancer cell death

195
Q

Describe the targets for antimicrobial action?

A
  • The targets are diverse, but most drugs target the synthesis of:
    Ø Peptidoglycan of the bacterial cell wall
  • Other targets include:
    Ø Protein synthesis
    Ø Intermediary metabolism - involves folate coenzymes
    Ø Biosynthesis of DNA or RNA + cell membranes
    ○ These are the main 3
196
Q

Bacterial cell wall characteristics

A
  • Peptidoglycans (sugars + amino acids structure)
    • Semi rigid structure within the cell wall.
    Ø Tight knit molecular complex; enables the bacterium to resist osmotic lysis
    • Polysaccharide portion - NAG & NAM
    • Protein portion - short chains of amino acids that link layers of polysaccharide together by NAM. The peptide cross bridges are linked to NAM
  • LPS consists of lipid portion, called lipid A + a polysaccharide portion
  • Lipid A (endotoxin) - triggers fever and shock
  • NAM = peptides that come off, start as pentapeptides wwhich get continually linked . There is transpeptidase which is needed for the cross link formation
  • Transpeptidase = links the 4 amino acids together
197
Q

The antibacterials that inhibit cell wall synthesis

A
  • Penicillin
  • Benzylpenicillin
    • Active against aerobic, gram positive and gram negative cocci and many anaerobic microbes
  • Flucloxacillin
    • Good against penicillin resistant staphylocicci as it is not inactivated by Beta lactamase
  • Amoxicillin and ampcillin
    • Broad spectrum
  • Other examples that inhibit bacterial cell wall synthesis

Penicillin:
Ø benzylpenicillin, phenoxymethyl penicillin, amoxycillin, ampicillin, flucloxacillin

Cephalosporins (β-lactams):
Ø cefadroxil, cephadrine, cefuroxime, cefamandole, cefaxime, cefotaxime

198
Q

The antibacterials that inhibit cell wall synthesis -

Penicillin characteristics

A
  • Mechanisms of action
    • Bactericidal agents
    • Bind to more than one type of protein• Binding to penicillin binding proteins on susceptible microbes - inhibition of peptide cross-linking within the microbial cell wall (inhibit transpeptidation)
    • Autolytic enzymes = cell lysis and cell death
    ○ Autolysins
    ○ Are very tightly controlled by bacteria
    ○ Once the penicillin is in = autolysin enzyme
    • Side chain from the beta lactam ring
    ○ Determines unique pharmacological properties of different penicillins

TRANSPEPTIDASE role
Ø Formation of peptide bridge that cross links the penta peptides that are coming off the NAM
Ø Connects each row of sugars with adhacent row
Ø Connects each layer of peptidogylcan with its adjacent layer
• This forms a tight knit molecular complex

  • Transglycosylase links the new monomer with the old and seals them together
  • Penicillin also binds to that
  • To transport the new monomer in there is peptoprenol
  • Therefore they are the penicillin binding proteins
199
Q

Adverse effects of penicillin, an antibacterial which inhibits cell wall synthesis

A 
- Hypersensitivity reactions including 
	Ø Rash = common
	Ø Anaphylactic reaction - rare 
	Ø Neurotoxicity - with high [CSF]
	Ø GI disturbances
200
Q

What is the mechanism of penicillin

A
  • Inhibits transpeptidation of the cell wall

• 5-10ATM

201
Q

What are the known weaknesses of penicllin

A
  • Resistance (beta lactamase and other mechanisms)
  • Allergic reactions
  • Cross hypersensitivity
    • 1-3% with cephalosporins
202
Q

Antibacterials that inhibit cell wall synthesis - penicillin

A
  • Contraindications: known hypersensitivity to penicillin or cephalosphorin
  • Therapeutic notes
    • Resistance due to production of beta lactamase
    • The resistance gene is plasmid- borne
    • Flucloxacillin is resistant to Beta lactamase
203
Q

How dose beta lactamase work within penicillin

A
  • The beta lactamase, will BREAK a bond that is in the beta lactam ring
  • Of the pencillin
  • This will disable the molecule
  • Bacteria with this enzyme can resist the effects of penicllin and other beta lactam antibiotics.
204
Q

