QUICK HINT (2025)

08/07/2023

Levothyroxine or L-thyroxine (Eltroxin 50 mcg and 100 mcg).

Introduction:
Levothyroxine or L-thyroxine is synthetic form of thyroxine hormone or tetra-iodo-thyronine (T4) hormone.

Pharmaco-kinetics:

a. Absorption;
Oral bio-availability of Levothyroxine or L-thyroxine is equal to about 70 to 80%.
Absorption of Levothyroxine or L-thyroxine is decreased by;
•Food (Particularly fatty meals and coffee).
•Calcium ion (Ca2+) containing pharmaceutical preparations.
•Aluminium ion (Al3+) containing pharmaceutical preparations e.g. antacids.
Therefore, should be taken in fasting state referring to 30 to 60 minutes before breakfast.

b. Distribution;
More than 99% of Levothyroxine or L-thyroxine present in blood circulation, is bound (Pharmacologically inactive form) towards plasma proteins;
•Higher ratio for thyroxine-binding globulin (TBG).
•Lower ratio for thyroxine-binding pre-albumin (TBPA).
Less than 1% of Levothyroxine or L-thyroxine present in blood circulation, is unbound or free (Pharmacologically active form) transporting into cell by adenosine tri-phosphate (ATP) dependent process.
There are some drugs which displace Levothyroxine or L-thyroxine from serum binding proteins e.g.
•Acetyl salicylic acid.
•Phenytoin.
•Carbamazepine.
•Furosemide.
There are some drugs causing increase in concentration of thyroxine-binding globulin (TBG) e.g.
•Estrogens.
•Tamoxifen.
There are some drugs causing decrease in concentration of thyroxine-binding globulin (TBG) e.g.
•Androgens.
•Corticosteroids.
•Niacin (Vitamin B3).

c. Metabolism;
There are 3 chemical reactions of metabolism of Levothyroxine or L-thyroxine;
1. Sequential de-iodination reaction (Major); About 80% of tri-iodo-thyronine (T3) present in blood circulation, is produced from tetra-iodo-thyronine (T4) by sequential de-iodination reaction which occurs in liver and kidneys.
There are some drugs causing inhibition of previous reaction e.g.
•Amiodarone (Cordarone 200 mg).
•Propranolol.
•Corticosteroids.
There are some drugs causing stimulation of previous reaction due to stimulation of hepatic microsomal enzymes e.g.
•Rifampin.
•Phenobarbital.
•Phenytoin.
•Human immuno-deficiency virus (HIV) protease enzyme inhibitors.
2. Conjugation reaction with Glucuronides and Sulfates; Produced molecules from previous reaction are excreted in f***s.
3. De-amination and de-carboxylation reaction; Produced molecules from previous reaction are excreted in urine.

d. Excretion;
About 80% of Levothyroxine or L-thyroxine is excreted in urine, while about 20% of Levothyroxine or L-thyroxine is excreted in f***s.
Tetra-iodo-thyronine (T4) hormone showing variable half-lives related towards thyroid gland case;
•6 to 7 days for Eu-thyroid.
•9 to 10 days for Hypo-thyroid.
•3 to 4 days for Hyper-thyroid.

Mechanism of action:

According to inactive phase;
Unliganded tri-iodo-thyronine (T3) receptor dimer is bound towards thyroid hormone response element (TRE) along with co-repressors acts as suppressor of gene transcription.

According to active phase;
Unbound or free (Pharmacologically active form) tetra-iodo-thyronine (T4) transports into cell by adenosine tri-phosphate (ATP) dependent process.
Tetra-iodo-thyronine (T4) is converted towards tri-iodo-thyronine (T3) by 5’-de-iodinase enzyme (5’-DI) within cytoplasm.
Tri-iodo-thyronine (T3) transports towards nucleus.
Tri-iodo-thyronine (T3) binds towards ligand-binding domain of thyroid receptor (TR) monomer causing;
•Disruption of thyroid receptor (TR) homodimer.
•Heterodimerization with retinoid X receptor (RXR) on thyroid hormone response element (TRE).
•Displacement of co-repressors.
•Binding of co-activators.
Thyroid receptor (TR)-coactivator complex causing;
•Stimulation of gene transcription.
•Change in protein synthesis.
•Change in cellular phenotype.

