SBT Flashcards Preview

Semester 4 Revision > SBT > Flashcards

Flashcards in SBT Deck (159)
Loading flashcards...
1
Q

What are causes of inflammation?

A
  1. Invasion – pathogens (disease-causing), allergens (non-disease)
  2. Injury – heat, UV, chemicals
2
Q

What are signs of inflammation?

A

Signs:

  • Calor - warmth (increased blood flow)
  • Rubor – redness (increased blood flow)
  • Dolor – pain (sensitisation/activation of sensory nerves)
  • Tumor – swelling (increase post-capillary venule permeability)
  • Functio laesa – loss of function (pain/injury)

Inflammation: produced by both innate and adaptive immune systems
Clinically: these processes are very important
Chronic inflammation: severe tissue damage eg atherosclerosis
Acute responses: eg anaphylaxis, sepsis

Anti-inflammatory drugs are regularly prescribed.

3
Q

What are the cardinal signs of inflammation?

A
  • heat
  • redness
  • swelling
  • pain
  • loss of function
4
Q

What are the beneficial effects of inflammation?

A
  • Entry of antibodies. Increased vascular permeability allows antibodies to enter the extravascular space, where they may lead either to lysis of microorganisms, through the participation of complement, or to phagocytosis by opsonisation. Antibodies are also important in neutralization of toxins.
  • Fibrin formation. Fibrin formation from exuded fibrinogen may mechanically impede the movement of micro-organisms, trapping them and so facilitating phagocytosis.
  • Stimulation of immune response. The drainage of this fluid exudate into the lymphatics allows particulate and soluble antigens to reach the local lymph nodes where they may stimulate the immune response.
5
Q

What are the harmful effects of inflammation?

A
  • Destruction of normal tissues. Enzymes such as collagenases, elastases and other proteases may degrade normal tissues, resulting in their destruction. For example in type III hypersensitivity reactions and in some types of glomerulonephritis small vessels are damaged.
  • Swelling. The swelling of acutely inflamed tissues may be harmful. At right is a dog with a swollen face due to an anaphylactic reaction. If that swelling occurs in the larynx, VERY BAD. Inflammatory swelling is especially serious when it occurs in an enclosed space such as the cranial cavity. Thus, acute meningitis or an intra-cerebral abscess may raise intracranial pressure to the point where blood cannot move easily in the brain, there is depression of cardiac and respiratory centers and, death.
  • Inappropriate inflammatory response. Sometimes, acute inflammatory responses appear inappropriate, such as those which occur in type I hypersensitivity reactions where the provoking environmental antigen (e.g. pollen) otherwise poses no threat to the individual.
6
Q

What is the involvement of local hormones in inflammation?

A

Many of the signs of inflammation are produced by chemical mediators that orchestrate the complex responses involved: ‘local hormones’ or ‘autacoids’.

  • Produced in response to a wide range of stimuli
  • Synthesised or released only as and when required
  • Local release for local action
  • Inactivated locally to minimise systemic effects

Some of the above properties are similar to other forms of chemical signaling, whereas others differ.

Examples of local hormones: gastrin, CCK, glucagon, VIP, substance P, motilin,
Others that mediate chemical signalling different to above: NA, DA, 5-HT, etc

7
Q

What is histamine?

A

• Synthesised from histidine amino acid by histidine decarboxylase
• Metabolised by imidazole-N-methyltransferase (INMT) and diamine oxidase
• Synthesised, stored and released from,
- Mast cells, which express receptors for IgE, C3a and C5a on cell surface (connective tissues)
- Basophils (blood)
- Neurones in brain
- Histaminergic cells in gut
• Pre-made, ‘ready-to-go’ in secretory granules composed of heparin and acidic proteins
• Released by allergic reactions (IgE-mediated), production of complement agents C3a and C5a, insect stings, trauma etc through a rise in [Ca2+]i.
• Release of histamine inhibited by stimulation of β-adrenoceptors

8
Q

What is the complement system?

A

c3b, C3bi= opsonins; c5b-9: cell lysis; c3a, c5a: ↑vascular permeability; ↑ chemotaxis

Histamine, a dibasic vasoactive amine, is held by ionic forces within intracellular granules by macroheparin

C3a and C5a, the small (approximately 10KDa) cleavage fragments released by complement activation, are potent mediators of inflammation. They are anaphylatoxins and act as cell activators with nanomolar affinity, exerting their functions through binding to specific receptors (C3aR and C5aR or C5L2 respectively). Recent studies suggest that locally generated complement effector molecules including C3a and C5a contribute to pathological processes in inflammatory and immunological diseases as well as adaptive immune response besides its host defence mechanism. Targeting the receptors and/or their ligands can reduce undesired inflammatory responses and tissue damage in certain pathological conditions. In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses.

9
Q

About histamine receptors…

A
  • Four types of histamine receptors- H1, H2, H3, H4
  • All G-protein-coupled receptors which produce physiological effects by activating second messenger systems
  • Differential expression of receptors:
      H1 -  	Gq/PLC, PIP2 production, generation of DAG/IP3 - smooth muscle, endothelium, CNS
      H2 -   	Gs/AC, generation of cAMP, stimulation of PKA - parietal cells to  gastric acid secretion, heart 
      H3 -   	Gi, decrease in cAMP levels - neuonal presynaptic terminals
      H4 -   	Gi, decrease in cAMP levels - basophils, bone marrow, gut
  • Stimulation of H1 and H2 receptors produce many of the actions of histamine-mediated inflammation
  • H1 and H2 antagonists are clinically important
10
Q

Where do H1 and H2 receptors have effects?

A
  • cardiovascular
  • non-vascular smooth muscle
  • algesia
  • gastric acid
  • associated exocrine secretions
11
Q

What are the cardiovascular effects of H1 and H2 receptor stimulation?

A
  • Dilates arterioles, decreases TPR (H1)
  • Increased permeability of post-capillary venules, decreased BV (H1)
  • Increase in heart rate (H2) – in vivo reflex to try and retain BP to normal
  • Generally involved in decreasing BP (decreases vascular resistance)
12
Q

What are the non-vascular smooth muscle effects of H1 and H2 stimulation?

A

contraction (H1) eg bronchoconstriction

13
Q

What are the algesia effects of H1 and H2 receptor stimulation?

A

pain, itching and sneezing caused by stimulation of sensory nerves (H1)

14
Q

What are the effects on gastric acid caused by H1 and H2 receptor stimulation?

A

increase secretion (H2)

15
Q

What are the effects on exocrine secretions caused by H1 and H2 receptor stimulation?

A

increased, due to increased blood flow

16
Q

What are the pathological roles of histamine?

A

The most important clinical roles of histamine are:

  • Acute inflammation (H1 effects)
  • Stimulating gastric acid secretion (H2)
17
Q

What is the triple response in acute inflammation?