Antibacterial agents can inhibit protein synthesis

A
  • Everything needs proteins to stay alive = these are potent and inhibit bacterial protein synthesis
  • If bacteria cannot make proteins, they will not grow
  • e.g. Aminoglycosides- gentamycin, streptomycin, netilmicin, amikacin, neomycin
205
Q

The antibacterial agents that inhibit protein synthesis

- Ø Chloramephenicol

A
  • Binds to the 50S portion

- Inhibits formation of peptide bone

206
Q

The antibacterial agents that inhibit protein synthesis Ø Tetracycline

A
  • Interferes with attachment of tRNA to mRNA ribosome complex
207
Q

The antibacterial agents that inhibit protein synthesis Ø Erythromycine

A
  • Binds to the 50s portion

- Prevents translocation movement of ribosome along m RNA

208
Q

The antibacterial agents that inhibit protein synthesis Ø Streptomycine

A
  • Changes the shape of the 305 portion

- Causes the code on the m RNA to be read wrongly

209
Q

Saphrophyte characteristics

A
  • Live on & derive their food from dead decaying organic matter
210
Q

Describe the site of action of antifungal agents

  • act on Cell membrane
A
  • Polyenes
    • Bind to the membrane
    • Ergosterone, altering the membrane slightly
    • Imidazole (ketoconazole) - inhibits the cytochrome p450 which leads to membrane disruption
211
Q

Describe the site of action of antifungal agents

  • act on Nuclear division
A
  • GRISEFULVIN

• Inhibits fungal mitosis by binding to intracellular microtubular protein

212
Q

Describe the site of action of antifungal agents

  • act on Nucleic acid synthesis
A
  • FLUCYTOSINE
    • Converted in fungal cells,
    • Into 5 flouroacil
    • Which is a potent inhibitor of DNA synthesis
213
Q

Examples of polyene macrolides

A

Ø Amphotericin B (lipophilic)

Ø Nyastatin

214
Q

What is the mechanism of action of polyene macrolides

A
  • Targets ergosterol in fungal cell membrane, and forms pores within in
  • Loss of cell contents + cell death ensues
  • Selectively toxic: humans have cholesterol instead of ergosterol
215
Q

Indications of polyene macrolides

A
  • Interacts hydrophobically with the membrane
    • Components from inside start leaking out from the inside of the cell
    • This creates selectivity
    ○ Controls aldosterone synthesis
  • Amphotericin B : broad - spectrum (serious systemic infections)
  • Nyastatin: thrush (oral and vaginal)
216
Q

Zidovudine (ZDV) mechanism of action

A
  • Involved in the life span above
  • Inhibit HIV
  • Prodrug: phosphorylation to active metabolite (ZDVTP) + thymidine is also phosphorylated to TTP

ZDV = synthetic thymidine analogue with potent broad spectrum activity

  • Basically the same as thmidine = but with an avido groupØ The OH = phosphorylation sites
    Ø Drug has to be phosphorylated first before you can get any activity
    Ø ZIDOVUDINE structure = really important to how it works
217
Q

Describe the mechansim of action of zidovudine

A
  • ZDVTP competes with endogenous thymidine (structures of ZDV & thymidine are similar, but
    • Incorporated into the growing DNA strands and then system grows to a halt
    • New slid
  • ZDV has an azido group in the place of OH in thymidine for the same enzyme RT)
  • ZVDTP causes chain termination
    • Because of the AZIDO group that is there rather than the OH group
    • As the OHH group provides the next attachment point for the reaction to keep going
  • ZDVTP causes the selective inhibition of RT enzyme
    • Inhibit the production of new cells
  • ZDV has higher affinity for RT that for other mammalian polymerase enzyme

ZDVTP inhibits infection of new cells

218
Q

How does zidovudine work?

A
  1. Series of phosphorylation steps, convert ZDV ==> ZDVTP
  2. ZDVTP competes, with endogenous thymidine for the same enzyme (RT)
  3. ZDVTP incorporated into growing DNA strand & terminates the synthesis because of the LACK of OH group
219
Q

What does ZDVTP cause?