Uses:
Treatment of hypo-thyroidism.

Side effects:
•Nervousness.
•Palpitations.
•Tachycardia.
•Heat intolerance.
•Unexplained weight loss.

Safety:
Safe for pregnant women and breastfeeding women.

References:
www.medicines.org.uk
www.webmd.com
www.medbroadcast.com
www.mims.com

02/07/2023

Goserelin (Zoladex 3.6 mg and long-acting (LA) 10.8 mg).

What is Gonadotropin-releasing hormone (GnRH)?
Gonadotropin-releasing hormone (GnRH) is decapeptide hormone which is composed of 10 amino acids.
Gonadotropin-releasing hormone (GnRH) stimulates synthesis and secretion of;
a.Gonadotropins referring to;
•Follicle stimulating hormone (FSH).
•Luteinizing hormone (LH).
b.Gonadal Steroid hormones referring to;
•Androgens.
•Estrogens.

Introduction:
Goserelin is Gonadotropin-releasing hormone (GnRH) analogue.

Mechanism of action:
Goserelin is pharmacologically effective in decrease in synthesis and secretion of both Gonadotropins and Gonadal Steroid hormones;
•Initial increase in synthesis and secretion of Gonadotropins which is called “Hyper-gonadal effect” due to up-regulation.
•Sustained stimulation of Gonadotropin-releasing hormone (GnRH) receptors.
•Following decrease in synthesis and secretion of Gonadotropins which is called “Hypo-gonadal effect” due to down-regulation.
•Following decrease in synthesis and secretion of Gonadal steroid hormones.

Use:
Use is related towards Conc.;
Conc. 10.8 mg is used for;
•Treatment of prostate cancer Stage T2b-T4 (Stage B2-C).
Conc. 3.6 mg is used for;
•Treatment of breast cancer.
•Treatment of uterine fibroids.
•Treatment of endometriosis.
•Treatment of early puberty.

Side effects:

According to short-term administration;
•Increase in urination difficulty.
•Absence of menstrual periods.
•Ovarian cysts may be developed due to flare effect on synthesis and secretions of Gonadotropins and generally resolve after additional 6 weeks.
•Temporary worsening of signs and symptoms of prostate or breast cancer including bone pain may sometimes develop during first few weeks of treatment.

According to long-term administration;
Typical signs and symptoms similar towards menopause;
•Hot flushes and sweats.
•Vaginal dryness and decrease in libido.
•Osteoporosis.
•Headache.
•Depression, mood swings and hallucinations.
•Generalized pain.
•Hair loss.

Safety:
Not recommended for either pregnant women or breastfeeding women.
Patients with diabetes or heart diseases should have special medical attention due to;
•Increase in blood glucose level.
•Change in heart rhythm (QT prolongation) and sudden death.

Dosage form, route of administration and frequency:
Provided in injected dosage form.
May be administrated either;
•Subcutaneously (SC) (May cause hypersensitivity towards skin referring to local swelling and dermatitis).
•Intramuscularly (IM).
Frequency is related towards Conc.;
•Conc. 10.8 mg is usually injected every 12 to 13 weeks.
•Conc. 3.6 mg is usually injected every 4 weeks.

References:
www.zoladex.com
www.webmd.com
www.medicines.org.uk
www.drugs.com
www.reference.medscape.com

17/06/2023

Somatostatin (SST) which is also called “Growth hormone inhibiting hormone (GHIH)”.

What is Somatostatin (SST)?
Peptide hormone (14-amino acid) which is secreted from;
•Hypothalamus.
•Central nervous system (CNS).
•Pancreas.
•Other sites of gastro-intestinal tract (GIT).

About its pharmacological action?
Inhibition of paracrine factor (Cell to cell communication).
Inhibition of release of following hormones.
•Growth hormone (GH).
•Thyroid stimulating hormone (TSH).
•Gastrin.
•Insulin and glucagon.

Why not used?
There are 2 reasons;
•Half-life of Somatostatin (SST) is between 1 to 3 minutes (Ultra-short duration of action).
•Somatostatin (SST) showing multiple effects in several secretory systems.

