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Pharmacology 3 > Week 9 > Flashcards

Week 9 Flashcards

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1
Q

Describe the following details of Histamine as an Inflammatory mediator:
a) What sort of compound it is
b) Where it is stored (what cells)
c) Its complement inflammatory components
d) Receptors it interacts with

A

a) Basic amine
b) Stored in granules within mast cells and basophils, bound to heparin / heparin-like molecules
c) Stimulated by complement components C3a and C5a
d) Interacts with H1, H2 and H3 receptors

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2
Q

What are the main actions of Histamine in humans? (5 of em)

A
  • Stimulates gastric acid secretion
  • Contract smooth muscle
  • Cardiac stimulation
  • Vasodilation
  • Increased Vascular Permeability
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3
Q

Describe the simplified process of histamine release starting with detection of antigens.

A

1) Antigen present in environment
2) Mast cell of Basophil with IgE on the surface detects antigen
3) Histamine released from granules
4) Histamine interacts with H receptors

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4
Q

What are Eicosanoids?

A

20 carbon fatty acid chains from which prostaglandins and leukotrienes are formed

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5
Q

Prostaglandins are long chain fatty acid inflammatory mediators. a) How are they synthesised from arachidonic acid (AA)
b) What are their actions

A

a) COX enzymes metabolise AA to form a variety of PGs (PGE2, PGD2, PGI2)
b)
- Vasodilation
- Platelet aggregation
- Smooth muscle effects
- Modulation of inflammatory effects

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6
Q

PGE2 acts on 4 classes of EP receptor. What is the action of each receptor?

A
  • EP1 - contraction of bronchial and GI tract smooth muscle
  • EP2 - relaxation of smooth muscle
  • EP3 - Inhibit gastric acid secretion, increase gastric mucus secretion, contracts smooth muscle
  • EP4 - Many inflammatory responses
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7
Q

How do non-steroidal anti-inflammatory drugs work?

A

By inhibiting COX, and therefore interfering with arachidonic acid metabolism into PGs etc

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8
Q

What are some examples of NSAIDs

A

Aspirin
Ibuprofen
Naproxen

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9
Q

What are the main effects of NSAIDs (3) and how do they do each? (Hint = all of the effets are due to a decrease in PG production)

A
  • Anti-inflammatory effect: Decrease in vasodilator PGs
  • Analgesic effects: Decrease PG generation = less sensitisation of nociceptive nerve endings to inflammatory mediators (5HT and BK)
  • Antipyretic effects: Decrease PGs (that are made in response to IL-1) that are responsible for elevating hypothalamic set point for temp control (fever)
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10
Q

Aspirin is known to produce many side-effects that are now being better dealt with with newer selective COX-2 inhibitors.
Describe the mechanism behind
a) GI disturbances
b) Increased bleeding

A

a) COX-1 inhibition –> decrease in PGE2 —> reduced GI mucus secretion –> ulcers

b) Inhibition of thromboxane synthesis which interferes with platelet aggregation. Results in increased bleeding

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11
Q

The adrenal cortex releases 2 main classes of steroid. What are they?

A
  • Glucocorticoids
  • Mineralocorticoids
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12
Q

How do corticosteroids work?

A
  • Inhibit formation of inflammatory mediators by acting on the DNA (nuclear action)
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13
Q

How to glucocorticoids work?

A
  • Regulate the release of corticotropin releasing hormone (CRH) in the hypothalamus
  • CRH releases adrenocorticotropic hormone (ACTH)
  • ACTH leads to cortisol production in the adrenal zone fasciculata
  • Cortisol can then exert many effects through receptor activation
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14
Q

The main effect of glucocorticoids is to supress the inflammatory response.

How does it do this?

(Hint1 - blood)

A
  • Inhibit inflammatory cell filtration into the airways and reduce oedema formation by acting on the vascular endothelium.
  • Induce the synthesis of mediators with anti-inflammatory potential (e.g., lipocortin 1, an IL-1 receptor antagonist)
  • Inhibit synthesis of many pro-inflammatory mediators by preventing the action of key transcription factors (AP-1, NF-kB)
  • Can resolve established inflammatory responses (induce apoptosis of lymphocytes)
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15
Q

There are 3 key mechanisms of how glucocorticoids work, what are they?

A
  • Trans-activation: Anti-inflammatory
  • Cis-Repression: Side effects
  • Trans-repression: Decrease in inflammatory mediators
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16
Q

How do the following processes work?

a) Trans-activation
b) Cis-repression
c) Trans-repression

A

a) - Glucocorticoid receptor (GR) homodimers bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory proteins

b) - Less commonly, GR homodimers can interact with negative GREs to supress genes (usually to do with supressing side effects)

c) - Nuclear GRs also react with coactivator molecules such as CBP which can be activated by proinflammatory T.Fs, thus switching off the inflammatory genes that are activated by these T.Fs

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17
Q

Where does NFkB fit into the glucocorticoid mechanism?