A
  • Selective inhibition of RT enzyme
  • ZDV has higher affinity for RT, than for other mamallian polymerase enzyme
  • ZVDTP causes chain termination

ZDVTP inhibits the infections of new cells

220
Q

What are the characteristics of

Antifolates and protozoal infections

A
  • Malaria treatment
    Ø Also cancer chemo
    Ø Methotrexate targets the folate pathway
  • Specific DHFR inhibitors, human host also has DHFR
  • DHFR in man - target for anticancer chemotherapy
    Ø (e.g. methotrexate is effective against mammalian DHFR)
  • High doses of the drugs can cause some inhibition of host DHFR (anti tumour activity)
  • Target the very late stage of asexual reproduction (no broad spectrum of activity against RBC stage)
  • Slow acting
    Ø Want to kill malaria fast
  • Not to be given to individuals in critical situations (time is essence)
221
Q

Characteristics of Antifolates

A
  • There are similarities between what occurs in host vs parasite
    • Folatereductase = end result is that thymidylate is produced which can help in DNA sytnehsis
    • Molecular weight is 10x higher than in mna (of folate reductase)
      ○ Drug has strong affinity for enzyme, 2000x more than for parasite
      ○ Target for selectivity but the right dose must be used
    • Porguanyl = will compete with the substrate - if you inhbit those then you hit the parasite very effectively
    • Effect on bacteria
      ○ Some can trick the enzyme
      ○ May compete with dihpoteate synthase
      § Sulphamethoxazole which inhibits DHTS
      § Trmethoprim which inhibits DHFR
      □ End up generating “pseudo-folates”
      ® which look like the real thing, but are not
      □ Therefore CANNOT make proper amino acids
      sULFAMETHOXAZOLE = V EFFECTIVE
      TRIMETOPRIM
    • These 2 can be used together
    • Eg for a UTI
    • One inhbitis DHTS on the top
    • And the other targets the one at the bottom
      ○ So there are 2 SEPARATE treatments
222
Q

Proguanil (chloeeoquanide)

A
  • Selective inhibitor of plasmodial DHFR and thymidlate synthetase
  • Proguanil has intrinsic antimalarial activity
  • Affects primary liver and asexual RBC stages
  • Provides adequate control in acute malarial attacks/eradicates infection
  • Destroys acute p.vivax malaria, but has no effects on latent tissue stages or P. vivax
  • Gametocytes unaffected, but fertilsed gametes in the gut of the mosquito do not develop
    Ø Gametocytes = malaria mosquito sucks this up
    Ø Block gamete fertilisation in the midgut = like a mosquito contraceptive
223
Q

What is the mechanism of action of proguanil

A
  • Converted into active triazine metabolite (cycloquanil)
    • We do NOT all express this enzyme
    • If you do not make this enzyme then you will not benefit from the drrugs
  • Selective inhibition of DHFR thymidylate snyhtestase (DHFR-TS) of sensitive parasites by cycloguanil
    • Thymidylate synthetase - phosphorylation of thymidine
    • DNA synthesis and repair
  • Inhibition of DNA synthesis, and folate cofactor become depleted
224
Q

Characteristics of Antimicrobials

A
  • Anti: biotics, virals, fungals, protosoals, nematodes
    • Anti microbials that target bacteria = antibiotics
    • These are all the specific names
    • Antibiotics CANNOT TREAT VIRAL OR PROTEOSOAL INFECTIONS have to get the terminology correct - they are against BIOTICS (Bacteria)
225
Q

What are antibiotics

A
  • Prevent growth or kill other organisms in vicinity.
    • Selective advantage to grow in ecological niche
    • Some are synthetic but they are mostly organic
  • Natural antagonism + selective advantage
  • Kill / inhibit the growth of other microorganisms
226
Q

Principles of antibiotics and therapeutic agents :

- Selective toxicity
A

Ø Key thing about this - there are DIFFERENCES that need to be targeted, as there are differences in structure and metabolic pathways between the host and pathogen
Ø Need to make sure to only harm micro-organisms, not the host
• Target in microbe, not the host if possible
• Difficult for viruses (intracellular), fungi and parasites
• Variation between microbes

227
Q

Principles of antibiotics and therapeutic agents :

- Therapeutic Margin
A
  • Active dose vs. toxic effect
  • Narrow for toxic drugs
    • Aminoglycosides (ototoxic)
    • Vancomycin (nephrotoxic)
    • Measuring levels of drugs = high enough to work, but not too high.
      Even relatively safe antibiotics can have negative effects so the balance below has to be achieved
  • Understanding the mode of action leads = clinical utility.
228
Q

What happens when there is loss of flora?

