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Medicine year 2 semester 2 > Case 20- Pharmacology > Flashcards

Case 20- Pharmacology Flashcards

1
Q

What lipoproteins is atherosclerosis associated with

A

Atherosclerosis is strongly associated with elevated concentrations of low density lipoproteins, Triglycerides and decreased levels of high density lipoproteins. Anti-hyperlipidaemic drugs prevent the onset of atherosclerosis.

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2
Q

Types of Lipoproteins

A

HDL, LDL, VLDL

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3
Q

Ezetimibe

A

Prevents cholesterol absorption by inhibiting the transport of cholesterol into the blood

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4
Q

Fibrates

A

Enhances the activity of lipoprotein lipase and reduce secretions of VLDL from the liver

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5
Q

Resins

A

Binds to bile acids, reducing its reabsorption. By preventing the recycling of bile acids, this diverts hepatic cholesterol to synthesis of new bile acids, reducing the amount of cholesterol

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6
Q

Statins

A

Inhibits the enzyme HMG CoA reductase which synthesises cholesterol in the liver. Statins, resins and fibrates increase LDL uptake in the liver

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7
Q

The 5 main classes of drugs used to treat hyperlipidaemia

A
  1. HMG-CoA reductase inhibitors (statins)
  2. Fibrates
  3. Cholesterol absorption inhibitors- Ezetimibe, Bile-acid binding resins
  4. Nicotinic acid
  5. Omega fatty acids
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8
Q

Examples of HMG-CoA reductase inhibitors (Statins)

A

Simvastatin, Lovastatin, Atorvastin (long lasting)

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9
Q

HMG-CoA reductase inhibitors (Statins)

A

Short acting statins are more effective at bedtime to reduce peak cholesterol synthesis in the early morning. Simvastatin and lovastatin are inactive prodrugs. It undergoes extensive first pass effect via CYP3A4 and glucuronidation pathways except rosuvastatin. Drug interactions can happen when other drugs are metabolised in this pathway.

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10
Q

The QRISK score needed to start treatment

A

10%

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11
Q

Statins MoA

A
  • Inhibits the enzyme HMG CoA reductase in cholesterol synthesis- only contributes a small amount but the liver then compensates by increasing the number of high affinity LDL receptors which clear LDL and VLDL from the blood
  • Upregulates LDL receptor synthesis, LDL is cleared from plasma into liver cells and there is decreased hepatic cholesterol synthesis. Reduces LDL and TG, increases HDL
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12
Q

Clinical use and side effects of Statins

A

• Primary Hyperlipidaemia
• Secondary Hypercholesterolaemia i.e. raises HDL by 20%
• Secondary prevention of MI and stroke in patients with atherosclerosis
Side effects= Headaches and myalgia, Nausea and insomnia, rise in serum transaminase, rashes and angioedema. Contraindicated in pregnancy as teratogenic

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13
Q

Fibrates examples and Pharmacokinetics

A 
Examples= Gemfibrozil, Fenofibrate, Bezafibrate
Pharmacokinetics=  high degree of protein binding to albumin. Metabolised by CYP3A4, potential for drug interactions, primarily excreted by the kidneys.
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14
Q

Fibrates

A

Agonists at PPAR-alpha nuclear receptor which regulates lipid metabolism
• Reduces TG and VLDL by increasing synthesis of lipoprotein lipase by adipose tissue and stimulating fatty acid oxidation in the liver
• Increases expression of apoA-I and apoA-II which increases HDL
• Increases hepatic LDL uptake
• Decreases VLDL, TG and LDL. Increases HDL

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15
Q

Fibrates- Clinical use and side effects

A

• Hypertriglyceridemia
• Mixed hyperlipidaemia- raised TG and cholesterol
Side effects= Nausea, Skin rashes (Gemfibrozil), Decreased WBC, Increased risk of gallstone (Clofibrate), Myopathy/Rhabdomyolysis (with statins)

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16
Q

Cholesterol absorption inhibitors

A

1) Ezetimibe

2) Bile acid-binding: Colestipol, Cholestyramine

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17
Q

Ezetimibe MoA and Pharmacokinetics

A

MoA= inhibits intestinal absorption of cholesterol by interfering with the NPCILI transport protein. Reduces enterohepatic recycling of cholesterol. Doesn’t affect TG or bile acids. Mainly reduces LDL and VLDL
Pharmacokinetics- Administered orally and absorbed into intestinal epithelial cells. It is extensively metabolised into an active metabolite. Enterohepatic recycling slows elimination

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18
Q

Ezetimibe clinical use and side effects

A

Clinical use- treatment of hyperlipidaemia in combination with statins
Side effects= Diarrhoea, abdominal pain, headache, rash and angioedema. Secreted in breast milk contraindicated in breast feeding

