Anti-Thyroid, Anti-Diabetogenic Drugs Flashcards
Anti-thyroid drugs
mechanisms
1. Block Na+/I- symport: Thiocyanate, perchlorate, fluoborate 2. Block thyroid peroxidase: Propylthiouracil, carbimazole 3. Block thiol endopeptidase: KI, Lugol’s iodine 4. Block 5’-deiodinase: PTU, Amiodarone, β 🅱️
Na+/I- symport inhibitors and their side effects
1. Thiocyanate: Neuropsychiatric symptoms 2. Perchlorate: Aplastic anaemia 3. Fluoborate Not preferred due to toxicity
Thyroid peroxidase inhibitors and their side effects
1. Propylthiouracil: Short acting but hepatotoxic 2. Carbimazole: Long acting but teratogenic Common S/E: • Agranulocytosis • GIT upset • Allergic dermatitis
Propylthiouracil PTU
• Short acting thyroid peroxidase inhibitor
• Requires multiple dosing
• S/E hepatotoxic
Uses:
1. DoC in 1st trimester of🤰 for hyperthyroidism and Grave’s disease
2. Preferred in breast feeding
3. DoC in severe thyrotoxicosis/ thyroid storm because it inhibits peripheral T4 ➡️ T3
Carbimazole (prodrug of methimazole)
Longest acting thyroid peroxidase inhibitor Single dose Teratogenic: • choanal/oesophageal atresia • cutis aplasia Uses: DoC of hyperthyroidism and Grave’s disease overall (preferred in 2nd/3rd trimester of 🤰, but not in breast feeding) They are 10 times more potent than PTU
Thiol endopeptidase inhibitors
Inhibit T3-T4 release
Fastest anti-thyroid drugs
• Potassium iodide, Lugol’s iodine
Develop tolerance:
1. Inhibit vasculogenesis in thyroid
2. Make thyroid tissue firm and reduce size of thyroid gland
Use: prior to thyroid surgery to reduce complications
Side effects of thiol endopeptidase inhibitors
- Hypersensitivity: rash, angioedema
- Iodism ➡️ headache
- Dysgeusia ➡️ metallic taste in mouth
The drugs are potassium iodide and Lugol’s iodine
5’ de-iodinase inhibitors
Block peripheral conversion of T3-T4 Drugs: 1. PTU 2. Amiodarone 3. β-blockers 4. Steroids
Radioactive iodine
Two isotopes: 1. I-123 Emits γ rays Used in thyroid scan 2. I-131 Emits γ and β rays β-rays are destructive Used in thyroid ablation
Uses of I-131
- Hyperthyroidism: elderly and arrhythmia patients
- Thyroid cancer except medullary
- Recurrent Grave’s disease:
Worsens ocular symptoms ➡️ steroids given 2 months before - Toxic nodular goitre
Side effects of I-131
- Permanent hypothyroidism
- 2° cancer
- Hyperparathyroidism
Contraindications of I-131
- Pregnancy 🤰
- Thyroid peroxidase inhibitor is stopped 4 days before I-131 therapy:
It decreases uptake of I-131
Treatment of hypothyroidism
1. Levothyroxine: Na+ salt of T4 Long acting In 🤰, dose 🔼 by 30% Oral bioavailability is 80% ➡️ dose 🔽 by 20% in IV 2. Liothyronine: Na+ salt of T3 Short acting 100% bioavailability, so no dose reduction
Liothyronine (T3) is more potent than T4 but not recommended as routine therapy
in hypothyroidism
Liothyronine (T3) has shorter halflife (24 hours), requires multiple daily doses.