A

reddening (local vasodilation), wheal and flare

18
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) 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 cause vasodilation distant from the site of irritation → the third phase of inflammation, the flare response

When histamine stimulates afferent fibres, it is known to stimulate an axon reflex:
It orthodromically stimulates nerve impulse travel towards the spinal cord and the dorsal root ganglia, passing antidromically down the other branches of sensory nerves. These antidromic impulses release nerve impulses → vasodilation (flare, reddening) distant from the site of irritation

Degranulation of mast cells, changes in smooth muscle contractility, stimulation of lymphocytes and granulocytes → neurogenic inflammation (Kupfermann, 1991; Dockray, 1992)

19
Q

About c fibres, substance P and inflammation…

A

Interestingly, the C fibers interact with the process of inflammation. Observe the figure below. The directions that action potentials conduct should seem quite surprising, because action potentials in certain branches of an afferent neuron aremoving peripherally!! The is called theaxon reflex. In this way, certain painful stimuli not only lead to the sensation of pain in the central nervous system, but also to the release of substance P locally. This increases inflammation by causing histamine release and dilation of blood vessels.

20
Q

What is dermographia in the triple response?

A

Reddening: oedema (increase in vascular permeability induced by substance P (SP) and histamine increase in leakage of fluid and plasma proteins from capillaries (ie increase in plasma protein extravasation))

21
Q

What H1 antagonists are used to treat acute inflammation?

A

1st Generation
- Mepyramine, diphenhydramine, promethazine

2nd and 3rd generation

  • Terfenadine, pro-drug with potential cardiac arrhythmia actions in high concentrations, these are increased with grapefruit juice (which inhibits P450-mediated drug metabolism pathways in liver)
  • Fexofenadine, active, non-toxic metabolite of terfenadine
22
Q

What is the therapeutic and side effects of H1 antagonists?

A
  • Reduce minor inflammatory reactions (eg insect bites, hayfever), BUT NO significant value in asthma
  • 1st generation drugs are sedative – drowsiness is a major side effect, but sometimes used as a therapeutic effect
  • some (eg promethazine) are anti-emetic – ‘motion sickness’
  • anti-muscarinic actions (common in 1st generation drugs) eg atropine-like effects of blurred vision, constipation etc
23
Q

What are the therapeutic and side effects of using H2 antagonists for gastric problems?

A

Archetypal

  • cimetidine = tagamet
  • ranitidine = zantac

Therapeutic and side effects

  • reduce gastric acid secretion in treatment of duodenal and gastric ulcers and Zollinger-Ellison syndrome (duodenum and pancreas tumours increasing gastrin secretion)
  • increase INMT activity so more rapid breakdown of histamine
  • mental confusion, dizziness, tiredness and diarrhoea sometimes as side effects
  • cimetidine, decrease in cytochrome P450 activity so adverse drug interaction potential, gynecomastia
24
Q

What is the generation of bradykinin a result of?

A

The generation of bradykinin as a result of activation of:

  1. Hageman factor (HF) and production of plasma kallikrein
  2. Production of Iysylbradykinin by tissue kallikreins
  3. Action of cellular proteases in kinin formation

Hageman factor = coagulation factor XII

25
Q

What is the synthesis of bradykinin via the kinin-kvllikrein system?

A

Fibrin formation. Fibrin formation from exuded fibrinogen may mechanically impede the movement of micro-organisms, trapping them and so facilitating phagocytosis.
kallidin (bradykinin with a lysyl group attached to the amino terminus)- the lysyl group is removed by aminopeptidase

Bradykinin is metabolised by ACE, aminopeptidase, carboxypeptidase
It is unlikely that binding to negatively charged surfaces alone is sufficient to activate XII, since highly purified preparations of XII and plasma deficient in prekallikrein and high molecular weight kininogen do not undergo this “autocatalysis”

26
Q

What are the pharmacological effects of bradykinin?

A
  • Potent vasoactive peptide
  • Increase vascular permeability
  • Vasodilation (decreased 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
27
Q

What is the metabolism of bradykinin via?

A

kininases (ACE, amino peptidase P, carboxypeptidase)

28
Q

What are the effects of kinins?

A
  • blood coagulation
  • regulation of BP & blood flow via RAAS
  • cellular proliferation and growth
  • angiogenesis
  • apoptosis
  • inflammation
  • vasodilation
  • ↑ vascular permeability
  • release of tPA
  • production of NO
  • mobilisation of AA (PGI2, an antiaggregatory vasodilator) by endothelial cells
29
Q

What is the distribution of 5-HT?

A
  • platelets release 5-HT (and TXA2)
  • the EC cells of gastrointestinal tract (mediates gut movement, diarrhoea)
  • brain (cognition, aggression, mating, feeding, sleep, pain, vomiting and regulation of behaviour
  • some tumours (eg carcinoid) secrete excess 5-HT

Carcinoid - is a slow-growing type of neuroendocrine tumour originating in the cells of the neuroendocrine system
5HT is mainly found in EC cells (distributed in the epithelium small intestine, colon and stomach.
Mediates peristaltic and vagal reflexes. Important in the generation of nausea (via 5-HT3 receptor mediation) – ondansetron (antiemetic) is an antagonist at 5HT3 receptors

30
Q

What are the inflammatory actions of 5-HT?

A

• 5-HT stimulates mast cell adhesion and migration
• 5-HT enhances inflammatory reactions of skin, lungs and gut
• 5-HT promotes inflammation by increasing the number of mast cells at the site of tissue injury
• 5-HT may synergise with TXA2 to stimulate platelet activity and vasoconstriction
o Activation of TXA2 receptors increases 5-HT-mediated responses in blood vessels

31
Q

Why are eicosanoids important?

A

• Molecules with powerful inflammatory actions
• Targets of major anti-inflammatory drugs:
- NSAIDs
- Glucocorticoids
- Lipoxygenase inhibitors
- Leukotriene antagonists

Important: you need to know how Eicosanoids are made.

32
Q

How are prostanoids formed?

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

Thrombin binds to platelet glycoprotein Ib (Gp Ib), and this interaction contributes to platelet activation.

Bradykinin and adrenaline are known initiators of the cascade and can initiate phospholipase action at the cell membrane.

33
Q

What are cyclooxygenases?

A

¥ Conversion of AA to prostanoids requires the enzyme cyclooxygenase (COX)
¥ Two main isoforms COX-1 and COX-2
¥ COXs are fatty acids, attached to endoplasmic membrane
¥ COX-1
- constitutively active
- responsible for ‘physiological’ roles of PGs/TXs such as regulation of peripheral vascular resistance, renal blood flow, platelet aggregation, gastric cytoprotection
¥ COX-2
- Needs to be stimulated (e.g. by inflammatory cytokines- IL-1, TNF)
- Responsible for role of PGs/TXs in inflammatory responses (pain and fever)
¥

COX-3
- Variant of COX-1; pain perception of CNS

34
Q

What is the cyclooxyrgenase pathway?

A

Membrane prostaglandin E2 synthase-1 (mPGES-1) is a terminal prostaglandin synthase that isomerizes PGH2 into PGE2.