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19
Q

Bile acid-binding resins: Colestipol, Cholestyramine MoA and Pharmacokinetics

A

MoA= binds to bile acids in the gut, preventing reabsorption, diverting hepatic cholesterol to Bile acid synthesis reducing cholesterol levels in the liver, upregulates LDL receptors increasing LDL removal from the blood.
Less effective then Ezetimibe, often second choice
Pharmacokinetics= administered by mouth, not absorbed systemically, stays in the GIT

20
Q

Bile acid-binding resins: Colestipol, Cholestyramine clinical use and adverse effects

A

Clinical use= primary hypercholesterolemia when statins are contraindicated, pruritis in patients with partial biliary obstruction
Adverse effects= constipation, bloating, malabsorption of vitamin K, ascorbic acid. Interferes with absorption of certain drugs like warfarin

21
Q

Nicotinic drugs- Niacin MoA

A
  1. Reduces VLDL synthesis in the liver- reduces VLDL and LDL
  2. In adipose tissue it activates a signalling pathway that reduces hormone sensitive lipase activity- reduces TG
  3. Reduces catabolic rate for HDL- increases HDL
  4. Increases clearance of VLDL by activating lipoprotein lipase- reduces TG
  5. Causes decreased LDL, VLDL, TG and increased HDL
22
Q

Nicotinic drugs- Niacin Pharmacokinetics and clinical use

A

Pharmacokinetics- readily absorbed by GIT following oral administration, metabolised in the liver and excreted in the kidneys
Clinical use- adjunct of statins, used in Hypercholesterolemia, Hypertriglyceridemia with low levels of HDL

23
Q

Adverse effects of Nicotinic drugs- Niacin

A

Cutaneous flushing which is associated with pruritis and palpitations and is reduced with treatments of aspirin and other NSAIDs. Dose-dependent nausea and abdominal discomfort. There is moderate elevation of liver enzymes to severe hepatotoxicity. Can cause gout

24
Q

Omega 3 fatty acids (fish oil)

A

MoA= reduces plasma TG concentrations but increases LDL by an unknown mechanism
Other effects- inhibits platelet function causing prolongation of bleeding time and reduction of plasma fibrinogen. Has anti-inflammatory effects
Pharmacokinetics= oral absorption and bioavailability of these PUFA is a complex processes which is influenced by age, fat content of the meal, position of the fatty acids etc.

25
Q

Omega 3 fatty acids (fish oil) Pharmacokinetics, Clinical use, Adverse effects

A

Pharmacokinetics= oral absorption and bioavailability of these PUFA is a complex processes which is influenced by age, fat content of the meal, position of the fatty acids etc.
Clinical use- Hypertryglyceridemia, prevention of recurrent events after MI
Adverse effects= Gi complaints (abdominal pain, diarrhoea), Rash, Pruritis, Bleeding tenderness, May increase LDL

26
Q

Class 1 of Hyperlipoproteinemia

A 
LP elevated- Chylomicrons
Cholesterol- +
TG- +++
Atherosclerosis risk- NE
Drug treatment
27
Q

Class 2a of Hyperlipoproteinemia

A 
LP elevated- LDL
Cholesterol- ++
TG- NE
Atherosclerosis risk- High
Drug treatment- Statin, Ezetimibe
28
Q

Class 2b of Hyperlipoproteinemia

A 
LP elevated- LDL + VLDL
Cholesterol- ++
TG- ++
Atherosclerosis- High
Drug treatment- Fibrates, statins, nicotinic acid
29
Q

Class 3 of Hyperlipoproteinemia

A 
LP elevated= beta VLDL
Cholesterol- ++
TG- ++
Atherosclerosis risk- Moderate
Drug treatment- Fibrate
30
Q

Class 4 of Hyperlipoproteinemia

A 
LP elevated- VLDL
Cholesterol- +
TG- ++
Atherosclerosis risk- moderate
Drug treatment- Fibrates
31
Q

Class 5 of Hyperlipoproteinemia

A 
LP elevated- Chylomicrons + VLDL
Cholesterol- +
TG- ++
Atherosclerosis risk- NE
Drug treatment- Fibrate, niacin, fish oil and statin combination
32
Q

Drugs for blood clotting disorders

A
  1. Anticoagulants- modify blood clotting mechanisms i.e. Heparin and oral anticoagulants
  2. Antiplatelet agents- inhibits COX-1 activity to inhibit platelet aggregation i.e. Aspirin
  3. Thrombolytic/Fibrinolytic agents- break down fibrin i.e. Streptokinase, Alteplase
33
Q

The 4 classes of anticoagulants

A
  1. Heparin and low molecular weight Heparins
  2. Warfarin
  3. Selective factor Xa inhibitors
  4. Direct thrombin (factor IIa) inhibitors i.e. Lepirudin (parenteral), Dabigatran (oral)
    Anticoagulants target various factors in the coagulation cascade thereby preventing formation of a stable fibrin mechwork.
34
Q