A
  • There will be bacterial or pathogen overgrowth. e.g.
    • Antibiotic Associated Coilitis
    • Clindamycine, broad spectrum lactams, fluoroquinolones
    • Pseudomembranous colitis
    Can disturb the normal flora in the gut
  • Causes overgrowth of Clostridium difficile = part of normal flora of 3% of the population = causing it to overgrow and this will cause it to show its virulence determinants
  • Candida, staphylococcus
  • But also found without the presence of pathogens
  • Cytotoxins
  • There are ulcerations - inflammation to produce fibrinous coating
  • Severe diarrhoea as colon cannot work to reabsorb water - this is what happens with C difficiles infection
    • Just because of overgrowth - due to antibiotics suppression growth of other factors
  • Serious hospital cross infection risks - carriage rate is up to 70%
  • Treatable with antibiotics
229
Q

Antibiotics and immunity

A
  • There is bacterial clearance - and cure because of combination of immunity and Antibioitcs
  • If someone is neutropenic = hard to treat the infection in immuno-competent person
  • Antibiotics and immunity work to get clearance
  • Immunosuppression = makes treating bacterial infections more complicated
  • Antibiotics + immunity –> bacterial clearance
  • Immunosuppression
230
Q

How are antibiotics classified?

A
  1. Type of activity that they have
    Ø Bactericidal or bacteriostatic
    Ø Certain antibiotics do not kill the bacteria that you are using antibiotics to treat
  2. Structure
  3. Target site for activity
    Ø Taret = easiest way to understand them
231
Q

Bactericidal antibiotics

A
  • Kill bacteria
    • Therefore COMPLETE stopping of its growth
  • Used when the host defence mechanisms are impaired
  • Needed in endocarditis, kidney infection
  • Would be used in a life threatening illness
232
Q

Bacteriostatic antibiotics

A
  • Inhibit bacteria
  • Used when the host defence mechanisms are intact
  • Used in many infectious disease
  • Can be static for one type of bacteria and then static for another
    • E.g. the tetracycline’s
233
Q

What is the spectrum of activity of antibiotics - Broad spectrum antibiotics

A
  • Effective against many types like cefotaxime

- Wide range of activities against a wide range of bacteria

234
Q

What is the spectrum of activity of antibiotics - Narrow spectrum antibiotics

A
  • Effective against very few types
  • Like penicillin G -
  • Extremely useful and v potent but over a narrow range
235
Q

Classification of antibiotics

- Molecular structure

A
  • There is a nitrogen atom that is attached to the beta carbon atom
    • Beta lactam ring is part of the core of several antibiotic families
      ○ That inhibit bacterial cell wall synthesis
236
Q

What are Cephalosporins

A
  • are a class of antibiotics that have beta lactam rings
    • Confer its antimicrobial properties
    • The rest of it confers its microbiological effects of the drug
237
Q

What are Beta lactams ring

A

Ø Penicilin, Cephalosporins, Monobactams, Carbapenem, Subactam all have it
○ This drives it activity against bacteria’s

238
Q

What is the active structure in penicillin

A
  • The Beta lactam ring is the active structure in penicillin
239
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Cell wall synthesis

A
  • Cycloserine
  • Vancomycine
  • Teichoplanin
  • Bacitracin
  • Penicillins
  • Cephalosphorins
  • Monobactams
  • Carbapenems
240
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Folic acid metabolism

A
  • Trimethoprim

- Sulfonamides

241
Q

What are the different bacterial targets for current antibiotics that are used in clinic - DNA gyrase + DNA directed RNA polymerase

A
  • Quinilones
242
Q 
What are the different bacterial targets for current antibiotics that are used in clinic - 
#Protein synthesis (50S inhibitors)
A
  • Eryhthromycine - macrolides
  • Chroamphenicol
  • Clindamycin
243
Q

What are the different bacterial targets for current antibiotics that are used in clinic - Protein synthesis (30S inhibitors)

A
  • Tetracycline
  • Spectinomycin
  • Streptomycin
  • Gentamycin
  • Tobramycin (aminoglycosides)
  • Amikacin
244
Q

Why is it not ideal to target bacterial cell membranes?