Both lipopolysaccharide (LPS) and cytokines activate intracellular signaling cascades in endothelial cells in small blood vessels and in vascular-associated macrophages, termed perivascular cells, in the brain (Fig. 1) [5–7]. This cascade results in phospholipase A2 degrading phospholipids into arachidonic acid and increased expression of cyclooxygenase type 2 (COX-2) [8, 9]. COX-

2 converts arachidonic acids to PGH2, from which specific PG synthases synthesize various PGs [10, 11]. In addition, macrophages and dendritic cells of the abdominal cavity
including Kupffer cells in the liver can produce PGE2 in response to LPS [12, 13] and sensory neurons of the vagus nerves express receptors for PGE2 that can activate afferent
nerve fibers [14] (for review see [15, 16])

35
Q

About 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
How?
Ð 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-B activation (helps to ↓ activation of inflammatory genes)

36
Q

What are cyclopentenone prostaglandins (cyPG)?

A

Activated neutrophils control inflammation including mediator release from distant immune cells but simultaneously mediate pulmonary tissue damage. Thus, keeping in mind potential inflammatory adverse effects, modulation of neutrophil activation or trafficking might be a reasonable therapeutic approach in chest trauma-induced lung injury.

37
Q

What are the actions of eicosanoids - 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

38
Q

About EP receptors…

A

EP receptors are G-protein-coupled receptors and classified into four subtypes: EP1, EP2, EP3, and EP4. These receptors can be grouped into three categories on the basis of their signal transduction: the EP1 receptor increases intracellular Ca2+. The receptors, which mediate increases in intracellular cyclic adenosine monophosphate (cAMP), consist of the EP2 and EP4 receptors. The EP3 receptor expressed in the brain is an inhibitory receptor that mediates decreases in intracellular cAMP, although other splicing variants of the EP3R have different signaling pathways

39
Q

About 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:
Ð Prevention of mild to moderate asthma
Ð Early to late bronchoconstrictor effects of allergens
Ð Exercise-induced asthma and asthma provoked by NSAIDs

40
Q

What are side effects of leukotriene receptor antagonists?

A

Ð GI upset
Ð Irritability
Ð Dry mouth, thirst
Ð Rashes, oedema

41
Q

What is more potent out of leukotrienes and histamine?

A

leukotrienes

42
Q

About 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
43
Q

About poly-unsaturated fatty acids in inflammation…

A

¥ Fish oils provide substrates for the generation of alternative eicosanoids
¥ Fish oils cause increased proportion of ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in inflammatory cells at the expense of AA
¥ Less natural 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
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

TXB2 (Thromboxane B2) is a stable metabolite of thromboxane A2 in platelets which may be released during anaphylaxis. Reportedly possesses chemotactic properties. Often used to measure arachidonic acid metabolism. It is a prostaglandin derivative that is released during anaphylaxis, which induces arterial contraction and platelet aggregation by stimulating TP-α receptors.
TXB2 is a stable, biologically inert metabolite formed from the non-enzymatic hydrolysis of TXA2, which has a half-life of about 30 seconds.1 Urinary analysis of TXB2 accurately reflects intrarenal TXA2 synthesis,2 while measurement of 11-dehydro and 2,3-dinor thromboxane metabolites gives the best estimate of systemic TXA2 secretion

44
Q

What are the 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.
45
Q

What are the basics of NSAIDs?

A

• Archetypal NSAID is aspirin (ASA)
• NSAIDs are:
- Analgesic (prevention of pain)
- Anti-pyretic (lowering of raised temperature, fever)
- Anti-inflammatory (decrease an immune response)
• NSAIDS are used to treat:
- Low grade pain (chronic inflammation eg arthritis)
- Bone pain (cancer metastases)
- Fever (associated with infections)
- Inflammation (decrease symptoms – oedema, redness, itch)

Responses are depended on inhibitory profiles on different COXs.

46
Q

What are the pharmacological mechanisms of NSAIDs?

A

Main therapeutic action is by inhibition of COX:

  • COX converts AA to PGs and TXs
  • COX-1 (constitutively active, platelets)
  • COX-2 (inducible enzyme eg by IL-1beta and TNFalpha)
  • Inhibition of COX-2 reduced PGs/TXs inflammatory agents
  • Aspirin acts irreversibly on COX; others act reversibly and tis 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 are ‘super aspirins’?
  • Paracetamol is a special case
47
Q

About paracetamol…

A

• Analgesic without anti-inflammatory effects
• Little inhibiton of COX-1 or COX-2 in peripheral tissue
• Weakly inhibits COX-3 in CNS – this doesn’t explain all of its effects
• Modulates serotonergic neurotransmission??
• Inhibits COX-mediated generation of hydroxypeptides from AA metabolism?
- Hydroxypeptides stimulare COX activity

Other NSAIDs include etodolac, meloxicam, ibuprofen, naproxen, indomethacin, etc

48
Q

What is the antipyretic action of NSAIDs?

A

• Bacterial endotoxins produced during infections stimulate macrophages to release interleukin-1 (IL-1)
• IL-1beta acts on the hypothalamus to cause PGE2 release (via COX-2)…
- Increased PGE2 depresses temperature sensitive neurons
• PGE2 elevates set point temperate – onset of fever
• NSAIDs block PGE2 production, so set point is lowered back to normal value and fever dissipates
• NSAIDs have no effect on normal body temperature

49
Q

What is the analgesic action of NSAIDs?

A
  • PGs sensitise and stimulate nociceptors
  • Oedema produced by inflammation also directly activated nociceptive nerve fibres
  • PGs interact synergistically with other pain producing substances (eg kinins, 5-HT, histamine) to produce hyperalgesia (increased sensitivity to pain)
  • Blockade of PG production breaks this cycle and leads to pain relief
  • Useful for pain associated with production of inflammatory agents (PGs/TXs) eg arthritis, toothache headache (as NSAIDs inhibit PGs-mediated vasodilatation)

COX-1, COX-2 and COX-2 inhibition in CNS.

50
Q

What is the anti-inflammatory action of NSAIDs?

A

PGE2 and PGI2 have powerful acute inflammatory effects

  • Arteriolar dilatation (increased blood flow)
  • Increase permeability in post-capillary venules
  • Both processes increase influx of inflammatory mediators into interstitial space

Inhibition of their formation reduced redness and swelling.

NSAIDs provide only ‘symptomatic relief’

  • They do not cure the underlying cause of inflammation
  • Eg help, but do not cure arthritis

Decreased COX-2-generated PGs; effects develop gradually.

51
Q

What are the systems involved in the pharmacology of NSAIDs?

A
  • Cardiovascular system
  • Skeletal
  • Gastrointestinal tract
  • CNS
  • Genital tract
  • Kidney and body fluids
  • Lung and respiratory
  • Skin
52
Q

How do NSAIDs act 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
- Possibly problematic in surgery or childbirth

Where platelet aggregation is increased in disease, aspirin has a role in prophylactic treatment.

53
Q

Why is aspirin beneficial in cardiovascular disorders?

A

over time less irritant effects, benefit of PGI2 and PGE2 not lost

54
Q

What effects do NSAIDs have on the skeletal system?

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.

55
Q

What effects do NSAIDs have on the GI tract?

A

PGs (PGE2/PGI2) important in protecting the gastric mucosa

  • Stimulate mucus secretion
  • 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 may be gastric-friendly’, as it is suggested that COX-1 is expressed in gut.