Octreotide (Sandostatin).
Introduction:
Octreotide is synthetic analog of Somatostatin (SST) (Most widely used).

Mechanism of action:
Octreotide is about 45 times more potent compared towards Somatostatin (SST) according to inhibition of release of growth hormone (GH).
Octreotide is also about twice more potent compared towards Somatostatin (SST) according to inhibition of release of insulin.
Why?
As half-life of Octreotide is about 30 times longer than half-life of Somatostatin (SST);
•Half-life of Octreotide is about 80 minutes (Long duration of action).
•Half-life of Somatostatin (SST) is between 1 to 3 minutes (Ultra-short duration of action).

Uses:
On-label uses;
•Treatment of acromegaly (Medical condition in which hyper-secretion of growth hormone (GH) occurs after fusion of epiphysis causing increase in thickness of bones appears as large extremities and characteristic facies).
•Treatment of carcinoid tumors (Type of neuroendocrine tumors (NETs)) (Inhibits severe diarrhea and flushing episodes).
•Treatment of vasoactive intestinal peptide tumors (Inhibits profuse water diarrhea).
Off-label uses;
•Treatment of chylothorax (Medical condition in which lymphatic fluid leaks into space between lung and chest wall).
•Treatment of esophageal variceal bleeding.
•Treatment of dumping syndrome (Medical condition in which food (Particularly high in sugar content) moves from stomach to small intestine too quickly after eating).
•Treatment of gastro-intestinal (GI) or pancreatic fistula.
•Treatment of Ileostomy-related diarrhea.
•Treatment of chemotherapy-related diarrhea.
•Treatment of acquired immuno-deficiency syndrome (AIDS)-related diarrhea.

Frequency:
•Whether provided in non-depot formulation; Every 8 hours daily.
•Whether provided in depot formulation (long-acting release (LAR) formulation); Once every 4 weeks.

Side effects:
•Bradycardia.
•Hypothyroidism.
•Abdominal cramps with bulky bowel movements.
•Nausea and vomiting.
•Steatorrhea.
•Gallbladder problems.
•Dys-glycemia (Either hypo or hyper).
•Vitamin B12 deficiency may occur with long-term use.

Safety:
Not recommended for either pregnant women (However, food and drug administration (FDA) Pregnancy Category B - No proven risk in humans) or breastfeeding women.

References:
www.hcp.novartis.com
www.sandostatin.com
www.drugs.com
www.news-medical.net
www.reference.medscape.com
www.mayoclinicproceedings.org

10/06/2023

Azathioprine (AZA) (Imuran).

Class:
Cyto-toxic agent.

Mechanism of action:
Azathioprine (AZA) is pro-drug of 6-mercaptopurine (6-MP), and similar towards 6-mercaptopurine (6-MP), functions as anti-metabolite;
Azathioprine (AZA) is antagonist of purine metabolism causing inhibition of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis.

Uses:
•Azathioprine (AZA) is used in organ transplantation e.g. kidney transplantation (First agent to be used).
•Azathioprine (AZA) is also used in auto-immune diseases e.g. rheumatoid arthritis (RA), Crohn’s disease and ulcerative colitis (As immunosuppressant more widely compared towards Mercaptopurine).

Side effects:
•Nausea and vomiting.
•Diarrhea.
•Hepatotoxicity.
•Myelosuppression.

Safety:
Azathioprine is safe during pregnancy and breastfeeding (Unless administration of high doses requires additional blood tests).

Drug-drug interactions:
Dose of Azathioprine (AZA) should be decreased whether used concurrently with Allopurinol.
Why?
In liver, Azathioprine (AZA) is non-enzymatically metabolized towards 6-mercaptopurine (6-MP) (Active metabolite) then enzymatically metabolized towards both;
•6-methyl-mercaptopurine derivative (Inactive metabolite) by thiopurine S-methyl-transferase (TPMT) enzyme.
•6-thiouric acid (Inactive metabolite) by xanthine oxidase enzyme.
Allopurinol as xanthine oxidase enzyme inhibitor causing;
•No production of 6-thiouric acid (Inactive metabolite).
•Increase in production (Accumulation) of 6-mercaptopurine (6-MP) (Active metabolite).
Therefore, excessive toxicity occurs.