A

Very little difference between a bacterial membrane and a human membrane therefore thse that target bacterial membranes will also hurt the human membranes

245
Q

Describe cell wall inhibitors - mechanism of action in more detail and how you treat gram positive and gram negative - Gram positive

A
  • Lipoteichoic acids, traversing wall and anchored in membrane
  • Inner mmebrane that encloses the bacteria and then large peptidoglycan structure on the outside
  • This is synthesised by enzymes that are released across the mamebrane
    • Taret productio of peptidoglctan - can get antiobitocs fast to the site where they can inhibit the enzymes
246
Q

Describe cell wall inhibitors - mechanism of action in more detail and how you treat gram positive and gram negative - Gram negative

A
  • Polysaccharide O antigen
  • There is a porin and lipid A
  • Inner membrane and smaller peptidoglycan structure
  • Outer membrane is impermeable
    • Only way things can get through is via the porins
    • Which are selective transporters
  • Treatment is more difficult
  • Cannot get accros the outer membrane
  • Cannot get to its site of action, via the impermeable membrane
247
Q

• CYCLOSERINE

A

Ø Will inhibit the reactions that are involved
Ø In the incorporation of alanine into the cell wall precursor
Ø Blocks the ability of the bacteria to add 2x alanines
□ If you have antibiotic that is going to block the ability to build precursor molecules - this will block the peptidoglycans
□ And prevents the bacteria from making the proteins

248
Q

VANCOMYCIN

A

(which is a glyco peptide)
• Binds to the terminal D-ala-D-ala residues
• Prevents incorporation of sub units into growing peptidoglycan
• The bacteria is building dimers + want to build a chain formation
Ø Will find the “delaregion” which will prevent cross linking occuring, which will prevent the chain from proliferating
Ø Peptidoglycan precursor chain proliferation is stopped by binding to the de-ala regions.

249
Q

BACITRACIN

A
  • Prevents the de-phosphorylation of phospholipid carrier

* Which prevents the regeneration of carrier that is necessary for synthesis to continue

250
Q

PENICILLINS & CEPHALOSPORINS - beta lactams

A

• bind to, and inhibit enzymes, which catalyse the link
• The peptidases will control the cross linking
• Pencillin binding proteins = peptidases
Ø Bind to enzymes that cross this structure
Ø Antibiotics, will inhibit the enzymes = penicillins and the cephalosphorins
Ø When the cross link occurs, and they recognise the de ala terminal, they will make a cross link mesh
□ They all have slightly different mechanisms!

251
Q

What is the action of beta lactams on PBP in Gram negative bacteria

A
  • Gram negatives = have outer and inner membrane
  • Porin = defines specificity of what gets across

Ø Inner membrane is where the green penicillin binding protein sites and there are precursors

252
Q

The importance of the peptidoglycan cell wall

A

Ø Mycoplasma pneumonia = cannot treat with penicllins
Ø Not going to work because it does have the correct enzymes that would be inhibited ==> nothing to inhibit ==> nothing to kill
Ø Has no effect if there are not peptidogylcan cell walls
Could treat with something else like
Ø Protein synthesis inhibitor like erythromcyin

253
Q

How would you treat bacterial infections

A
  1. Antibiotics
  2. Surgery - drainage of abscess
    Ø Gets rid of necrotic tissue and pus
    Ø Have to reestablish vascularity to be able to hit the MIC and get to the correct threshold that is needed
  3. Immunological (rare) - use of antitoxin in tetanus
    Ø Toxin that is released (tetanus toxin)

Semester 4 (10 decks)

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