Chemotherapy & Endocrine Drugs
1. What this chapter covers, and how NEET PG actually tests it
These two subjects appear unrelated but share a single organising method: locate where the drug acts, and its effects follow.
For cytotoxics, the location is a point in the cell cycle, and the shared toxicity comes from whichever normal tissues divide fastest.
Marrow, gastrointestinal mucosa, hair follicles and germ cells divide rapidly, which is why myelosuppression, mucositis, alopecia and infertility are common to almost the whole class.
For endocrine drugs, the location is a point in a hormonal axis, and both the therapeutic effect and the feedback consequences follow from that point.
| Area | The question actually being asked | Usual clue |
|---|---|---|
| Cytotoxic classes | Which phase, which mechanism | A named drug |
| Organ-specific toxicity | Which drug caused this | An organ complication |
| Targeted therapy | Which molecular target | A receptor or mutation |
| Thyroid drugs | Which step in synthesis | A pregnancy or crisis setting |
| Corticosteroids | Which effects, which risks | Duration of use |
| Diabetes drugs | Mechanism and cardiovascular effect | A comorbidity |
2. Cytotoxic chemotherapy
2.1 Cell cycle specificity
Cell cycle non-specific agents act at any phase and include the alkylating agents and platinum compounds.
Phase-specific agents act at one point: antimetabolites in S phase, vinca alkaloids in M phase, taxanes also in M phase, and bleomycin and etoposide largely in G2.
Phase-specific agents show a plateau in their dose-response curve, because only cells in the vulnerable phase can be killed however much drug is given, which is why they are given as repeated cycles rather than as one large dose.
Non-specific agents show a linear dose-response, which is the basis of high-dose therapy before stem cell transplantation.
2.2 The classes and their signature toxicities
| Class | Examples | Signature toxicity |
|---|---|---|
| Alkylating agents | Cyclophosphamide, busulfan | Haemorrhagic cystitis, pulmonary fibrosis |
| Platinum | Cisplatin, carboplatin | Nephrotoxicity, ototoxicity, neuropathy |
| Antimetabolites | Methotrexate, 5-fluorouracil | Mucositis, myelosuppression |
| Vinca alkaloids | Vincristine, vinblastine | Peripheral neuropathy, marrow sparing for vincristine |
| Taxanes | Paclitaxel, docetaxel | Neuropathy, hypersensitivity |
| Anthracyclines | Doxorubicin | Cumulative cardiotoxicity |
| Antitumour antibiotics | Bleomycin | Pulmonary fibrosis, minimal marrow toxicity |
| Topoisomerase inhibitors | Etoposide, irinotecan | Myelosuppression, diarrhoea for irinotecan |
Cyclophosphamide causes haemorrhagic cystitis through its metabolite acrolein, and mesna binds acrolein in the urine, which is why mesna protects the bladder without reducing antitumour effect.
Vincristine and bleomycin are the two agents notable for sparing the marrow, which is why they appear in regimens alongside strongly myelosuppressive drugs.
Doxorubicin cardiotoxicity is cumulative and dose-limited, mediated by free radical generation, and dexrazoxane reduces it by chelating iron.
Methotrexate inhibits dihydrofolate reductase, and folinic acid rescue bypasses the block by supplying reduced folate directly.
Folinic acid rescues normal cells but not tumour cells in high-dose regimens because of differences in uptake, which is what makes the strategy work.
2.3 Targeted therapy
| Drug | Target | Indication |
|---|---|---|
| Imatinib | BCR-ABL, c-KIT | CML, gastrointestinal stromal tumour |
| Trastuzumab | HER2 | Breast, gastric |
| Rituximab | CD20 | B cell lymphoma |
| Bevacizumab | VEGF | Various solid tumours |
| Erlotinib, gefitinib | EGFR | Lung adenocarcinoma with mutation |
| Checkpoint inhibitors | PD-1, PD-L1, CTLA-4 | Melanoma, lung, renal |
Trastuzumab causes cardiotoxicity that is usually reversible, unlike the cumulative irreversible damage of doxorubicin.
Bevacizumab impairs wound healing and causes hypertension, bleeding and gastrointestinal perforation, all consequences of inhibiting new vessel formation.
Checkpoint inhibitor toxicity is autoimmune in character, producing colitis, hepatitis, pneumonitis and endocrinopathies, and it is treated with corticosteroids rather than by dose reduction alone.
2.4 Managing the predictable complications
Much of oncology pharmacology is supportive, and these agents are examined as often as the cytotoxics themselves.
Chemotherapy-induced vomiting has three patterns, and each responds to a different drug.
Acute vomiting within 24 hours is serotonin-mediated and responds to ondansetron, since chemotherapy releases serotonin from gut enterochromaffin cells.
Delayed vomiting after 24 hours is substance P-mediated and responds to aprepitant, a neurokinin-1 antagonist.