NSAIDs = acidic

They causes:

  • Decreased mucus secretion
  • Decreased HCO3-
  • Increased acid secretion
  • Increased LT production
  • Increased blood loss

Interfere with tissue healing (COX-2 inhibition)
Nausea, dyspepsia, GI contraction (COX-1 inhibition)

56
Q

What are COX-2 selective agents?

A

Examples: celecoxib, valdecoxib, etoricoxib, rofecoxib

¥ Etoricoxib is most selective COX-2 inhibitor
¥ They have no effect on TXA2 in platelets, but decrease PGI2 in blood vessels
¥ Rofecoxib – withdrawn due to CV effects
¥ Not suitable for RA/osteoarthritis; use meloxicam, etodolac, etc. instead
¥ COX-2 + NSAID → ULCER
¥ Diclofenac (an NSAID) - selective for COX-2, but inhibits COX-1 in GIT → ulcers
¥ Less effective analgesic - less inhibition of COX-3 in brain and spinal cord

57
Q

What are the effects of NSAIDs on the CNS?

A
  • NSAIDs inhibit pyrexia – therapeutic use
  • In overdose NSAIDs produce paradoxical hyperpyrexia, stupor and coma
    increased metabolism and increased metabolic acid production
  • Reye’s syndrome risk (brain and liver damage) when used in children with influenza or chicken pox
58
Q

What are the effects of NSAIDs on the genital tract?

A

¥ PGs cause pain and smooth muscle spasm during menstruation - NSAIDs used as treatment
Ð Note mefanamic acid reduces blood loss
Ð NSAIDs may be useful in primary dysmenorrhoea
¥ PGs (PGE2 and PGF2α) - important in uterine contractions in childbirth, thus NSAIDs delay contractions
¥ Many NSAIDs increase post partum blood loss because TXA2 production prevented
¥ NSAIDs delay and retard labour

59
Q

What are the effects of NSAIDs on the kidney?

A

¥ Vasodilator PGs (E2/I2) regulate renal blood flow
¥ NSAIDs thus reduce renal blood flow
Ð Chronic renal injury may result
Ð Effectiveness of some antihypertensive drugs is reduced by concurrent treatment with NSAIDs
Ð Inhibition of COX-2 ↓ sodium excretion and ↑intravascular volume
Ð Average BP rise = 3/2 mmHg, but varies
Ð Low dose aspirin doesn’t seem to interfere with antihypertensive therapy, but regular use should be avoided

60
Q

What are the effects of NSAIDs on the respiratory system?

A

¥ PGs (PGD2, PGF2α) have both constrictor and 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
Ð ca. 20% asthma patients wheeze when given aspirin or other NSAIDs because they are hypersensitive to these drugs
¥ At toxic doses aspirin initially stimulates respiration
Ð Actions on respiratory centre and uncoupling of oxidative phosphorylation - medulla stimulated
Ð Respiratory alkalosis caused by hyperventilation (→CO2 washout from lungs)

61
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)
¥ Surgical closure
¥ Do not give NSAIDs in 3rd trimester to avoid premature closure of ductus

Low birth weight infants
Treatment is individualised
May close by age 1

Fast breathing/shortness of breath;
Sweating while feeding;
Tiring very easily

  • Decrease colonic polyps and prevent colon cancer
  • May decrease Alzheimer’s disease risk
  • Post-operative pain relief
  • Renal colic – upper part of abdominal pain/groin usually caused by kidney stones
62
Q

What are the aims of treatment of ulcerative colitis?

A

¥ Reduce symptoms, known as inducing remission (a period without symptoms)
¥ Maintain remission
¥ First-line treatment options: aminosalicylates (sulfasalazine and mesalazine)
¥ ↓ inflammation for mildor moderate ulcerative colitis.
¥ Short-term treatment of flare-ups.
¥ Useful in the long term to maintain remission.

63
Q

What is the mechanism of action of sulfasalazine?

A

¥ Metabolised to 5-aminosalicylic acid (5-ASA), and sulfapyridine
¥ Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase
¥ Cyclooxygenase and lipoxygenase activities are high in ulcerative colitis?

64
Q

What are the side effects of sulfasalazine?

A

¥ Indigestion, feeling or being sick, abdominal pain, diarrhoea,
¥ Dizziness, headache, difficulty sleeping, tinnitus,
¥ Coughing; itchy rash, may affect your taste and cause sore mouth

65
Q

What are anti-inflammatory agents for gout?

A
  • Gout (a type of arthritis): accumulation of uric acid crystals in joints;
  • Painful inflammation caused by build up of uric acid in joints
  • Uric acid (from purines) is in the blood and is harmless at low levels
  • Uric acid prevents damage to blood vessel linings
  • Passed out with the urine and faeces
  • High levels 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
  • Examples of anti-gouts drugs: naproxen, diclofenac and indomethacin
66
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).

67
Q

What are the side effects of naproxen?

A

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

68
Q

About the synthesis of corticosteroids?

A

• Both synthesised, released from the adrenal cortex
- Often termed the ‘salt and sugar’ hormones
• Glucocorticoids
- ‘sugar’ hormone, carbohydrate and protein metabolism
- potent anti-inflammatory (asthma)/immunosuppressant (graft vs host)
• Mineralocorticoids
- ‘salt’ hormone, controls H2O and electrolyte in the kidney

Corticosteroids can mediate their effects either as glucocorticoids (eg cortisol) or mineralocorticoids, so there are two receptors giving the tow options.

69
Q

About control of cortisol release…

A

Stress causes the release of CRH by the paraventricular nucleus (PVN) of the hypothalamus.

Cortisol has a number of functions. It promotes normal metabolism, maintains blood sugar levels and BP, provides resistance to stress and acts as an anti-inflammatory agent. It also plays a part in regulation of fluid balance in the body.

Favours immediate use of glucose, promotes gluconeogenesis, some glycogen synthesis in the liver, effects on fat cells, defend the body against infection.

CRH: corticotrophin releasing hormone
ACTH: adreno cortico trophic hormone

70
Q

About control of aldosterone release…

A

High levels of cortisol has effects on aldosterone. The increased cortisol overwhelms the enzyme involved in clearing the cortisol and so this can cause aldosterone release. Cortisol can interact with specific receptors that will do this.

Aldosterone: Na and K increase blood volume get RAAS system, ANGII mediates aldosterone effects Na resorption.

71
Q

What are the different types of effects of glucocorticoids?

A
  • metabolic actions
  • hormonal regulation
  • cardiovascular system
  • CNS
72
Q

What are the metabolic actions of glucocorticoids?

A
  • breakdown of protein and fats (muscle wasting etc)
  • decreased glucose usage and increased gluconeogenesis
  • tendency to hyperglycaemia and increase glycogen storage
73
Q

What is the hormonal regulation associated with glucocorticoids?

A

negative feedback on both hypothalamus and pituitary gland

74
Q

What are the effects of glucocorticoids on the cardiovascular system?

A

disease in both microvascular permeability and vasodilation?

75
Q

What are the effects of glucocorticoids on the CNS?

