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PHAR2005 > Pharmacology of inflammation > Flashcards

Pharmacology of inflammation Flashcards

1
Q

What are the three main types of inflammations ?

A

Acute
Chronic
Contributory

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2
Q

What did John Hunter say about inflammation ?

A

“Inflammation is a salutary process”

Treatise on the blood, Inflammation and Gun-shot Wounds. (1794)

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3
Q

What is the purpose of inflammation ?

A

Kill
Dilute
Wall-off
Prepare

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4
Q

What kind of dysfunctional inflammations exist ?

A

Primary immunodeficiency

Acquired immunodeficiency

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5
Q

What are the 5 principal symptoms of inflammation ?

What are these symptoms due to (inflammatory mediators) ?

A 
Heat (calor) + Redness (rubor) --> increased blood flow
- Histamine
- 5-HT
- Platelet Activating Factor (PAF)
- NO
- Bradykinin
- PGE2
- PGI2
Swelling (tumor) --> Increased vascular permeability + cellular infiltration 
- Histamine
- Anaphylatoxins  C3a C5a
- LTB4
- TNF-alpha + IL-1
- PGE2
- IL-8
- VEGF
- PAF
- Bradykinin
Pain (dolor)
- SP
- CGRP
- Bradykinin
Loss of Function (functio laesa)
- Lipases
- Proteases
- Free radicals
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6
Q

What is the Lewis triple response ?

A

The triple response of Lewis is a cutaneous response that occurs from firm stroking of the skin, which produces an initial red line, followed by a flare around that line, and then finally a wheal. The triple response of Lewis is due to the release of histamine.

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7
Q

What is the precursor of histamine ?

A

Histidine (converted to histamine by histidine decarboxylase)

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8
Q

Where is histamine found ?

A

Mast cells (found in complex with acidic protein & heparin (1:6:3))
Basophils (blood)
Histaminergic Neurons

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9
Q

In response to which molecules is histamine released ? - inhibited ?

A 
Stimulate histamine release :
- IgE
- C5a, C3a
- Substance P, VIP
- Tubocurarine
- Morphine
Inhibit histamine release : 
- cAMP
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10
Q

How is histamine metabolized ?

A

Metabolism
Oxidation : Diamine oxidase
N-Methylation : N-methyltransferase
Acetylation : Gut flora

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11
Q

How many histamine receptors do we know ?

A 
Four histamine receptors : 
H1 --> Gq 	
Increases in Ca2+
- ileum contraction
- modulate circadian cycle
- itching
- systemic vasodilatation
- bronchoconstriction (allergy-induced asthma)
H2 --> Gs
↑ cAMP2+ 	
- Speed up sinus rhythm
- Stimulation of gastric acid secretion
- Smooth muscle relaxation
- Inhibit antibody synthesis, T-cell proliferation and cytokine production
H3 --> Gi 	
Inhibition of cAMP
- Decrease Acetylcholine, Serotonin and Norepinephrine 
- Neurotransmitter release in CNS
- Presynaptic autoreceptors
H4 --> Gi 	
Increases in Ca2+
- Mediate mast cell chemotaxis
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12
Q

Name 2 first generation H1 antagonists you know.

A

Diphenhydramine

Chlorpheniramine

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13
Q

Name 4 second generation H1 antagonists you know.

A

Loratadine
Fexofenadine
Cetirizine
Terfenadine

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14
Q

Name 2 H2 antagonists you know.

A

Cimetidine

Ranitidine

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15
Q

What effects does histamine have on :

  • smooth muscle
  • endothelial cells
  • glands
  • heart
  • C-fibers
A 
Smooth muscle :
- contraction (H1) EXCEPT in arteries and arterioles (relaxation
Endothelial  :
- increased permeability (H1)
Glands :
- stimulates gastric secretion (H2) & adrenal medulla, pancreas,salivary, lacrymal and bronchial gland secretion (H1)
Heart :
- Positive chronotropic H2
- Positive inotropic H2+ H1
- Induction of arrhythmia's
C fibers : 
- stimulation (H1) --> pain
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16
Q

Can histamine act as a NT ?