Pharmacogenomics:
Thiopurine S-methyl-transferase (TPMT) enzyme screening should be performed prior towards administration of Azathioprine (AZA) in whole patients because thiopurine S-methyl-transferase (TPMT) enzyme is responsible for, in part, for biological inactivation of 6-mercaptopurine (6-MP).

References:
www.uptodate.com
www.pubs.acs.org
www.go.drugbank.com
www.ncbi.nlm.nih.gov
www.sciencedirect.com
www.reference.medscape.com

26/05/2023

Monoclonal antibodies (mAb or moAb).

Why to be nomenclated monoclonal?
Due to binding mono-specifically towards specific proteins or cells.

General concept:
•In vivo, antibodies are part of immune system; produced in response of antigens entering.
•In vitro, antigens on surface of cancer cells (Specific target) are analyzed in order to determine protein (From either mouse or human) to match these antigens then this protein is used to produce antibodies which bind to these antigens.
Therefore, these antibodies showing higher potency and fewer side effects as being directed specifically.

Steps for production process:
Production process is still very expensive and time consuming;
•Animal (Often mouse) is immunized multiple times with specific antigen.
•B cells from spleen of this immunized animal are removed to be fused with cancerous B cells which are called “Myeloma cells” in order to produce “Hybridoma cells”.
•Previous cells which can grow continuously in culture during production of antibodies, are screened for desired antibodies.

Types:
There are 4 major types;
•Whether ends with suffix -omab referring to Murine which means that antibodies are produced from mouse by percentage 100%, so causing allergic reactions and anaphylactic shock.
•Whether ends with suffix -ximab referring to Chimeric which means that antibodies are produced from mouse and human by percentage 50% to 50%.
•Whether ends with suffix -zumab referring to Humanized which means that antibodies are produced from mouse and human by percentage 5% to 95%.
•Whether ends with suffix -umab referring to Human which means that antibodies are produced from human by percentage 100%.

Mechanism of action:
Monoclonal antibodies are designed to function in different ways. Particular medication may actually function by more than one means as following;
•Flagging cancer cells; Some immune system cells depend on anti-bodies to locate target of attack. Cancer cells which are coated in antibodies may be more easily detected and targeted for destruction.
•Directly attacking cancer cells; Some antibodies may attack cell more directly. When these antibodies attach to cell, series of events inside cell may cause it to self-destruct.
•Triggering cell-membrane destruction; Some antibodies can trigger immune system response which can destroy outer wall (membrane) of cancer cell.
•Blocking cell growth; Some antibodies block connection between cancer cell and proteins which promote cell growth - biological activity which is necessary for cancer growth and survival.
•Preventing blood vessel growth; In order for cancerous tumor to grow and survive, needs blood supply. Some antibodies block protein-cell interactions required for development of new blood vessels.
•Blocking immune system inhibitors; Your body keeps your immune system from being overactive by making proteins which control pharmacological activity of immune system cells. Antibodies can interfere with this process so that your immune system is allowed to work without controls against cancer cells.
•Delivering radiation treatment; Because of antibody's ability to connect with cancer cell, antibody can be engineered as delivery vehicle for other medications. When antibody is combined with small radioactive particle, it transports radiation treatment directly to cancer cells and may minimize effect of radiation treatment on healthy cells.
•Delivering chemotherapy; Similarly, some antibodies are combined with chemotherapy medication in order to deliver treatment directly to cancer cells while avoiding healthy cells.
•Binding cancer and immune cells; Some medications combine two antibodies, one which attaches to cancer cell and another which attaches to specific immune system cell. This connection may promote immune system attacks on cancer cells.

Uses and Examples:
Treatment of cancer (As antibodies can be used to carry medications, toxins or radio-active substances towards cancer cells) e.g.
•Trastuzumab.
•Bevacizumab (Avastin).
•Cetuximab.
•Rituximab.
Treatment of auto-immune diseases e.g.
•Etanercept.
•Adalimumab.
•Golimumab.
•Certolizumab.
•Infliximab.
Treatment of Alzheimer’s disease e.g.
•Gautenerumab.
•Bapineuzumab.
•Solanezumab.
Treatment of asthma e.g. Omalizumab.

