Block 4 drugs

Question 1

Vitamin B12

Answer 1

Vitamin B12 exists in 4 forms known as cobalamins:

• deoxyadenosylcobalamin
• methylcobalamin
• hydroxocobalamin
• cyanocobalamin

Question 2

Hydroxocobalamin

Answer 2

Drug class: Synthetic Vitamin B12

Indications: treatment of pernicious anemia and vitamin B12 deficiency

Mechanism: absorbed from the GI tract in the lower half of the ileum.

Contraindications: none

Side effects:
- urine discoloration, diarrhea

Question 3

Ferrous sulphate

Answer 3

Drug class: iron supplement

Indication: used to prevent and treat iron deficiency in anemia

Mechanism:
1. iron is transported by the divalent metal transporter 1 (DMT1) to teh macrophage.
2. Iron is oxidized into Fe3+ which combines with porphyrin and globin chains to form hemoglobin.

Contraindications:
none

Side effects:
none

Question 4

Folic acid (aka as folate)

Answer 4

Drug class: Vitamin B9

Indications: to treat megoblastic anemia, folic acid deficiency, pregnancy

Mechanism:
- Folic acid is biochemically inactive
- It is converted to tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase (DHFR).
- These folic acid congeners are transported across cells by receptor-mediated endocytosis where they are needed to maintain normal erythropoiesis.

Contraindications: none

Side effects: none

Question 5

Azathioprine

Answer 5

Drug class: immunosuppressant

Indication: used to prevent renal transplant rejection, treat rheumatoid arthritis, crohns disease and ulcerative collitis.

Mechanism:
- inhibition of purine synthesis
- inhibition of B cells and T cells

Contraindications:

Side effects:

Question 6

Cyclosporin

Answer 6

Drug class: immunosuppressant

Indication: organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis and atopic dermatitis.

Mechanism:
1. Calcineurin inhibitor that inhibits T -cell activation.
2. Cyclosporin binds to the receptor cyclophilin and forms a complex called cyclosporine-cyclophilin.
3. This complex inhibits calcineurin, which stops the dephosphorylation and activation of (NFAT) that produce cytokines and inflammatory reactions.

Side effects:
- hypertension
- hyperlipidemia
- hirsutism ( excessive hair growth)
- hyperuricemia ( gout)

Question 7

Clopidogrel

Answer 7

Drug class: Antiplatelet agent / ADP receptor inhibitor

Indication: used to prevent blood clots in vascular disease, coronary artery disease and cerebrovascular disease which reduces the risk of heart attack and stroke

Mechanism:
- clopidogrel is a prodrug
- its metabolized to its active form by carboxylesterase.
- The active form irreversibly binds to P2Y12 ADP receptors on platelets.
- The binding prevents ADP binding to P2Y12 receptors, which prevents activation of the glycoproteins GP11b/111a complex and stops platet aggregation.

Contraindications:

Side effects:
- increase risk of bleeding
- thrombotic thrombocytopenic purpura

Question 8

Heparin (9, 10, 11, 12)

Answer 8

Drug class: Anticoagulant

Indication:
- treatment of venous thrombosis, DVT and Pulmonary embolism.
- Administered intravenously or subcutaneously

Mechanism:
- antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa.
- Heparin binds to ATIII and leads to inactivation of thrombin (IIa) and Xa.
- The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin

Contraindications:
- any sort of haemorrage

Side effects:
- heparin induced thrombocytopenia
- hemorrhage
- skin reactions

Reversal drug: protamine

Question 9

Apixaban

Answer 9

Drug class: Anticoagulant ( direct factor Xa inhibitor)

Indication:
- prevention of DVT, PE
- prevention of stoke in patients with atrial fibrillations and systemic embolism

Mechanism:
- inhibits factor Xa in its free and bound forms, independent of antithrombin III.
- Apixaban also inhibits prothrominase
- These steps prevent the formation of a thrombus.

Contraindications:

• Apixaban is metabolized by cytochrome P450, so cannot be taken with cimetidine and amiodarone or metrondiazole as it will cause accumulation of the drug in the body which will lead to bleeding.

Side effects:

• excessive bleeding

Reversal drug: Andexanet alfa

Question 10

Why is Apixaban better than warfarin ?