A
  • Glucocorticoids suppress activated inflammatory genes
  • This is done through interactions with NFkB
  • NFkB is usually inhibited by inflammatory stimuli
  • Glucocorticoids prevent this inhibition
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18
Q

TNF is an inflammatory mediator that activates inflammatory cells. What are some drugs that can bind TNF to prevent its action?

A
  • Infliximab
  • Adalimumab
  • Etanercept
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19
Q

What is the equation for blood pressure?

A

BP = Cardiac Output x Peripheral (systemic) vascular resistance

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20
Q

What is peripheral vascular resistance?

A
  • The main contributor to afterload
  • Determined by the dilation of the artery/arterioles (the tone)
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21
Q

What is afterload?

A

The force against which the heart has to pump

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22
Q

What are the bodily systems that control blood pressure?

A

Autonomic nervous system
- Mainly sympathetic
- a1 adrenoreceptor

Circulating hormones
- Vasopressin
- Angiotensin II
- Adrenaline

Local control
- Endothelium derived factors (NO)

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23
Q

What is preload?

A
  • The initial stretching or tension on the cardiac muscle fibres just before contraction
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24
Q

Stroke volume is the amount of blood pumped out the heart per beat. What does stoke volume consist of?

Study These Flashcards
A

Venous Return
Cardiac contractility

25
What determines venous return (amount of blood entering the ventricle during diastole)?
- blood volume (SymNS decreases Na+ and water retention leading to increased BV) - venous tone (SymNS decreases capacitance) Both affect preload
26
What is the frank-starling mechanism?
That the strength of contraction of the heart is directly proportional to the length of muscle fibres right before contraction
27
How does the vascular endothelium regulate vascular tone?
- NO is produced by the endothelial cells and works in the smooth muscle cells to cause relaxation - Inhibition of the NO synthase pathways lead to vasoconstriction and an increase in blood pressure
28
Important How does the NO pathway work in the vascular endothelium to influence smooth muscle? Think what does NO activate, and what does that go on to do?
- L-arginine ---[NO synthase]---> NO - NO activates guanylate cyclase - GTP --[guanylate cyclase]--> cGMP---> PKG---> REDUCED Ca2+- --> muscle relaxation
29
How is the NO synthase pathway influenced in the treatment of angina?
- Extra NO is inserted in the system - Causes more smooth muscle relaxation
30
How does Viagra work?
- Inhibits PGE5 that breaks down cGMP - Leads to increased cGMP in cells - Results in decreased Ca2+ - Smooth muscle relaxation - Vasodilation
31
Heart rate is regulated by both the parasympathetic and the sympathetic nervous system. What specific receptors mediated this control?
Sympathetic: beta-1 adrenoreceptors (increase HR) Parasympathetic: M2 receptors (decrease HR)
32
Physiological control of blood pressure is governed by many different system, not just the localised NO pathway. What are other mechanisms?
- Kidneys - Autonomic control - Baroreceptor
33
The kidneys play a big role in long-term BP control. BP is detected in specialised juxtaglomerular cells in the kidneys. When low pressure is detected, Renin is secreted. Explain the Renin-Angiotensin-Aldosterone pathway
- Renin is secreted - Renin converts Angiotensinogen to Angiotensin I. - An enzyme in endothelial cells (angiotensin-converting enzyme (ACE)) then converts angiotensin I to angiotensin II - Angiotensin II increases PVR and after-load - Angiotensin II also causes the adrenal cortex to produce aldosterone, which leads to an increase in blood volume through Na+ manipulation. So also increases pre-load!!
34
How is BP influenced by autonomic control? Think sympathetic and parasympathetic!
- Sympathetic nerves (beta-1) increase HR, conduction and contractility - Parasympathetic nerves (M2) reduce HR and contractility - Arterioles (alpha-1) increase afterload - Veins increase preload - Heart sympathetic (beta-1) leads to renin secretion
35
What is the baroreceptor reflex?
- Baroreceptors monitor blood pressure in the brain - Receptors in the carotid artery and aortic arc detect change in BP - Acts through sympathetic NS to increase HR and preload and afterload
36
What are the 3 types of anti-hypertensive drugs? How do they work? Give an EXAMPLE of each!
Diuretics: - Increase Na+ and water loss, therefore reduce blood volume and PRELOAD. Some also have effects on arteriolar tone so reduce afterload too - Example: Chlorothiazide Beta-adrenoreceptor antagonists - Reduce cardiac output and reduce renin secretion from the kidney (decreasing preload and afterload) - Example: Propranolol Calcium-channel blockers - Block L-type voltage gated Ca2+ channels, decrease Ca2+ entry and reduce muscle contraction - Example: Verapamil
37
Drugs have also been developed that target the RAAS. What are 3 ways of doing this? WITH EXAMPLES
- ACE inhibitors, decrease pre- and afterload. Example: Enalapril - Angiotensin receptor antagonists. Example: Losartan - Renin inhibitors
38
What are sympatholytic drugs? With some examples?
Drugs that inhibit the release of NA or block its effects at receptors Examples: Ganglion blockers (methyldopa), adrenergic neuron blockers (guanethidine), reserpine.