A
  • mood changes, linked with changes in memory/stress
  • A complex hormonal cascade ensues, and the adrenals secrete cortisol.
  • Cortisol prepares the body for a fight-or-flight response by flooding it with glucose, supplying an immediate energy source to large muscles.
  • Cortisol inhibits insulin production in an attempt to prevent glucose from being stored, favoring its immediate use.
  • Cortisol encourages synthesis (glycogenesis) and storage of glycogen
76
Q

What are the anti-inflammatory effects of glucocorticoids?

A

Decreased microvascular fluid exudation
- Reduces influx of cells to areas of inflammation

Decreased inflammatory mediators and cytokines

  • Decreased expression of COX-2
  • Reduced levels of eicosanoids
  • Decreased levels of cytokines and complement levels

Decreased function of inflammatory effector cells

  • Inhibition of ell migration and mediator release
  • Reduced clonal expansion of T and B cells
  • Reduction in chronic inflammatory events
  • NG healing and repair inhibited

impaired keratinocyte migration

77
Q

What are the cellular mechanisms of glucocorticoids?

A

Glucocorticoid receptors are found intracellularly in almost all tissues. Glucocorticoids enter cells through passive diffusion and form a complex with a receptor protein. This complex then undergoes an irreversible activation and enters the cell nucleus, where it binds to DNA, leading to biological effects induced by these hormones, including increased hepatic gluconeogenesis, increased lipolysis, muscle catabolism, and inhibition of peripheral glucose uptake in muscle and adipose tissue (Gans & Smith, 1999; Greenspan & Stewler, 1997). The exact mechanism of action of corticosteroids remains unknown despite more than 40 years of research.

The unbound receptor is usually sequestered in the cytoplasm of the target cell bound to the heat-shock protein (HSP) complex (- comprises chaperone molecules hsp90 and hsp70 and immunophilin FKBP59).

Heat shock proteins coming off where haven’t bound to receptor. Glucocorticioids bound to their receptors find their way to nucleus. Once in the nucleus have a range of effects.

Switch some genes on and some genes off, inflammatory response, cytokines, IL-1, TNFalpha.

78
Q

How do glucocorticoids switch gene expression on/off?

A

1) Interaction of steroid/receptor with promoter regions
- these gene promoters have ‘glucocorticoid response elements’ (GREs) and occupancy of GREs turn on/off certain genes
2) Steroid/receptor complexes prevent gene activation by other transcription factors
- e.g. AP-1, NFkB: transcription factors involved in switching on COX-2, cytokines

Induction of inhibitor kappa B alpha

Leading to:

Increased expression of anti-inflammatory proteins
- lipocortin which arachidonic acid / eicosanoids

Decreased expression of pro-inflammatory proteins
- cytokine production (e.g. TNF-)

79
Q

What is the mechanism of action of dexamethasone?

A

Dexamethasone is a glucocorticoid agonist. Unbound dexamethasone crosses cell membranes and binds with high affinity to specific cytoplasmic receptors. This results in a modification of transcription and, hence, protein synthesis in order to achieve inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in oedema or scar tissue. The antiinflammatory actions of dexamethasone are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.

Overall, central to the action of dexamethasone is the induction of inhibitor kappa B alpha (IB) which binds to and inhibits NF-B by sequestering it in the cytoplasm.

80
Q

What are the therapeutic uses of glucocorticoids?

A

• Adrenal insufficiency or failure (Addison’s Disease)
- congenital or drug-induced
- treatment requires combined GC and MC
• Treatment of inflammation
- asthma, rhinitis, skin disorders, sports injuries, reduction of cerebral oedema in patients with brain tumours
• Immunosuppression
- inhibit graft v host reaction in tissue transplantation
• Examples:
- Hydrocortisone, prednisolone, dexamethasone, betamethasone, beclomethasone

81
Q

About mineralocorticoids…

A

• Endogenous mineralocorticoid – aldosterone
• Secretion controlled by renin-angiotensin system and ACTH
• Increases Na+ retention in distal tubules of kidney
- Stimulates Na+/H+ exchanger via aldosterone receptors
- Enters cells and up-regulates Na+-permeable ENaC channels in cell membrane
- Enters cells and stimulates up-regulation of basolateral Na+/K+ ATPase pump
- Also causes H2O retention, and loss of K+ and H+
• Mineralocorticoid receptors found in only few tissues, kidney, colon, bladder
• Low Na+ plasma levels increase aldosterone by directly activating adrenal gland and stimulating RAA system to produce Ang II

ENaC = epithelial sodium channel

82
Q

What are the therapeutic uses of mineralocorticoids?

A

Adrenal insufficiency
- e.g. Addison’s disease

Electrolyte disorders
- cerebral salt wasting

Orthostatic hypotension (postural hypotension)
-	Failure of baroreceptor reflex

Example:
- Fludrocortisone

83
Q

What are the side effects of corticosteroids?

A
  • Cushing’s syndrome
  • Opportunistic infection
  • Osteoporosis
  • Gastric ulceration
  • Growth suppression
  • Behavioural or reproductive problems
  • Prolonged HPA suppression after cessation of therapy
  • Redistribution of fat
  • Sodium retention
  • Cataracts, glaucoma
  • Clinical features of Cushing’s
  • Hepatic enlargement (long term use); acute liver injury (especially with high dose methylprednisolone); liver failure
  • Insulin resistance
  • Diabetes
  • Weight gain
  • Thinning of skin
  • Suppress LH

Useful drugs with wide ranging actions and thus an expected penalty of wide ranging side effects.

84
Q

What are the principles of selective toxicity?

A

There must be..
¥ Differences between the biochemistry of host tissues and infectious agents
¥ Differences between normal and cancer 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)
Paul Ehrlich (1854-1915) and the “magic bullet”: selectively target a disease-causing organism
¥ Basis of chemotherapy

85
Q

What are the hallmarks of cancer?

A

In order for cancerous cells to develop and form a tumour, mutations and other alterations that allow the cell to acquire a succession of the following biological capabilities must occur.

Although the details of each hallmark are beyond the scope of this lecture, suffice to say that we have made remarkable progress toward understanding the mechanistic underpinnings of each hallmark

86
Q

What are the aims of cancer chemotherapy?

A

Diagnosis: social stigma, myths
¥ Eradicate the disease
¥ Induce remission – state of no disease, but it can come back
¥ Control symptoms
Selectivity of cancer chemotherapy
¥ Cancer cells: high rate of cell division compared to non-tumouric cells
How do we achieve selectivity?
¥ Look at cellular, biochemical, and molecular differences between cancer cells and healthy cells
For maximum benefit, the aims of therapy must be defined at the outset and must be patient-centred.

87
Q

What are the principles of cancer treatment?

A

¥ The drugs can be given singly

¥ Combination therapy – 2 to 6 drugs (watch out for toxicity, e.g. myelosuppression)

88
Q

What is the criteria for choosing drug combinations?

A

¥ 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

Successful treatment also requires psychological and social support

89
Q

What are 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 ie G0)

90
Q

What is the mechanism of action of alkylating agents?

A

We get very reactive species formed and a whole range of results. There is a decreased level of cell proliferation as a result. This is good news for the human! Also alkylate proteins and RNA – widening negative effects on tumour cells.