Heparin and low molecular weigh

A
  • A family of sulphated mucopolysaccharides found in the secretory granules of mast cells
  • Inhibits coagulation by activating antithrombin III which is a strong inhibitor of serum protease or clotting factors
  • AT III is a naturally occurring inhibitor of thrombin and clotting factor IX, Xa, XI and XII
  • In the presence of heparin, AT III becomes x1000 more active and inhibition of clotting factors is instantaneous
  • Both the extrinsic and intrinsic pathway are inhibited
  • Heparin and AT III form a complex with the clotting factors inhibiting them
35
Q

What does Heparin bind to

A
  • To inhibit Thrombin, Heparin must bind to AT III and IIa

* To inhibit Xa, Heparin only has to bind to AT III

36
Q

Low molecular weight Heparins

A

Are fragment of natural heparins, synthetic heparins which have more consistent activity and predictable course of action. For example, Enoxaparin, dalteparin and Tinzaparin. LMWHs inactivates factor Xa by binding to antithrombin III. Heparin and LMWH have immediate onset of action. They are not absorbed in the gut so cant be given orally. LMWH have a longer half life so can be given less frequently

37
Q

Heparin characteristics

A

Route of administration= IV or SC. Both Heparin and LMWH are inactive orally
Half-life= Shorter then LMWH. Heparin must be given frequently or as a continuous infusion
Distribution= Large molecule, low Vd, do not cross the placenta
Elimination= Metabolised partially by the liver and 20-50% excreted unchanged in the urine

38
Q

LMWH characteristics

A

Route of administration= SC, greater bioavailability
Half-life= Longer, OD-BID dosing
Distribution= Large molecule, low Vd, do not cross the placenta
Elimination- mainly eliminated in the urine, contraindicated in renal failure

39
Q

Side effects of Heparin and LMWH

A

Bleeding, hypersensitivity and heparin-induced thrombocytopenia and thrombosis, osteroporosis and hypoaldonsteronism.

40
Q

Heparin overdose and APTT

A

Heparin prolong APTT as it affects the intrinsic pathway more but LMWH does not. Heparin is a highly acidic molecule and overdose is treated by IV protamine (strongly basic protein) which neutralises it.

41
Q

Heparin clinical use

A

• Treatment for established venous thromboembolism
• Prevention of venous thromboembolism- LMWHs are used to prevent post-operative venous thrombosis
• Cardiac disease- reduces risk of venous thromboembolism in patients with angina and following acute MI
• If long term anticoagulation is required heparin is only used to initiate anticoagulation therapy until oral anticoagulants take effect
Heparin MoA- activation of antithrombin III

42
Q

Oral anticoagulant- Warfarin

A

Warfarin means that inactive clotting factors cant bind stably to the blood vessel endothelium and cannot activate clotting. Its an oral vitamin K antagonist used to treat and prevent blood clots. It has a low margin of safety and frequent blood tests are required to individualise the dose and prevent bleeding.

43
Q

Warfarin- vitamin K

A

Vitamin K is needed to activate the inactive clotting factors II, VII, IX, X. Warfarin competitively inhibits the enzyme Vitamin K reductase which is needed to convert the Vitamin K quinone form to the Vitamin K reduced form which the activates the inactive clotting factors. Mostly inhibits the extrinsic pathway.

44
Q

Warfarin facts

A
  • Takes 1-2 days to be effective
  • The clotting factors with the smaller half-life’s (factor VII) are affected first
  • A small population of patients are genetically resistant to warfarin due to reduced binding to Vitamin K reductase
  • Side effects- bleeding and skin necrosis. Skin necrosis can be prevented by starting to Heparin and then switching to Warfarin.
  • Overdose is treated with Vit K or Fresh Frozen Plasma
  • Warfarin is a small, lipid-soluble molecule and is absorbed rapidly and almost totally from the GIT. Levels peak in the blood 0.5-4h after administration.
  • Low volume of distribution as its mostly protein bound (albumin), crosses the placenta (not suitable if pregnant
45
Q

Warfarin metabolism and excretion

A

Metabolism- action is terminated by metabolism in the liver by CYP450 enzymes, possible drug-drug interactions
Excretion- metabolites are conjugated to glucuronide and excreted in urine and faeces

46
Q

Warfarin clinical use

A
  • To prevent the progression or reoccurrence of venous thrombosis, pulmonary embolus
  • To prevent arterial thromboemboli in patients with atrial fibrillation or cardiac disease (including mechanical heart valve)
47
Q

Anticoagulants

A
  • Acute anticoagulation usually starts with heparin and an oral anticoagulant i.e. warfarin
  • Heparin is rapidly effective= effect of Heparin is monitored by APPT.
  • In LMWH usually no monitoring is needed, has less side effects and fewer bleeding complications
  • Warfarin takes several days to achieve full anticoagulation. The effect of anticoagulant is monitored using the prothrombin time (converted to INR). Target INR is 2-3 (2.5)
  • Heparin covers the lag period and can be removed

Medicine year 2 semester 2 (47 decks)

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