Contraindicated in cardiac patients as it poses greater risk of cardiotoxicity. More expensive
than levothyroxine. Difficulty in monitoring its adequacy by routine lab tests
Uses of levothyroxine
Via oral route: 1. Replacement in hypothyroidism OD 30 min before breakfast 🍳 on empty stomach 2. Thyroid cancer: to 🔽 TSH 3. Thyroid nodules: if TSH 🔼 Via IV route: 4. Myxedema coma: Dose calculated based on lean body mass
Side effects of levothyroxine
- 🔼 atrial fibrillation, so 🔽 dose in patients with arrhythmia
- Osteoporosis
- Hyperglycaemia
- Asthenia
Uses of liothyronine
- Treatment of myxedema coma
- Preparation of thyroid cancer
- Patients for I-131 therapy
Receptors of the pancreas for glucose metabolism
GLP-1-R
GLUT-2-R
Absorption of disaccharides into circulation
It is converted into glucose by α-glucosidase and then absorbed into circulation
GLP-1 receptor is stimulated by what mechanism
- Glucose ➡️ Intestinal epithelial cells
- 🔼 release of GLP-1 (Incretin)
- Reaches plasma
- GLP-1 metabolised in plasma by DPP-4 ➡️ GLP-1-short acting
- Both stimulates GLP-1-R receptor
Action of GLP-1-short acting (and its precursor)
- Act on GLP-1-R (+)
- Inhibits motility of stomach
➡️ delays gastric emptying
➡️ induces satiety
➡️ blunt’s post prandial hyperglycemia
Action of GLP-1-Receptor of pancreas
- Releases insulin ➡️ bring GLUT-4 out on cell membrane
- Releases amylin ➡️
negative motility of stomach ➡️
delays gastric emptying ➡️
blunts post-prandial hyperglycemia
Insulin secretion by GLUT-2 Receptor
- Post prandial hyperglycemia
- Sensed by GLUT-2-R on β-islet cells
- Glucose enters β-cells through GLUT-2
- ATP generated based on inner glucose level
- ATP sensitive K+ channels are blocked
- 🔼 Ca2+ in cell
- Insulin release
α-glucosidase inhibitors
examples and uses
Pseudocarbohydrates FDA approved only for DM-type II
1. Acarbose
2. Voglibose
3. Miglitol-max absorption
Source: bacteria
Use: prandial and post prandial hyperglycemia
Taken after 1st bite of food
α-glucosidase inhibitors
side effects
- Flatulence due to excess disaccharide digestion by 🦠
- Diarrhea (osmotic)
- 🔽 absorption of other drugs ➡️ other drugs should be taken 2hr before or after this
The drugs are Acarbose, Voglibose, Miglitol
α-glucosidase inhibitors
CI
- Renal failure
- IBD
- Gastroparesis
The drugs are Acarbose, Voglibose, Miglitol
GLP-1 releasing drugs
types and common features
Two types: 1. GLP-1-R agonist 2. DPP-4 receptor Use: T2 DM S/E: 1. Pancreatitis: by its overstimulation 2. 🤢, 🤮: delayed gastric emptying 3. Weight loss
GLP-1 agonist drugs
types, examples and their dosing intervals
1. Exendin-4 (from Gila monster) and its derivatives: • Exenatide - BD • Lixisenatide - OD 2. Synthetic: • Liraglutide - OD • Albiglutide • Dulaglutide • Semaglutide Last 3 are long acting, given weekly once
GLP-1 agonist
route, use, CI
Subcutaneous route Recently oral semaglutide Use: T2 DM maintained Monotherapy or not CI: 1. Renal failure: • Exenatide: S/E: renal failure • Lixisenatide: renal excretion 2. MEN-II 3. Medullary Thyroid Cancer
GLP-1 agonist
side effects
- Pancreatitis
- 🤢,🤮: 🔽 with Albiglutide
- Weight loss:
2° use of Liraglutide for obesity - 🔼 risk of diabetic retinopathy:
with semaglutide
Teduglutide
GLP-2 agonist Use: short bowel syndrome to 🔼 absorption Mechanism: 🔼 proliferation of intestinal epithelial cells S/E: 1. Colon cancer 2. Flu like symptoms 3. GIT upset
DPP-4 inhibitor drugs
Gliptans 1. Sita 👱🏽♀️ 2. Saxa: CHF 3. Alo 4. Lina 👩🏽🦰: not CI in renal failure 5. Vilda 🧑🏻🦰: Hepatitis Like linagliptan
DPP-4 inhibitors
route, use and contraindications
Orally for T2 DM maintenance as monotherapy or not
CI: renal failure except linagliptin excreted by liver.