A

Histaminergic neurons.

  • Involved in vasopressin release
  • Emesis, consciousness & temperature regulation.
  • Presynaptic histamine receptors (H1)
17
Q

How do antihistamines work ?

A

Antihistamines work by preventing the histamine affects via H1 receptors main affect is on vascular permeability.

18
Q

In what cases are antihistamines used ?

A

Insect bites
Allergic rhinitis
Drug hypersensitivity
Urticaria

19
Q

What are the side effects of antihistamines ?

What about the newer antihistamines ?

A
  • Side effect associated with these drugs is usually due to other receptor interactions and may be clinically beneficial i.e. sedative & anti-emetic
  • Some drugs cross CNS therefor cause such as dizziness, tinnitus & fatigue
  • Older drugs also have atropine- like actions (muscarine antagonists)
  • Newer H1 antihistamines do not cross CNS e.g. astemizole, terfenadine, cetirizine
20
Q

What are the 2 bradykinin receptors ?

A 
B1 (353)
- GPCR (Gaq/Gai)
- Induced, via cytokines, LPS
- G protein-linked receptor
- Not internalised, thus resistant todesensitization
- Agonist des-Arg10 kallidin;
- des-Arg 9 bradykinin (DABK)
- Antagonist des-Arg HOE140
B2 (391)
- GPCR (Gaq/Gai) (PLC, PLA2)
- Constitutive
- Acts through release of other mediators
- Nitric oxide and prostaglandins
- Quickly desensitised throughinternalisation
- Agonist bradykinin, kallidin
- Antagonist HOE140 (icatibant)
21
Q

Where are the 2 bradykinin B1 and B2 receptors expressed ?

A 
Endothelial cells
Vascular smooth muscle
Fibroblast
Epithelial
Sensory Nerves
Leukocytes (limited research)
22
Q

How can B1 receptors be up-regulated ?

A
  • LPS treatment of smooth muscle preparations
  • Kinins can cause contraction.
  • IL-1, IL-2 LPS EGF, TNFa, oncostatin M
    NFkB signalling
23
Q

What are anaphylatoxins ?

How are the inactivated ?

A

Anaphylatoxins, or complement peptides, are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system. They cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability.
They are inactivated/cleaved by carboxypeptidase N, B and R.

24
Q

How are prostoglandins synthesized ?

A

Prostaglandin E synthase (PGES) produced by most cells
Cytosolic PGES constitutive production
Membrane PGES induced with inflammatory mediators

25
Q

What are the prostoglandin receptors ?

What effects do these receptors mediate ?

A

EP1 : Contraction of bronchial & gastrointestinal muscle smooth muscle, Pain
EP2 : Bronchodilatation, vasodilatation, stimulation of intestinal fluid secretion & relaxation of GI smooth muscle
EP3 : Contraction of intestinal smooth muscle, inhibition of gastric acid secretion, increase gastric mucus secretion, inhibition of lipolysis, Inhibition of autonomic
neurotransmitter
EP4 : Contraction of bronchial & vasodilation, leukocyte supression

26
Q 
How do prostoglandins cause :
- fever ?
- pain ?
- oedema ?
What effects does PGE2 have on leukocytes ?
A

Fever : PGE2 causes an increase in body temperature via hypothalamus
Pain : PGE2 induces hyperalgesia working both at the peripheral terminals ofprimary afferent nociceptors and in the spine
Oedema : PGE2 is a powerful vasodilator and synergises with other mediators. It does not directly induce vascular permeability but potentates the action of other inflammatory mediators.
Leukocytes : PGE2 inhibits the actions of many leukocytes

27
Q

How is PGD2 synthesized ?

What effects does it have ?