References:
www.mayoclinic.org
www.cancer.org
www.my.clevelandclinic.org
www.cancer.gov
www.cancerresearchuk.org

26/05/2023

Gemcitabine.

Introduction:
Gemcitabine is ranked as 3rd anti-cancer agent prescribed worldwide.

Class:
Anti-metabolite agent - De-oxy-cytidine analog.

Mechanism of action:
Gemcitabine is biologically active in S-phase of cell cycle causing inhibition of DNA synthesis and function as following;

Gemcitabine is converted into Gemcitabine mono-phosphate substrate then Gemcitabine di-phosphate substrate (dFdCDP) then Gemcitabine tri-phosphate substrate (dFdCTP) by de-oxy-cytidine kinase (dCK) enzyme at higher extent and by extra-mitochondrial thymidine kinase 2 enzyme at lower extent;

Gemcitabine di-phosphate substrate (dFdCDP) causing;
•Inhibition of ribonucleotide di-phosphate reductase enzyme which is responsible for conversion of ribonucleotide di-phosphate into de-oxy-ribonucleotide di-phosphate.
•Decrease in synthesis of de-oxy-ribonucleotide di-phosphate which is required for DNA synthesis.

Gemcitabine tri-phosphate substrate (dFdCTP) competes with de-oxy-cytidine tri-phosphate (dCTP) causing “Masked DNA chain termination”;
•Incorporation into DNA.
•No DNA repair by 3′5′-exonuclease enzyme.

Use:
Treatment of solid tumors e.g.
•Non-small cell lung cancer (NSCLC) (In combination with Cisplatin).
•Breast cancer (In combination with Paclitaxel).
•Pancreatic cancer (1st-line treatment for patients with locally advanced non-resectable (Stage II and Stage III) or metastatic (Stage IV).
•Cholangiocarcinoma and other biliary tract cancers (Off-label use).
•Ovarian cancer relapsed at least 6 months after completion of platinum-based therapy (In combination with Carboplatin).
•Bladder cancer (In combination with Cisplatin) (Off-label use).

Side effects:
Common;
•Nausea and vomiting.
•Flu-like syndrome.
•Myelosuppression.
•Alopecia.
Rare;
•Pulmonary toxicity.
•Hepatotoxicity.
•Renal microangiopathy syndrome (Including hemolytic-uremic syndrome).

Safety profile:
Gemcitabine can be attractive option in pediatric cancers because its toxic profile is considered as mild as compared towards other cyto-toxic drugs.
Gemcitabine is contra-indicated in pregnant women (Particularly 1st tri-mister) and breastfeeding women.

References:
www.cancerresearchuk.org
www.ncbi.nlm.nih.gov
www.go.drugbank.com
www.pfizermedicalinformation.com
www.doctorlib.info

26/05/2023

Docetaxel and Paclitaxel.

Introduction:
Docetaxel is also called “Taxotere”, while Paclitaxel (First discovered of whole Taxanes) is also called “Taxol” by original researchers in 1971, and later is marketed under trade name Taxol.

Class:
Taxanes which are plant alkaloids derived from bark of;
•Pacific yew (Taxus brevifolia).
•European yew (Taxus baccata).

Pharmaco-kinetics:
Taxanes like Vinca alkaloids related towards;
a.Metabolism; Metabolized in liver by cytochrome CYP450 enzyme.
b.Excretion: Excreted in bile and f***s.
Therefore, dose should be modified in patients with impaired function of liver.

Mechanism of action:
Biologically active in G2-phase and M-phase of cell cycle causing mitotic spindle poison;
•High-affinity binding towards beta-tubulin protein.
•No depolymerization.
•Inhibition of assembly of microtubules in mitotic spindle.

Use:
Treatment of solid tumors e.g.
•Head and neck cancer.
•Esophageal cancer.
•Breast cancer (Advanced metastatic).
•Lung cancer.
•Stomach cancer.
•Pancreas cancer.
•Urinary bladder cancer.
•Ovary cancer.
•Prostate cancer.
•Kaposi’s sarcoma (Type of bone cancer).
•Acquired immuno-deficiency syndrome (AIDS).
In treatment of breast cancer, lung cancer and pancreas cancer, albumin-binding dosage form of paclitaxel (Abraxane) is used.