Anticipatory vomiting is a conditioned response and responds to a benzodiazepine such as lorazepam rather than to any antiemetic.
Dexamethasone is added across all three patterns and is a genuinely effective antiemetic in this setting.
Granulocyte colony-stimulating factor shortens the duration of neutropenia and is used prophylactically in regimens with high febrile neutropenia risk.
Tumour lysis syndrome occurs when a large, rapidly proliferating tumour is destroyed quickly, releasing intracellular contents: potassium, phosphate and nucleic acids.
The resulting biochemistry is hyperkalaemia, hyperphosphataemia, hyperuricaemia and hypocalcaemia, with acute kidney injury from urate and calcium phosphate deposition.
Prevention is hydration with allopurinol, or rasburicase where risk is high, since rasburicase converts urate to the far more soluble allantoin.
Calcium phosphate deposition explains why the calcium falls, and it is why the phosphate rather than the calcium is the target of treatment.
3. Corticosteroids and immunosuppressants
3.1 Corticosteroid actions and consequences
Corticosteroids act on nuclear receptors, so their onset is hours rather than minutes.
They inhibit phospholipase A2, blocking both prostaglandin and leukotriene generation, which distinguishes them from non-steroidal anti-inflammatory drugs.
Every major adverse effect is an exaggeration of a normal glucocorticoid or mineralocorticoid action: hyperglycaemia, osteoporosis, immunosuppression, thin skin, proximal myopathy, cataract, and sodium retention with hypokalaemia.
Suppression of the hypothalamic-pituitary-adrenal axis is the reason steroids must be tapered after prolonged use, since abrupt withdrawal precipitates adrenal crisis.
Dexamethasone has negligible mineralocorticoid activity, which is why it is chosen where fluid retention must be avoided, as in cerebral oedema.
Fludrocortisone has the greatest mineralocorticoid activity and is used in Addison disease alongside a glucocorticoid.
3.2 Immunosuppressants
Ciclosporin and tacrolimus are calcineurin inhibitors, blocking interleukin-2 transcription; both are nephrotoxic.
Ciclosporin additionally causes gum hypertrophy and hirsutism, while tacrolimus causes more neurotoxicity and diabetes.
Azathioprine is converted to 6-mercaptopurine, and allopurinol blocks its breakdown by xanthine oxidase, so co-administration causes severe marrow suppression unless the azathioprine dose is greatly reduced.
Thiopurine methyltransferase deficiency causes the same problem genetically, which is why the enzyme is tested before starting treatment.
Mycophenolate inhibits inosine monophosphate dehydrogenase, affecting lymphocytes selectively because they lack a salvage pathway.
That absence of a salvage pathway is the whole basis of its selectivity, since every other cell type can obtain purines by an alternative route when synthesis is blocked.
Sirolimus inhibits mTOR rather than calcineurin, so it is not nephrotoxic, but it causes hyperlipidaemia and impairs wound healing.
Long-term immunosuppression of any kind raises the risk of opportunistic infection and of malignancy, particularly skin cancer and post-transplant lymphoproliferative disease driven by Epstein-Barr virus.
4. Thyroid, bone and reproductive endocrine drugs
4.1 Thyroid
Carbimazole and propylthiouracil both inhibit thyroid peroxidase and therefore block hormone synthesis.
Propylthiouracil additionally blocks peripheral conversion of thyroxine to triiodothyronine, which is why it is preferred in thyroid storm despite being more hepatotoxic.
Carbimazole is preferred otherwise, and both can cause agranulocytosis, so any sore throat during treatment requires an urgent full blood count.
Propylthiouracil is used in the first trimester because carbimazole is associated with aplasia cutis and other embryopathy, with a switch back afterwards to limit hepatotoxicity.
Levothyroxine absorption is reduced by calcium, iron and proton pump inhibitors, so timing matters, and the dose must rise in pregnancy.
The dose rises in pregnancy because oestrogen increases thyroxine-binding globulin, so more hormone is bound and more total hormone is needed to maintain the free fraction.
Beta blockers are used symptomatically in thyrotoxicosis, and propranolol has the additional benefit of modestly reducing peripheral conversion.
4.2 Bone
Bisphosphonates inhibit osteoclast-mediated resorption and must be taken upright with water on an empty stomach to avoid oesophagitis.
Their distinctive long-term risks are osteonecrosis of the jaw and atypical femoral fracture.
Denosumab is a monoclonal antibody against RANK ligand, and stopping it causes rapid rebound bone loss, so it cannot simply be discontinued.
Teriparatide is recombinant parathyroid hormone, and it builds bone only when given intermittently, since continuous exposure causes resorption instead.
That paradox is the point worth understanding: the same hormone builds or destroys bone depending entirely on the pattern of exposure.