A

Prostaglandin D2 (PGD2)
DP-receptors : Vasodilatation, inhibit platelet aggregation, relaxation GI muscle & uterine
TP-receptors : Bronchoconstrictor
Prostaglandin D synthase found predominantly in Mast cells also brain
CRTH 2 : Chemoattractant for Th2 cells

28
Q

Where does PGF2-alpha have ?

What effects does it have ?

A

FP-receptors : Smooth muscle contraction, bronchoconstriction, reproductive physiology

29
Q

Where are PGI2 and Thromboxane A2 synthesized ?

What effect do they have >

A

PGI2
IP-receptors : Vasodilatation, Inhibit platelet aggregation, renin release
Prostaglandin I synthase found predominantly in vascular endothelium
TXA2
TP-receptors : Vasoconstriction, platelet aggregation
Thromboxane A synthase found predominantly in platelets

30
Q

How do NSAIDs act ?

WHat are the side effects of the old Vs newer NSAIDs ?

A 
Inhibition of COX enzymes.
Non-specific COX inhibitors : old NSAIDs, serious side-effects : 
- Inhibit gastric acid
- Contract the uterus
- Increase renal blood flow
COX-1 specific inhibitors : newer NSAIDs, more efficient and selective :
- Anti- Pyretic
- Anti-inflammatory
- Anaalgesic
31
Q

What are the COX enzymes ?

A

The enzymes that produce prostaglandins are called cyclooxygenase (COX). There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.

32
Q

Name a few glucocorticoid-suppressed proteins with potential pro-inflammatory activity.

A 
Chemokine receptors CCR1 and CCR2
Complement components C1q, C3 and C5
Complement receptors C3aR1, CR2 and C5aR1
IL-1 receptor-I
IL-8 receptor
Interferon-γ receptor I
Interferon-γ receptor II
Macrophage migration inhibitory factor
Matrix metalloproteinases 7, 10, 16 and 19
Thrombospondins 1, 2 and 4
Tumour necrosis factor receptor family members
(including GITR)
Toll-like receptors 2 and 4
COX-2
IL-2
33
Q

Name a few glucocorticoid-induced proteins with potential anti-inflammatory activity.

A 
Anx-A1
β2-adrenergic receptor
Clara cell protein
GILZ
HbSR CD163
IkB
IL-10
IL-10 receptor
IL-1 receptor-2 (IL-1 decoy receptor)
MPK-1
Transforming growth factor-β3
34
Q

What is the overall effect of GCs ?

A

Decreased migration of neutrophils
Decreased activation of neutrophils and macrophages
Decreased activation of T-lymphocytes and clonal expansion
Decreased fibroblast activation, matrix deposition
Decreased osteoblast activation.

35
Q

Name 5 SAIDs.

State their duration of action.

A 
Short : 
- cortisol
Intermediate : 
- prednisolone 
- prednisone
Long : 
- dexamethasone
- betamethasone
36
Q

What are cytokines and chemokines ?

A

Cytokines are simple polypeptides or glycoproteins
with a molecular weight <30kD
Constitutive production cytokines is uncommon:
production regulated by including stimuli at the level
of transcription and translation
Cytokine production is transient and the action radius
is usually short
Cytokines act by binding to high-affinity cell-surface
receptors Kd=1E-9 - 1E-12M
Most cytokine actions are attributed to altered gene
expression in the target cells

37
Q

What are the effects of TNF-alpha ?

A
  • Induces fever
  • Stimulates acute phase protein release
  • Cytotoxic/cytostatic for cells
  • Activates granulocytes and macrophages
  • Promotes bone reabsorption by osteoclasts
  • Inhibits collagen synthesis and promotes breakdown
  • Induces cytokine synthesis
  • Promotes fibroblast proliferation
  • Activates endothelial cells
  • Promotes angiogenesis
38
Q

What treatment has is being developed that targets TNF-alpha ?

A

Anti-TNA-alpha antibodies.

PHAR2005 (24 decks)

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