Answer 10

• Apixaban does not require laboratory monitoring
• fewer drug interactions
• rapid onset of action

Question 11

Warfarin (2,7,9,10) ( proteins C and S )

Answer 11

Drug class: Anticoagulant

Indications:
- prevent and treat venous thromboembolism
- prevent and treat pulmonary embolism
- thromboembolism with cardiac valve replacement
- thromboembolic events post myocardial infarction.

Mechanism:
- vitamin K antagonist
- stops vitamin k epoxide from becoming active vitamin k by inhibiting the enzyme Vitamin K epoxide reductase
- Vitamin k is used in the y-carboxylation of coagulation factors VII, IX, X, and thrombin

Question 12

What are direct factor inhibitors ?

Answer 12

There are two types:

• Direct thrombin inhibitors
• Direct factor Xa inhibitors

Question 13

Dabigatran

Answer 13

Drug class: anticoagulant / direct factor inhibitor

Indications:
- used to is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation.
-Specifically it is used to prevent blood clots following hip or knee replacement

• given orally, used second line medication for DVT and PE. Useful for patients who have experienced HIT

Mechanism:
- reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors

Side effects:
- dyspepsia
- gastritis
- increase risk of bleeding

Reversal drug: idarucizumab

Question 14

Tetanus booster

Answer 14

Drug class: tetanus vaccine to prevent tetanus

Indication:

• The tetanus vaccine is given as part of the NHS childhood vaccination program.
• the first 3 doses are given as part of the 6-in-1 vaccine at age 8, 12 and 16 weeks

-a booster dose is given as part of the 4-in-1 pre-school booster at age 3 years and 4 months

-a final dose is given as part of the 3-in-1 teenage booster at age 14

Question 15

Where do glucorticoids come from ?

Answer 15

• Glucocorticoids are a group of steroid hormones, which are secreted by the two adrenal glands that sit like hats, one on top of each kidney. Each one has an inner layer called the medulla and an outer layer called the cortex.

The adrenal cortex secretes different corticosteroid hormones: like glucocorticoids under the control of adrenocorticotropic hormone, or ACTH.

Question 16

What is then hypothalamus function in cortisol release ?

Answer 16

-Normally the hypothalamus, located at the base of the brain, secretes corticotropin releasing hormone, known as CRH, which stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone, known as ACTH

-ACTH then travels to the pair of adrenal glands and binds to the ACTH receptors on adrenocortical cells.

-This causes the adrenocortical cells to release the glucocorticoids from the zona fasciculata, which have powerful anti-inflammatory and metabolic effects.

-These glucocorticoids have a negative feedback effect on the hypothalamic-pituitary-adrenal axis, meaning excess corticosteroids suppress the release of both CRH and ACTH into the circulation.

Question 17

What happens once glucocorticoids are released from teh adrenal glands ?

Answer 17

• once made, glucocorticoids enter the circulation and travel via the blood to reach the target cells. Steroids are lipophilic molecules, so they cross the cell membrane, enter inside the cell, and bind with a cytoplasmic receptor protein, called a ‘glucocorticoid receptor’.
• Now, this ‘glucocorticoid-receptor complex’ undergoes some structural changes, which allow them to enter inside the nucleus and bind with the ‘glucocorticoid response elements’ or GRE on the chromatin
• Now, this induces transcription of specific mRNA that’s used to synthesize different proteins, which in turn modifies various cell functions and metabolic effects in the body.

Question 18

Describe cortisol ?

Answer 18

-The most important glucocorticoid in humans is cortisol, and it’s generally released during times of stress, like during an illness or starvation

Immune repsonse:
- Cortisol helps to regulate both the immune response as well as cellular metabolism like gluconeogenesis.

-With regard to the immune response, cortisol promotes an overall anti- inflammatory state by inhibiting the two main products of inflammation - prostaglandins and leukotrienes - as well as inhibiting interleukin-2 production by white blood cells.

Cellular metabolism:

-for cellular metabolism, cortisol promotes overall catabolic effects on the body. In peripheral adipose tissue, cortisol triggers lipolysis, which is the breakdown of fats into free fatty acids.

-In the muscles, cortisol stimulates proteolysis, which is the breakdown of proteins into amino acids. Often these free fatty acids and amino acids serve as a substrate for gluconeogenesis - a process where the liver cells produce new glucose molecules from non-carbohydrate sources like amino acids and free fatty acids.