4.3 Reproductive endocrine drugs
Combined oral contraceptives suppress ovulation and increase venous thromboembolism risk, and their efficacy is reduced by enzyme inducers.
Selective oestrogen receptor modulators act differently by tissue: tamoxifen antagonises breast but agonises endometrium, raising endometrial cancer risk, while raloxifene does not.
Aromatase inhibitors work only after menopause, because before it the ovary produces oestrogen directly rather than by peripheral aromatisation.
That single mechanistic fact decides the whole question of which endocrine therapy a breast cancer patient receives, since a premenopausal woman gets tamoxifen while a postmenopausal woman may get an aromatase inhibitor.
Aromatase inhibitors accelerate bone loss because they remove oestrogen entirely, whereas tamoxifen's partial agonism at bone is mildly protective.
Clomiphene blocks hypothalamic oestrogen receptors, removing negative feedback and increasing gonadotrophin release, which is why it induces ovulation.
GnRH analogues illustrate the same pulsatile principle as parathyroid hormone: pulsatile administration stimulates gonadotrophin release, while continuous administration downregulates the receptor and suppresses it.
That is why leuprolide, given continuously, is used as chemical castration in prostate cancer, and why an initial testosterone flare occurs before suppression begins.
Clomiphene blocks hypothalamic oestrogen receptors, removing negative feedback and increasing gonadotrophin release, which is why it induces ovulation.
4.4 Pituitary and adrenal drugs
These drugs are best understood by asking where in the axis they act, since that determines both effect and monitoring.
Somatostatin analogues such as octreotide suppress growth hormone release and are used in acromegaly, as well as in variceal bleeding and neuroendocrine tumours, and they cause gallstones by reducing gallbladder contraction.
Pegvisomant is a growth hormone receptor antagonist, so it normalises insulin-like growth factor 1 while growth hormone levels rise, which makes growth hormone useless for monitoring on that drug.
Cabergoline and bromocriptine are dopamine agonists and are first-line for prolactinoma, since dopamine is the natural inhibitor of prolactin and shrinking the tumour medically usually avoids surgery.
Desmopressin is a vasopressin analogue with selective V2 activity, used in central diabetes insipidus and in mild haemophilia A and von Willebrand disease, where it releases stored factor VIII and von Willebrand factor.
Metyrapone and ketoconazole inhibit steroid synthesis and are used medically in Cushing syndrome while awaiting definitive treatment.
Spironolactone antagonises aldosterone and is used in Conn syndrome, and its anti-androgen action causes gynaecomastia; eplerenone is more selective and avoids that.
5. Diabetes drugs
5.1 The oral agents
| Class | Mechanism | Key points |
|---|---|---|
| Metformin | Reduces hepatic gluconeogenesis, improves sensitivity | First-line, weight-neutral, no hypoglycaemia, lactic acidosis risk |
| Sulphonylureas | Close K-ATP channels, release insulin | Hypoglycaemia, weight gain |
| DPP-4 inhibitors | Prolong incretin action | Weight-neutral, well tolerated |
| GLP-1 agonists | Incretin mimetics | Weight loss, cardiovascular benefit, injectable |
| SGLT2 inhibitors | Block renal glucose reabsorption | Weight loss, cardiac and renal benefit |
| Pioglitazone | PPAR-gamma agonist | Fluid retention, fracture risk, heart failure |
Metformin does not cause hypoglycaemia because it does not stimulate insulin release, which is the mechanistic reason it is safe as monotherapy and first-line.
It is withheld around iodinated contrast and in significant renal impairment because of lactic acidosis risk, and it causes vitamin B12 malabsorption on long-term use.
Sulphonylureas cause hypoglycaemia precisely because they release insulin regardless of the glucose level, which is the mirror image of metformin's safety.
SGLT2 inhibitors and GLP-1 agonists are the two classes with proven cardiovascular outcome benefit, which is why they are chosen ahead of others in patients with established cardiovascular or renal disease.
Euglycaemic diabetic ketoacidosis is the SGLT2 inhibitor complication most often missed, because the glucose is not high enough to prompt the diagnosis.
5.2 Insulin
Rapid-acting analogues such as lispro and aspart act within fifteen minutes and are given with meals.
Regular insulin acts within thirty to sixty minutes; intermediate NPH acts over hours; glargine and degludec provide flat basal cover without a pronounced peak.
The Somogyi phenomenon is rebound morning hyperglycaemia after nocturnal hypoglycaemia, while the dawn phenomenon is morning hyperglycaemia from overnight growth hormone and cortisol without preceding hypoglycaemia.
Distinguishing them requires a measurement during the night, and the managements are opposite: reduce the evening insulin in one, increase it in the other.
Insulin drives potassium into cells, which is why it is used with glucose to treat hyperkalaemia and why potassium must be replaced during treatment of diabetic ketoacidosis.