91
Q

About selectivity of cytotoxic drugs…

A

Side effects of chemotherapy: many and varied, but hair loss is a major concern for patients
¥ Overall, their selectivity is marginal at best
¥ Therapeutic index = 1 (it means that the concentration that causes toxicity is = conc. that causes cancer cell death)

You want the therapeutic index to be wide, not narrow
So basically,
¥ All dividing cells affected → massive side effects
¥ Some degree of selectivity, e.g. malignant tumours (tumours that display uncontrolled growth and invasion/metastasis)

The side effects of the drugs are related to their mode of action - gut, bone marrow, reproductive and endocrine systems are affected

92
Q

What are important considerations before prescribing antibiotics?

A

¥ Which route
¥ How many days
¥ Identify the organism responsible for or likely to be responsible for the symptoms
¥ Access the severity of illness, e.g. oral, parenteral antibiotics
¥ Previous antibiotic therapy, e.g. symptoms have not responded to 7-day course of penicillin
¥ Previous adverse/allergic responses to antibiotics, e.g. Penicillin
¥ Other medications being taken or their possible interactions, e.g. warfarin, phenytoin, oral contraceptive pill
¥ Ongoing medical considerations, e.g. renal failure; pregnancy, breast feeding

93
Q

What are possible targets for microbial action?

A

The targets are diverse, but most drugs target the synthesis of:
¥ Peptidoglycan of the bacterial cell wall

Other targets include:
¥ Protein synthesis
¥ Intermediary metabolism (involves folate coenzymes)
¥ Biosynthesis of DNA or RNA and cell membranes

94
Q

About the bacterial cell wall?

A

¥ Peptidoglycan (sugars and amino acids): semi-rigid, tight-knit molecular complex; enables the bacterium to resist osmotic lysis
Ð Polysaccharide portion: NAG and NAM
Ð Protein portion: short chains of amino acids that link layers of polysaccharide together by NAM
¥ The peptide cross bridges are linked to NAM
Ð LPS consists of lipid portion called lipid A and a polysaccharide portion. Lipid A (endotoxin): triggers fever and shock

95
Q

What is the spectrum of activity of antibacterials that inhibit cell wall synthesis?

A

Spectrum of activity:
- Active against aerobic gram-positive and gram-negative cocci and many anaerobic microbes

Amoxicillin and ampicillin are broad spectrum.

96
Q

What is the mechanism of action of penicillin?

A

Antibacterials that inhibit cell wall synthesis: penicillin

Mechanism of action:
¥ Bactericidal
¥ 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 death
¥ Side chain from the β-lactam ring determines the unique pharmacological properties of the different penicillins

Transpeptidase:
¥ Forms a peptide bridge that cross-links the pentapeptides coming off NAM
¥ Connects each row of sugars with its adjacent row
¥ Connects each layer of peptidoglycan with its adjacent layer
¥ → tight-knit molecular complex

97
Q

What are the adverse effects of penicillin?

A
Adverse effects: 
Hypersensitivity reactions including:
Ð	Rash – common
Ð	Anaphylactic reactions – rare
Ð	Neurotoxicity, with high [CSF]
Ð	GI disturbances

Inactivates inhibitor of autolysins cell lysis

98
Q

hat are autolysins?

A

break glycosidic bonds between peptidoglycan monomers to allow insertion of new peptiglycan monomers

99
Q

What are the contraindications and therapeutic notes of penicillin?

A

Contraindications:
¥ Known hypersensitivity to penicillin or cephalosporin

Therapeutic notes:
¥ Resistance due to production of β-lactamase
¥ The resistance gene is plasmid-borne
¥ Flucloxacillin is resistant to β-lactamase; good against penicillin resistant staphylococci as it is not inactivated by β-lactamase

100
Q

What is the site of action of anti fungal drugs?

A

Lanosterol is converted to ergosterol by 14alpha-demethylase (P450)

Lanosterol 14 α-demethylase (or CYP51A1) is a CYPenzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol.

101
Q

What is the mechanism of action of polyene macrolides?

A

¥ Interacts hydrophobically with ergosterol in fungal cell membrane and forms pores within it
¥ Loss of cell contents and cell death ensues
¥ Selectively toxic – humans have cholesterol instead of ergosterol

102
Q

What are the indications of polyene macrolides?

A

¥ Amphotericin B: broad-spectrum (serious systemic infections)
¥ Nyastatin: thrush (oral and vaginal)

103
Q

What is the mechanism of action of zidovudine?

A

Ð A series of phosphorylation steps converts ZDV to ZDVTP
Ð ZDVTP competes with endogenous thymidine for the same enzyme (RT)
Ð ZDVTP incorporated into growing DNA strand and terminates synthesis due to lack of OH group
¥ ZDVTP causes the selective inhibition of RT enzyme. ZDV has higher affinity for RT than for other mammalian polymerase enzyme.
¥ ZVDTP causes chain termination
¥ ZDVTP inhibits infection of new cells

104
Q

About antifolates and protozoal infections…

A

¥ Emerged in the 1940s for malaria treatment
¥ Specific DHFR inhibitors; human host also has DHFR
¥ DHFR in man: target for anticancer chemotherapy (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 activity against RBC stage)
¥ Slow-acting,
¥ Not to be given to individuals in critical situations (time is of essence)

105
Q

What is the mechanism of action of antifolates?

A

¥ Direct competition with substrate
¥ Incorporation into folate pathway leads to the synthesis of pseudofolate (does not function like the real thing)

Effect on bacteria – some of them can trick the enzyme and compete with dihropteronate Synthase.

106
Q

What is proguanil?

A

Proguanil (chloroquanide)

¥ Selective inhibitor of plasmodial DHFR and thymidylate synthase
¥ Proguanil has intrinsic* antimalarial activity (Fiddock & Wellems, 1997)

¥ 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 of P. vivax
¥ Relapses?
¥ Gametocytes unaffected; but fertilised gametes in the gut of the mosquito do not develop

107
Q

What is the mechanism of action of proguanil?

A
  • Converted into an active triazine metabolite (cycloquanil)
  • Selective inhibition of DHFR-thymidylate synthase (DHFR-TS) of sensitive parasites by cycloguanil
  • Thymidylate synthase – (phosphorylation of thymidine) – DNA synthesis and repair
  • inhibition of DNA synthesis, and folate cofactors become depleted
108
Q

What are the different types of antimicrobials?

A
  • Antibiotics bacteria
  • Anti-virals
  • Anti-fungals
  • Anti-protosoals
  • Anti-nematodes
109
Q

About the very basics of antibiotics…

A

Natural products of fungi and bacteria - soil dwellers

- natural antagonism and selective advantage
 	- kill or inhibit the growth of other microorganisms

Most derived from natural products by fermentation, then modified chemically:
pharmacological properties
antimicrobial effect

Some totally synthetic eg sulphonamides.

110
Q

What is the selective toxicity of antibiotics?

A

Ð Due to the differences in structure and metabolic pathways between host and pathogen
Ð Harm microorganisms, not the host
Ð Target in microbe, not host (if possible)
Ð Difficult for viruses (intracellular), fungi and parasites
Ð Variation between microbes

111
Q

What is the therapeutic margin of antibiotics?