DPP-4 inhibitors
side effects
1. Pancreatitis: max with Sita 👱🏽♀️ 2. Hypersensitivity (rare): • SJS • Angioedema 3. Block CD-26 (structurally similar) ➡️ 🔼 risk of infections 4. Saxa: CHF 5. Vilda 🧑🏻🦰: hepatitis
Amylin analogue
mechanism, side effects
Pramlintide Mechanism: 1. Delays gastric emptying ➡️ slow absorption of glucose 2. Satiety 3. 🔽 glucagon release S/E: 1. 🤢, 🤮 2. Weight loss
Amylin analogue
use
Pramlintide
Post prandial hyperglycemia
In T1 and T2 DM, it can be used along with insulin
📝 :
1. Dose of insulin 🔽 by 50%
2. Amylin has acidic pH of 4
So should not be combined with insulin in same 💉 (crystallization of insulin)
Oral hypoglycemic agents OHA
mechanisms
1. 🔼 insulin release: Inhibit ATP sensitive K+ channel 2. 🔽 insulin resistance: Act on insulin receptor 3. 🔽 hepatic glucose production 📝: these can be used only for T2 except 3. which can be used for both
SGLT-2 receptor inhibitors
Mechanism:
Reduce glucose reabsorption
Use: T2 DM
Common S/E for GLP-1 related drugs, insulin, OHA
Hypoglycemia
Insulin > OHA > GLP-1 related drugs
Insulin classification
1. Short acting: • Fast - Glulisine, lispro, aspart • Slow - regular insulin 2. Intermediate acting: • NPH, Lente insulin 4. Long acting: regular insulin + • SFA = Detemir • Arg + Gly = Glargine • HA = Degludec (longest acting)
Short acting insulin
1. Fast acting: • Glulisine, Lispro, Aspart • monomeric insulin: broken down into monomers immediately 2. Slow acting: • regular insulin (neutral pH)
Intermediate acting insulin
- NPH / Isophane
- Regular insulin + zinc protamine in PO4 buffer
- Also called NPH (Neural Protamine Hagedorn) or Isophane
- The only insulin with turbid solution - cloudy/milky appearance
Detemir and Glargine, 2 long acting insulins
1. Detemir: • Regular insulin + saturated FA • 🔼 albumin binding 2. Glargine: • + 2 arginine + 1 glycine • acidic pH • crystallizes when injected
Degludec longest acting insulin
- Regular insulin + Hexadecanoic acid
- 🔼 albumin binding
- When injected forms multiple hexamers
Insulin timings ⏱
• For post prandial hyperglycemia:- 1. Fast acting: Taken 20 min before food 2. Slow acting: Taken 60 min before food • Subcutaneously for maintenance of DM:- 3. Intermediate: BD dosing 4. Long acting: OD dosing
Insulin combinations in syringe 💉
One for post prandial hyperglycemia and one got maintenance of DM
1. Same 💉:
NPH + short acting drugs
Short acting drugs are withdrawn first
2. Different 💉:
Other insulin
Eg., Glargine will crystallize when with a short acting insulin in same 💉 ➡️ white cloudy 🌫 precipitate
Insulin
sites of subcutaneous administration
Abdomen M/C except periumbilical (lipodystrophy)
Ant. thigh/ upper buttock/ upper arm
Rate:
Maximum in abdomen except Glargine (depends on disintegration of crystals)
DoC for diabetic ketoacidosis and hyperkalemia
DoC is regular insulin
Lente insulin
Insulin + Zn It precipitates into: 1. Amorphous powder: Short acting ➡️ semilente 2. Crystals: Long acting ➡️ ultralente Combined both (30:70 resp.) to form intermediate acting lente insulin
Afrezza insulin
Inhalational insulin Fast acting Use: post-prandial hyperglycemia Available as color coded cartridges, BGY containing 4,8,12 units of insulin