In ketoacidosis the total body potassium is depleted even when the serum value looks normal or high, because acidosis has driven potassium out of cells, so starting insulin without replacement precipitates dangerous hypokalaemia.
Beta blockers mask the adrenergic warning signs of hypoglycaemia while leaving sweating intact, which matters when prescribing for an insulin-treated patient.
Glucagon is the out-of-hospital treatment for severe hypoglycaemia, but it fails in a patient with depleted glycogen stores, such as someone with alcohol-related hypoglycaemia.
6. Worked examples
Example 1
A patient on azathioprine for inflammatory bowel disease is started on allopurinol for gout and develops profound pancytopenia.
Azathioprine is converted to 6-mercaptopurine, which is inactivated largely by xanthine oxidase.
Allopurinol is a xanthine oxidase inhibitor, so it blocks that inactivation.
Active metabolite accumulates dramatically, producing severe marrow suppression at an unchanged azathioprine dose.
If the combination is unavoidable, the azathioprine dose must be reduced substantially, and the same vulnerability exists genetically in thiopurine methyltransferase deficiency.
Example 2
A woman in thyroid storm is treated. Why is propylthiouracil chosen over carbimazole here when carbimazole is preferred routinely?
Both drugs inhibit thyroid peroxidase and therefore block new hormone synthesis, which takes time to lower circulating levels.
Propylthiouracil has the additional action of blocking peripheral conversion of thyroxine to the more active triiodothyronine, which reduces hormone effect faster.
In a crisis, that speed outweighs propylthiouracil's greater hepatotoxicity.
Outside a crisis, carbimazole is preferred precisely because that hepatotoxicity matters more than a marginal speed advantage.
Example 3
A patient on high-dose methotrexate is given folinic acid 24 hours later. Why does this rescue normal cells without abolishing the antitumour effect?
Methotrexate blocks dihydrofolate reductase, depriving cells of reduced folate for thymidine synthesis.
Folinic acid is already reduced, so it bypasses the blocked enzyme entirely and restores synthesis.
The selectivity comes from differences in uptake between normal and malignant cells, together with careful timing, so normal tissue recovers while the tumour has already sustained its damage.
Folic acid would not work, because it still requires dihydrofolate reductase to be reduced.
7. Traps the exam sets repeatedly
Combining allopurinol with azathioprine at unchanged dose. Xanthine oxidase inhibition causes accumulation of active metabolite and severe marrow suppression.
Using an aromatase inhibitor in a premenopausal woman. Before menopause the ovary makes oestrogen directly, so blocking peripheral aromatisation achieves little.
Expecting metformin to cause hypoglycaemia. It does not stimulate insulin release, which is why it is safe as monotherapy.
Giving folic acid instead of folinic acid for methotrexate rescue. Folic acid still needs the blocked enzyme; folinic acid is already reduced.
Stopping denosumab without a plan. Rebound bone loss follows discontinuation, unlike bisphosphonates which persist in bone.
Starting insulin in ketoacidosis before checking potassium. Total body potassium is depleted even when the serum value looks normal, and insulin drives it further down.
Monitoring growth hormone in a patient on pegvisomant. The drug blocks the receptor, so growth hormone rises while the disease improves; insulin-like growth factor 1 is the correct measure.
Using an antiemetic alone for anticipatory vomiting. It is a conditioned response and needs a benzodiazepine, not a serotonin antagonist.
Summary
Cytotoxic drugs are located by cell cycle phase, and their shared toxicity reflects the normal tissues that divide fastest.
Phase-specific agents plateau in their dose-response, which is why they are given in repeated cycles.
Cyclophosphamide causes haemorrhagic cystitis through acrolein, and mesna binds it in the urine.
Vincristine and bleomycin spare the marrow, which is why they combine well with myelosuppressive agents.
Checkpoint inhibitor toxicity is autoimmune and is treated with corticosteroids.
Every corticosteroid adverse effect is an exaggeration of a normal glucocorticoid or mineralocorticoid action.
Allopurinol blocks azathioprine breakdown by xanthine oxidase, causing severe marrow suppression.
Propylthiouracil blocks peripheral conversion as well as synthesis, which is why it is preferred in thyroid storm.
Teriparatide builds bone only when given intermittently, since continuous parathyroid hormone exposure causes resorption.
Metformin cannot cause hypoglycaemia because it does not release insulin, while sulphonylureas do so regardless of glucose level.
Chemotherapy vomiting has three patterns with three different treatments, separated by their timing relative to the dose.
Tumour lysis syndrome releases potassium, phosphate and urate, and the calcium falls because it precipitates with phosphate.
SGLT2 inhibitors and GLP-1 agonists are the two diabetes classes with proven cardiovascular outcome benefit.
Somatostatin analogues suppress growth hormone and cause gallstones by reducing gallbladder contraction.