A
  • active dose versus toxic effect

- narrow for toxic drugs – eg aminoglycosides, vancomycin, ototoxic, nephrotoxic

112
Q

What is microbial antagonism?

A

Maintains flora – complex interactions and competition between flora.

Limits growth of competitors and PATHOGENS.

Loss of flora bacterial or pathogen overgrowth

113
Q

How can antibiotics be classified?

A
  • Type of activity
  • Structure
  • Target site for activity
114
Q

Bacterial vs bacteriostatic…

A

Bactericidal

  • Kill bacteria
  • Used when the host defense mechanisms are impaired
  • Required in endocarditis, kidney infection

Bacteriostatic

  • Inhibit bacteria
  • Used when the host defense mechanisms are intact
  • Used in many infectious diseases
115
Q

What are the options of spectrum of activity of antibiotics?

A

Broad spectrum antibiotics
- Effective against many types eg cefotaxime

Narrow spectrum antibiotics
- Effective against very few types eg penicillin G

116
Q

How can we treat bacterial infections?

A
  • Antibiotics
  • Surgery eg drainage of abscess
  • Immunological (rare) eg use of antitoxin in tetanus
117
Q

Why do we use antibiotics?

A

Treatment of bacterial infections
Prophylaxis - close contacts of transmissible infections
↓ carriage rates ( ~80% in outbreaks)
e.g. meningitis
- prevention of infection e.g. tuberculosis

	- peri-operative cover for gut surgery
	- people with  susceptibility to infection 		

Inappropriate use – viral sore throats – patient pressure

118
Q

About the route of administration of antibiotics…

A

Community infections often treated orally by GP.

Serious infection - hospitalization – systemic treatment eg IV, rapid delivery, high [blood] – often unable to take oral (vomiting, unconscious, poor gut absorption due to trauma).

?? IV with perivascular collapse (eg septicaemia), IM injections – meningitis case

Topical - conjunctivitis, superficial skin infections, burns, antiseptic creams, heavy metal ointments

119
Q

About antibiotic combinations…

A
  • BEFORE an organism identified in life-threatening infections
  • e.g. endocarditis, septicaemia
  • Polymicrobial infections e.g. abscess, G.I. perforation
    ♣ anaerobes and aerobes
  • Less toxic doses of an individual drug possible
  • Synergy - e.g. penicillin and gentamicin

Co-trimoxazole (sulphonamides + trimethoprim)
- reduce antibiotic resistance e.g. Tuberculosis

Access to drug – poor circulation. Polymicrobial infection. Natural defenses compromised. Poor tissue repair.

120
Q

About antimicrobial prescribing…

A

Antimicrobials are commonly started before lab results are available.

Empirical therapy “best guess”

121
Q

Why look at the distribution in the body relative to the distribution of bacteria?

A
  • some not absorbed from gut
    - many do not cross blood-brain barrier
    - some do not penetrate abscess
    - few accumulate inside cells
122
Q

What are the considerations in choosing an antibiotic?

A
Spectrum of activity - cidal or static
Toxicity
Excretion
Patient age  (renal capacity)
Route of administration (oral , i/v i/m,  topical)
Clinical condition
Type of bacteria
Sensitivity of bacteria  - mechanism of action of antibiotic
			- resistance mechanisms
Cost
123
Q

How can failure of antibiotic therapy occur from the drug?

A

inappropriate drug, improper route of administration - inadequate dose
poor tissue penetration - increased excretion

124
Q

How can failure of antibiotic therapy occur from the host?

A

immunocompromised host, retained infected body (catheter), poor circulation or damaged tissue (surgical scar), unusual site for a pathogen - undrained pus

125
Q

How can failure of antibiotic therapy occur from the bacteria?

A

natural or acquired resistance biofilms (ed endocarditis) - dual infections (not expected)

126
Q

How is antibiotic treatment is a social act?

A

One’s bacteria are not one’s own – shedding, spread, pools

Antibiotics treat populations and individuals.

Bacterial evolution drug resistance

127
Q

What are the paths to resistance?

A
  • Directed at antibiotic itself – degrading the drug, modifying the drug
  • Altered target – antibiotic no longer binds
  • Altered transport – actively pumping drug out – efflux pump porins no longer influx drug.
128
Q

What are the mechanisms of resistance?

A
  • Genetic mechanisms
  • Non-genetic mechanisms (growth phases)
  • Natural resistance
129
Q

What is natural resistance?

A

Natural resistance – as opposed to acquired
• Drug must reach target – natural barriers, porins, export pump
• G+ve peptidoglycan – highly porus – no barrier to diffusion
• G-ves outer membrane – barrier – resistant advantage

Porins – single mutation – multiple resistance

130
Q

What are the genetic mechanisms of resistance?

A
Chromosome mediated
Due to spontaneous mutation:
-	In the target molecule
-	In the drug uptake system
Mutant are SELECTED; they are NOT induced

Plasmid-mediated

  • Common in gram-negative rods
  • Transferred via conjugation
  • Multidrug resistance
131
Q

What is bacterial transformation?

A

Bacterial transformation is the process by which bacterial cells take up naked DNA molecules. If the foreign DNA has an origin of replication recognized by the host cell DNA polymerases, the bacteria will replicate the foreign DNA along with their own DNA.

132
Q

What is bacterial transduction?

A

Bacterial transduction is the process by which DNA is transferred from one bacterium to another by a virus. It also refers to the process whereby foreign DNA is introduced into another cell via a viral vector. Transduction does not require physical contact between the cell donating the DNA and the cell receiving the DNA (which occurs in conjugation), and it is DNase resistant (transformation is susceptible to DNase).

133
Q

What is bacterial conjugation?

A

Bacterial conjugation is the transfer of genetic material between bacterial cells by direct cell-to-cell contact or by a bridge-like connection between two cells.

134
Q

About resistance to beta-lactams…

A

Gram +ve

  • Beta-lactamase (penicillinase)
  • Alteration of the transpeptidase enzyme (PBP)

Gram –ve

  • Beta-lactamase (penicillinase)
  • Alteration of porins

Penicillinase destroys the active part of penicillin molecule.

135
Q

What is augmentin?

A

Clavulanic acid + amoxicillin

Binds to and inactivates beta-lactamases. No anti-bacterial activity of its own

136
Q

How does beta-lactam resistance occur in gram -ve bacteria?

A
  1. Porin mutates or new porin type multi-resistance
  2. PBP – mutates or bacteria acquires a new PBP
  3. Bacteria acquires a beta – lactamase enzyme
137
Q

Summary of genetic mechanisms of resistance…

A

¬ Production of drug-inactivating enzymes
¬ Modification of target structures
¬ Alteration of membrane permeability

138
Q

What is the non-genetic mechanism of resistance?

A
  • Inaccessibility to drugs (eg abscess, TB lesion)

* Stationary phase and biofilms (non-susceptible to inhibitors of cell wall synthesis)

139
Q

How can we prevent/overcome antibiotic resistance?