Side effects:
1.Hypersensitivity reaction (Fatal anaphylactic shock).
How to protect patient from previous side effect?
Throughout usage of;
•Cortico-steroids e.g. Dexamethasone.
•H1-antihistamines e.g. Diphenhydramine.
•H2-antihistamines.
2.Neurotoxicity (Peripheral neuropathy).
3.Myelosuppression.
4.Alopecia.

Contra-indications:
•Not used whether neutrophil count is less than 1500 cells/mm3.
•Not used in patients with pre-existing lung conditions e.g. chronic obstructive pulmonary disease (COPD) due to life threating conditions.
•Not preferred to be used in pregnant women, in addition to, not to be pregnant during treatment and for 2 months following last dose, however, limited available human data are not sufficient to inform drug-associated risk during pregnancy.
•Not preferred to be used in breastfeeding women, in addition to, not to breastfeed during treatment and for 2 weeks after last dose, however, no information regarding presence in human milk.

References:
www.ncbi.nlm.nih.gov
www.reference.medscape.com
www.go.drugbank.com
www.mayoclinic.org

26/05/2023

Doxorubicin and Epirubicin which are also called “Red Devil Chemo”.

Introduction:
Doxorubicin and Epirubicin are same, while;
• Related towards pharamco-kinetics, excretion of Epirubicin is higher than excretion of Doxorubicin.
• Related towards side effects, cardiotoxicity of Epirubicin is lower than cardiotoxicity of Doxorubicin.
Why?
Epirubicin is epimer of Doxorubicin as chemical structure differs from each other only in orientation of hydroxyl group (OH) present at position C4 of sugar.

Class:
Cytotoxic antibiotics - Anthracyclines (Dark red aromatic polyketides).

Pharmaco-kinetics:
a. Absorption;
Absorption is high, while bio-inactivation occurs in gastro-intestinal tract (GIT), so provided in parenteral dosage form (Intra-vascular (IV) infusion).
b. Distribution;
Distribution is high showing;
• Binding towards proteins with high affinity.
• No pe*******on throughout blood brain barrier (BBB) and te**es.
c. Metabolism;
Metabolism occurs majorly in liver, so dose should be decreased in liver dysfunction.
d. Excretion;
Excretion occurs in f***s throughout bile (Up to 50%), so dose should be decreased in liver dysfunction.

Mechanism of action:
There are 4 major mechanisms;
1. Inhibition of topoisomerase II enzyme which is responsible for cut both strands of DNA helix.
2. Intercalation with DNA and RNA causing blockage of synthesis of DNA and RNA.
3. Binding towards cellular membranes causing alteration of fluidity and transportation of iron ion.
4. Generation of 2 major types of free radicals;
•Semi-quinone free radicals.
•Oxygen free radicals.

Use:
Being from most effective anti-cancer drugs for treatment of solid tumors e.g.
•Thyroid gland cancer.
•Lungs cancer.
•Breast cancer.
•Stomach cancer.
•Liver cancer.
•Urinary bladder cancer.
•Ovaries cancer.
•Soft tissues sarcoma (Type of bones cancer).
•Multiple myeloma.
And others.
Also used for treatment of leukemia, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.
Also used for treatment of acquired immune-deficiency syndrome (AIDS).
Only Epirubicin is approved as adjunctive therapy in axillary node-positive patient.
Who are axillary node-positive patient?
Patients with axillary node cancer after removing primary breast cancer surgically.

Side effects:
Nausea and vomiting.
Irreversible dose-dependent cardiotoxicity due to production of super-oxide radicals and other reasons (More common in Doxorubicin “Black Box Warning” compared towards Epirubicin).
How to protect patient from previous side effect?
Throughout;
a. Using Dexrazoxane which is cardio-protective agent as being ethylene di-amine tetra-acetic acid (EDTA) derivative;
• Chelates with iron ions.
• Decreases number of metal ions complexed with anthracyclines.
• Decreases production of super-oxide radicals.
b. Using poly-ethylene glycol (PEG) coated liposomal-encapsulated form.
Other side effects: Congestive heart failure (Ratio of incidence is increased whether Trastuzumab is added towards therapy protocols with Doxorubicin and Epirubicin).
Arrhythmia.
Myelosuppression.
Alopecia.