Question 19

Cortisol and stress ?

Answer 19

The increased glucose level also stimulates the release of more insulin. And because this is similar to what happens in people with diabetes, this effect of cortisol is called diabetogenic. The end result is we have a lot more glucose in the blood which can be used as fuel during times of stress

Question 20

What do synthetic glucorticosteriods do ?

Answer 20

-Glucocorticoids inhibit neutrophil apoptosis and demargination.

Synthetic glucocorticoids in our body produce the same effect as endogenous cortisol; but, they also increase the number of neutrophils in the blood! Let’s put it this way. Glucocorticoids decrease the production of a protein that enables neutrophils to attach to the endothelial lining of the blood vessel. As a result, neutrophils detach from the endothelial lining and enter the circulation. This process is also known as “demargination”.

At the same time, these medications also reduce the number of lymphocyte, monocyte, basophil, eosinophil counts.

Glucocorticoids (GCs) increase peripheral blood neutrophil counts through genomic and non-genomic actions and reduce the numbers of lymphocytes, eosinophils, basophils, and monocytes.

Question 21

What are glucorticosteriods used for?

Answer 21

• First, glucocorticoids are used in the treatment of adrenal conditions which are characterized by low corticosteroid levels in the body, such as primary adrenal insufficiency, also known as Addison disease.
• Next, glucocorticoids are used as ANTI -INFLAMMATORY /IMMUNOSUPRESSIVE therapy in individuals with asthma; conditions with autoimmune and inflammatory components, such as rheumatoid arthritis, Crohn disease, ulcerative colitis, acute multiple sclerosis exacerbation, and idiopathic thrombocytopenic purpura; and in inflammatory conditions of skin, eye, ear or nose, like eczema, allergic conjunctivitis, or rhinitis.
  Also, these medications are used to treat hypersensitivity states, such as severe allergic reactions; and prevent graft-versus-host disease.
• NEOPLASTIC conditions. An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Neoplasms may be benign (not cancer) or malignant (cancer).

Finally, glucocorticoids are used in neoplastic conditions as adjuvant therapy, due to their anti-lymphocytic effect, which is characterized by a decreased clonal expansion of T and B lymphocytes. This makes them effective in the treatment of hematopoietic cancers, such as acute lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphomas.

Question 22

Betamethasone

Answer 22

Drug class: long acting glucocorticoids

Indication:
- orally, intramuscularly and intravenously and topically

• topically: inflammatory conditions such as eczema
• Injectable: used to manage endocrine disorders such as addisons disease, GI disorders and rheumatic disorders.

Mechanism:
- glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT)

-On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers

Question 23

Prednisolone

Answer 23

Drug class: Intermediate ( medium) acting glucocorticoids

Indications: orally, intravenously and topically

• treat adrenocortical insufficiency, inflammatory conditions, endocrine, rheumatic and dermatologic.

Mechanisms:
- The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation

• Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.

Question 24

Chlorphenamine

Answer 24

Drug class: histamine-H1 receptor antagonist

Indications:
-indicated for the management of symptoms associated with upper respiratory allergies.
-For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever

Mechanism:
Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine.

Question 25

Hydrocortisone

Answer 25

Drug class: short acting glucocorticoid

Indication:
- intravenously, intramuscularly, topically and orally

• endocrine, rheumatic, collagen, allergic, respiratory ….

Mechanism:
- The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation.

• Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10

Question 26

Adrenaline

Question 27

Aspirin

Answer 27

Drug Class: Blocks synthesis of Thromboxane A2

Indication:
- used in doses from 75-325mg

325mg: - treat acute strokes
- myocardial infarctions

81mg: - prevention of future heart attacks

Mechanism:

1. Aspirin accomplishes this by irreversibly inhibiting the activity of cyclooxygenase enzymes, abbreviated COX-1 and COX-2, via acetylation
2. When COX-1 and COX-2 get inhibited, thromboxane A2, which is a downstream product of the cyclooxygenase pathway can no longer be produced.

Side effects:
- risk of developing gastric ulcers and bleeding

Question 28

What do synthetic glucorticosteriods do ?

Answer 28

-