A
  • Control use: not in animal feeds, complete course (DOTS for TB), appropriate prescribing
  • New or modified drugs: few in past 25 years
  • Combination therapy: different targets, overcome mutation rates
  • Infection control: individual – ward – society

Re-establish susceptible flora?

140
Q

Summary of antibiotic resistance…

A

¬ resistance increasing with use
¬ clinical consequences or resistance are significant
¬ control measures identified… but will they be effective?
¬ Antibiotic stewardship personal and institutional level
¬ Specialist – medical microbiologist – local policies

141
Q

Why are there difficulties in developing a safe anti-viral agent?

A
  • Viruses use cellular receptors to get inside cells
  • Obligate intracellular parasites
  • Must replicate inside cells and take over host cell biochemistry
  • High mutation rate (quasispecies)
  • Latency common (herpes viruses)
  • Genetic integration (HIV, HBV)
142
Q

How to use anti-viral agents…

A
  • Choice is usually virus of virus-family specific
  • Can be used therapeutically or prophylactically
  • Safety profile
  • Expensive
  • Treatment of acute infection
  • Treatment of chronic infection:
  • Post-exposure prophylaxis and preventing infection:
  • Post-exposure prophylaxis and allowing infection
  • Pre-exposure prophylaxis
  • Prophylaxis for reactivated infection
  • MUST COMMENCE treatment early after diagnosis
  • e.g. aciclovir for chickenpox or oseltamivir for influenza
  • INCAPABLE of eradicating latent infection
  • RESISTANCE may develop if single agent is used during acute infection
  • RESISTANCE may also develop if long-term prophylaxis is used
  • CANNOT UNDO DAMAGE that has already occurred
143
Q

Why is aviclovir so effective and safe?

A

HSV thymidine kinase (TK) has 100x the affinity for ACV compared with cellular phosphokinases.

Aciclovir triphosphate has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase.

Aciclovir 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.

144
Q

When is aciclovir used?

A

Herpes simplex
• Treatment of encephalitis
• Treatment of genital infection
• Suppressive therapy for recurrent genital herpes

Varicella zoster virus
• Treatment of chicken pox
• Treatment of shingles
• Prophylaxis of chicken pox

CMV
• Prophylaxis only

145
Q

When is ganciclovir used?

A

CMV
• Treatment of reactivated infection in organ transplant recipients
• Treatment of congenital infection in newborn
• Prophylaxis in organ transplant recipients – mismatch

146
Q

About valaciclovir and valganciclovir…

A
  • Prodrug – valine ester of aciclovir
  • Used to treat varicella-zoster infections in the immune compromised or for anti-CMV prophylaxis in transplant patients
  • Better bioavailability
  • Prodrug – also an ester of ganciclovir
  • Used for treatment and prophylaxis of CMV infection
147
Q

What is foscarnet?

A

Used for CMV infection in the immunocompromised eg pneumonia in solid organ and bone marrow transplants. May be used because of granciclovir resistance or toxicity profile.
• Renal toxicity – so usually not used for renal transplant patients with CMV reactivation unless resistance to ganciclovir

148
Q

What is cidofloxir?

A

drug active against CMV, but much more nephrotic

149
Q

How does resistance to antivirals in herpes viruses come about?

A
  • Two main mechanisms
  • Thymidine kinase mutants
  • DNA polymerase mutants
  • If occurs in TK, drugs not needing phosphorylation are still effective (eg foscarnet, cidofovir)
  • If occurs in DNA polymerase, all drugs rendered less effective
  • VERY RARE in immune competent patients
150
Q

What is amantadine?

A

• Inhibit virus by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin – now rarely used

151
Q

What is zanamivir and oseltamivir?

A

• Inhibits virus release from infected cells via inhibition of neuraminidase – oseltamivir; oral, zanamivir; inhaled or IV – less likely for resistance to develop

152
Q

About neuraminidase inhibitors and their effectiveness?

A

Anti-influenza drugs

¥ Trials show marginal overall benefit e.g. 1-day reduction in symptom duration
¥ Treatment needs to be commenced early
Ð BUT, only 25% of patients are able to get to their GP within 36 hours of symptom onset
Ð Should be used for “at risk” groups
¥ Very useful in post-exposure prophylaxis or in the flu season
¥ Resistance rare – more likely in immunocompromised patients

153
Q

About influenza’s resistance to antivirals…

A
  • Resistance sometimes only requires a single amino acid change – seen recently with swine flu (H1N1) and Tamiflu (oseltamivir).
  • Point mutation (H275Y; tyrosine replacing histidine).
  • Seen in immunocompromised patients; shed virus for weeks/months.
  • Likely to be selected for among quasispecies on Rx.
  • Transmissible and virulent.
  • Remains sensitive to zanamivir; probably because of low levels of exposure.
154
Q

What is the treatment of hep B?

A
  • Hepatitis B: Pegylated interferon alfa
  • Specific anti-virals: lamivudine, tenofovir, entecavir, adefovir – used single or in combination
  • Complicated especially if co-infection (see NICE guidance)
155
Q

What is the treatment of hep c?

A
  • HCV is curable in some
  • Response influenced by viral genotype and host genotype
  • Treatment with pegylated interferon and ribavirin, but…
  • Rapidly advancing field with specific antivirals eg telaprevir and broceprevir and others…
  • Possible interferon free treatments
156
Q

What is the process of HIV infection?

A
  • The first step of infection is the binding of gp120 to the CD4 receptor and CCR5 co-receptor, which is followed by penetration and uncoating
  • The RNA genome is then reverse transcribed into a DNA provirus which is integrated into the cell genome
  • This is followed by the synthesis and maturation of virus progeny
  • Opportunities for antivirals
157
Q

What are examples of anti-retrovirals?

A
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Nucleotide reverse transcriptase inhibitors (NtRTI)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • CCR5 inhbitors
  • Integrase inhibitors
158
Q

What is anti-HIV therapy?

A

Complicated

  • Rapidly evolving field with new drug development
  • Needs specialist approach as many side effects and interactions

Combination approach – reduces the risk of drug resistance.

Multiple viral enzyme targets (reverse transcriptase, protease, integrase, viral receptor binding proteins).

Adherence to treatment is ESSENTIAL.

Use 3,4 and sometimes 5 drugs

  • May be combined in one pill
  • Once a day tablets best

Early treatment?

159
Q

About HIV anti-viral resistance?

A
  • Develops quickly and irreversibly on monotherapy eg AZT, nnRTIs
  • Transmitted resistance c. 1-2%
  • Multiple resistant virus c. 1%
  • Selection pressure and mutation frequency
  • Increased mutation rates seen in HIV (and HCV)
  • The viruses form a quasispecies (A ‘molecular swarm’ of related sequences clustered around a master sequence)
  • The error rate in copying an RNA viral genome is 1 base pair per 104-5 incorporations (error rate is 10,000 fold higher than DNA polymerase enzymes). Why? No proof reading capacity.
  • HIV, with 109-10 viruses produced every day, ALL possible viral variants would be produced
  • Capable of adapting very quickly to changes in the environment; their genome size is smaller than DNA viruses
  • Loss of fitness?