Precautions:
As their color is dark red and provided in parenteral dosage form (Intra-vascular (IV) infusion only) causing;
• Extravasation causing tissue necrosis.
• Veins become visible surrounding site of infusion, and also urine becomes red probably.
How to protect patient from previous precaution?
Throughout using Dexrazoxane which is extravasation antidote.

Contra-indications:
• Not safe for pregnant women (Not plan to be pregnant during therapy or even at least 6 months after therapy).
• Not safe for breastfeeding women due to coming through into breast milk (Not plan to breast feed during therapy or even at least 10 days after therapy).

References:
www.cancerresearchuk.org
www.reference.medscape.com
www.ncbi.nlm.nih.gov
www.go.drugbank.com
www.medlineplus.gov
www.sciencedirect.com
www.mayoclinic.org

26/05/2023

Methotrexate (MTX).

Class:
Anti-metabolites - Folic acid analogues.

Pharmaco-kinetics:
a.Absorption;
•Whether provided in oral dosage form; Absorption is high, while decreased by food (Patient should be consulted to take MTX without food).
•Whether provided in parenteral dosage form either intravenously (IV), intramuscularly (IM), subcutaneously (SC) or intrathecally; Absorption is also high, so whether patient should take large dose, preservative-free formulation of MTX which does not contain benzyl alcohol, should be used and vice versa.
b.Distribution; Distribution is high towards body cells.
c.Metabolism; Metabolism occurs inside body cells and liver related towards quantity;
•Major quantity of MTX is converted towards poly-glutamate form (Active form) by folyl-poly-glutamate synthetase (FPGS) enzyme then poly-glutamate form is converted back towards MTX by hydrolase enzyme.
•Minor quantity of MTX is converted towards 7-hydroxy-MTX by hydroxylase enzyme, solubility of 7-hydroxy-MTX is less than solubility of MTX, so crystalluria occurs (Patient should be consulted to drink plenty of water).
d.Excretion; Excretion occurs related towards quantity;
•Major quantity of MTX is excreted in urine within 24 hours (Patient should be consulted to drink plenty of water).
•Minor quantity of MTX is excreted in f***s.

Mechanism of action:
MTX inhibits DNA synthesis.
•How? MTX inhibits de-novo synthesis of nucleoside thymidine.
•How? MTX inhibits folic acid synthesis.
•How? MTX inhibits conversion of di-hydro-folic acid (Inactive form of folic acid) towards tetra-hydro-folic acid (Active form of folic acid).
•How? MTX competitively inhibits di-hydro-folate reductase (DHFR) enzyme which is responsible for previous conversion.
•How? Chemical structure of MTX is similar to chemical structure of folic acid, in addition to, affinity of MTX towards di-hydro-folate reductase (DHFR) enzyme is about 1000-fold compared towards di-hydro-folic acid (Inactive form of folic acid).

Resistance:
•Decrease in production of folate carrier causing decrease in transportation of MTX inside cells.
•Increase in production of P170 glyco-protein pump causing increase in transportation of MTX outside cells (No accumulation as stimulation of multi-drug resistance mechanism).
•Decrease in production of poly-glutamate form.
•Increase in production of di-hydro-folate reductase (DHFR) enzyme (Full enzymatic saturation by MTX does not occur).
•Change in affinity of MTX towards di-hydro-folate reductase (DHFR) enzyme.

Use:
•Treatment of cancer e.g. acute lymphocytic leukemia, Burkitt’s lymphoma, urinary bladder cancer, breast cancer, neck and head carcinoma … etc. (As adjunctive therapy).
•Treatment of auto-immune diseases e.g. psoriasis, rheumatoid arthritis, Crohn’s disease … etc. (As mono-therapy).
•Treatment of ectopic pregnancy.
•Medical abortion.