39
Changes in endothelial function precede endothelial dysfunction that leads to atherosclerosis etc. What are some of these changes?
- Elevated and modified LDL in hypercholesterolaemia - Oxygen free radical caused by smoking, hypertension, activated inflammatory cells - Infectious microorganisms - Physical damage and gene activation by turbulent flow, high blood pressure
40
What are foam cells?
Macrophages that take up LDLs oxidised by interaction with oxygen free radicals
41
Once the endothelium is damaged, the lesion can advance to a complex lesion. What constitutes an advanced complex lesion?
- Fibrous cap: healing response to injury - Smooth muscle cell proliferation - Leukocytes, lipid and cell debris from apoptosis, necrosis and proteolysis
42
If the fibrous cap of the complex lesion is stable, or unstable, results in two different conditions, what are they?
Stable cap = Angina Unstable cap = Myocardial infarction
43
Statins are drugs used to reduce lipid levels in the blood to prevent cardiovascular disease. What is the mechanism of Statins? What are some example drugs? Any side effects?
- Statins are HMG-CoA reductase inhibitors - Inhibit the pathway: HMGCoA---[HMG CoA reductase]--> Mevalonate ---> Cholesterol ---> LDL---> LDL receptors - (Pleiotropic effects) Not only decreases LDLs but Mevalonate is involved in intracellular signal transduction and there is more of it around when statins are used - Leads to improved endothelial function and plaque stabilisation - Examples: Lovastatin, Simvastatin Side effects: - Muscle pain - Increased risk of diabetes - Liver damage
44
Another form of antihypertensive drugs are Fibrates. What do they do? What is a drug
- Decrease circulating LDL and triglyceride - Increase HDL - Increase expression of genes associated with lipid clearance - Gemfibrozil
45
What does the drug Ezetimibe do?
- Inhibits cholesterol absorption - By blocking transport of cholesterol - Added to statins where response is inadequate
46
What is the mechanism behind haemostasis (blood clotting)
- Damage allows bleeding and exposes platelets to collagen in the vessel wall - Activated platelets undergo morphological changes - GPIIb/IIIa receptors cover the surface of the platelet which attaches to fibrin strands that link many platelets together - Platelets then aggregate to prevent blood loss - Fibrin is formed by the coagulation cascade to stabilize the platelet plug
47
Describe the rough pathway of platelet aggregation
- Stimulus e.g., collagen, thrombin - Arachidonic acid - COX - Cyclic endoperoxidases - Thromboxane A2 - TxA2 receptor - Platelet activation - Platelet degranulation
48
What is degranulation
- When platelets adhere to damaged vascular endothelium, they become activated - Activated platelets release the contents of their granules (degranulation) - Alpha granules contain clotting factors such as fibrinogen and PDGF - Dense granules contain ADP and serotonin. ADP activates more platelets, serotonin is a vasoconstrictor
49
How do COX inhibitors reduce platelet activation?
Inhibit the production of cyclic endoperoxidases from arachidonic acid
50
Outline the role of the P2Y12 receptor in blood clotting and name an inhibitor of this receptor. Considering this, what type of drug is commonly used as an anti-thrombotic?
- ADP (released from dense granules of platelets) binds to P2Y12 receptors - This plays a significant role in amplification of platelet aggregation through: - Activation of integrins - Further thromboxane A2 production (potent platelet aggregator) - P2Y12 receptor ANTAGONISTS (such as clopidogrel) irreversibly block the P2Y12 receptor
51
What is a common problem with 1st generation anti-thrombotic drugs
As platelets have no nucleus, platelet activation cannot be overcome until new platelets are made (3-5days)
52
How are 2nd generation P2Y12 receptor antagonists such as cangrelor better than 1st gen ones?
They are reversible. Act through non-covalent binding, no need for new platelets
53
The coagulation cascade involves the activation of a series of clotting factors, which are proteins that are involved in blood clotting. Each clotting factor is a serine protease, an enzyme, an enzyme that speeds up the breakdown/ACTIVATION of another protein. Anyway a series of these clotting factors eventually lead to what? (beginning with prothrombin)
- Prothrombin --[Xa]--> thrombin. - Fibrinogen ---[Thrombin]---> Fibrin - Fibrin---[XIIIa]--> Stabilised fibrin
54
What does anti-thrombin III do?
It is an enzyme secreted from the vascular endothelium and functions to BLOCK the clotting cascade!
55
What is the role of Heparin in blood clotting
Heparin is the main activator of ATIII. When heparin is present, you don't have coagulation.
56
Describe the function of heparin as an anticoagulant
- Activator of ATIII - Accelerates neutralisation of serine proteases - Not orally active
57
What is the mechanism of Warfarin
- Oral anticoagulant - inhibits vitamin K epoxide reductase - By interfering with the synthesis of various clotting factors, warfarin prolongs the time it takes for blood to clot. - Used to treat DVT, pulmonary embolism etc - Challenging to maintain but not toxic concentration
58
What are Factor Xa inhibitors and Thrombin inhibitors?
Newer alternative anti-coagulants - Both orally active - bleeding risk

Pharmacology 3 (7 decks)

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