Dose:
•Whether provided in oral dosage form; 2.5 mg 2 to 4 times per week.
•Whether provided in parental dosage form; 10 to 25 mg once weekly.

Side effects:
•Stomatitis.
•Anemia.
•Hepatotoxicity (Dose-related side effect).
•Kidney failure (Dose-related side effect).
Therefore, patient should take folic acid as external supplement once daily (Not within on-days, while off-days) regardless of previous causing decrease in efficacy of MTX by about 10%, while also decrease in severity of side effects of MTX.

Contra-indications:
•Not safe for pregnant women as being abortifacient agent, in addition to, MTX is classified as category X.
•Not recommended for breastfeeding women (Risk to benefit decision).

Drug-drug interactions:
There are medications causing increase in plasma concentration of MTX;
•Non-steroidal anti-inflammatory drugs (NSAIDs).
•Proton pump inhibitors (PPIs).
•Pencillins, cephalosporins and aminoglycosides.
•Valproates.

References:
www.medlineplus.gov
www.mayoclinic.org
www.drugs.com
www.reference.medscape.com
www.medicalnewstoday.com
www.nhs.uk

26/05/2023

Vitamin D.

Bio-activation of vitamin D.
Vitamin D which is also called “Calci-ferol”, fat-soluble vitamin undergoes 2 hydroxylation reactions for binding towards vitamin D receptors (VDRs) in human body;
• First hydroxylation reaction occurs in liver, converts to 25-hydroxy vitamin D [25(OH)D] which is also called “Calci-di-ol”.
• Second hydroxylation reaction occurs in kidney, converts to 1,25-di-hydroxy vitamin D [1,25(OH)2D] which is also called “Calci-tri-ol”.
Vitamin D2 vs vitamin D3.

Introduction:
Vitamin D2 and vitamin D3 are 2 major forms vitamin D;
• Vitamin D2 is also called “Ergo-calci-ferol”.
• Vitamin D3 is also called “Chole-calci-ferol”.

Source:
Vitamins D2 and vitamin D3 have slightly different molecular
structures;
• Vitamin D2 comes from plants and yeast.
• Vitamin D3 comes from animals.

Which one is better than other for human health?
• According to National Institute of Health’s Office of Dietary Supplements Trusted Source, both types will increase levels of vitamin D in person’s blood.
• According to 2012 review Trusted Source, Vitamin D3 may raise levels higher and for longer compared towards vitamin D2.
Vitamin D deficiency.

Dose regimens:
There are 2 major dose regimens;
• Dose regimen in order to make up for vitamin D deficiency in which patient takes vitamin D for specific period of time only.
• Dose regimen in order to be protected from vitamin D deficiency in which patient takes vitamin D for lifetime.

How to make up for vitamin D deficiency?
Patient should take vitamin D2 or D3 either;
• 5,000 to 10,000 IU every day for 6 to 8 weeks.
• 50,000 IU every week for 6 to 8 weeks.
• 200,000 IU every 2 weeks or every month (Only 3 doses).
• 600,000 IU once (Only 1 dose).

How to be protected from vitamin D deficiency?
Patient should take vitamin D2 or D3 either;
• 1000 IU only 1 time every day.
• 5,000 IU 2 times every week.
• 10,000 IU only 1 time every week.
• 50,000 IU only 1 time every month.
• 200,000 IU only 1 time every 3 to 6 months.
• 600,000 IU only 1 time every year.

How to know that there is vitamin D deficiency?
Throughout laboratory test in which quantity of 25-hydroxy vitamin D is measured;
• Whether less than 20 ng/ml, vitamin D is deficient.
• Whether between 20 to 30 ng/ml, vitamin D is insufficient.
• Whether between 30 to 80 ng/ml, vitamin D is within normal limits.
• Whether more than 100 ng/ml, vitamin D is toxic.

References:
www.journals.physiology.org
www.medicalnewstoday.com
www.healthline.com
www.ods.od.nih.gov
www.cancer.gov

QUICK HINT

08/07/2023

02/07/2023

17/06/2023

10/06/2023

26/05/2023

26/05/2023

26/05/2023

26/05/2023

26/05/2023

26/05/2023

Address

Website

Alerts

Shortcuts

Share