Afrezza insulin
side effects and CI
S/E: 1. M/C cough 2. 🔼 risk of 🫁 cancer CI: 1. Bronchial asthma/COPD 2. Smokers 🚬
Insulin
side effects
1. Hypoglycemia: M/C except Alfrezza 🔼 in short acting so max on regular insulin 🔽 in long acting 2. Lipodystrophy 3. Lipohypertrophy: Due to HSL ➡️ 🔽 lipolysis 4. Hypokalemia
Sulfonylureas and Meglitinides
Properties
Both are oral hypoglycemic agents, 🔼 insulin release
Sulfonylureas are more potent and longer acting
Both are metabolised by liver and excreted by kidney
Sulfonylureas and Meglitinides
uses
Sulfonylurea:
1. Maintaining type 2 DM
2. Maximum 🔽 in HbA1C
> than biguanides
Sulfonylureas and Meglitinides
side effects
Common S/E:
Hypoglycemia and weight gain
Higher in sulfonylureas (preferred in thin patients)
(HSL 🅱️)
Sulfonylureas and Meglitinides
contraindications
Sulfonylureas:
CI in renal and liver failure
Meglitinides:
Metabolised by liver and excreted by kidney
Can be used in renal and liver failure with dose adjustment
Sulfonylureas
first generation drugs
Not preferred due to low potency 1. Acetohexamide 2. Tolbutamide: hepatotoxic 3. Chlorpropamide: S/E: SIADH hyponatremia Disulfiram like reaction
Sulfonylureas
second generation drugs
1. Glyburide/ Glibenclamide: concentrated in β-islet cells 2. Glimepiride 3. Gliclazide 4. Glipizide: lesser risk of hypoglycemia
Glyburide
Glibenclamide
Most potent sulfonylurea
Concentrated in β cells ➡️ longer acting than t1/2
S/E:
1. Potent inhibitor of cardiac ATP sensitive K+ channels
➡️ blunt myocardial response to ischemia
2. Disulfiram like reaction
Glipizide
Less potent and short acting 2nd generation sulfonylurea
Lesser risk of hypoglycemia
Preferred in patients of renal failure and elderly patients
Mechanism of thiazolidinediones
1. Stimulates PPAR-γ (nuclear receptor) ➡️ transcription factor 🔼 ➡️ insulin resistance 🔽 2. Adipocyte proliferation 🔼 3. GLUT-4 production 🔼
Examples of OHA which 🔽 insulin resistance
Thiazolidinediones 1. Pioglitazone: black box warning 🕋 2. Rosiglitazone: banned, MI and bladder cancer 3. Troglitazone: banned, hepatotoxic
Pioglitazone
Thiazolidinedione available in India with a black box warning 🕋 Also stimulates PPAR-α ➡️ 🔼 LPL ➡️: 1. 🔽 TAG, VLDL, chylomicron 2. 🔼 HDL S/E: bladder cancer Use: T2 DM
Thiazolidinedione
common S/E
- Stimulates epithelial Na+ channels ➡️ Na+/water retention, edema, CHF, weight gain
- Macular edema
- 🔼 risk of bone fracture in females
OHAs which 🔽 hepatic glucose production
Biguanides
- Metformin
- Phenformin: banned due to severe lactic acidosis
Biguanides
mechanism
1. Stimulate AMP kinase: • gluconeogenesis 🔽 ➡️ hepatic glucose production 🔽 • 🔽 insulin resistance • 🔼 lipid oxidation ➡️ 🔽 LDL 2. Block gastric emptying ➡️ 🔼 satiety
Metformin
Uses
1. DoC for Rx and prophylaxis of DM 🔽 microvascular complications 2. Polycystic Ovarian Syndrome 3. AIDS related metabolic syndrome 4. Non- alcoholic fatty liver disease 5. Antipsychotic induced weight gain
Metformin
side effects
- 🔽 Ca2+ induced vitamin B12 absorption
- 🤢, 🤮
- Weight loss
- Lactic acidosis
Metformin
contraindications
🔼 risk of lactic acidosis in
- Elderly
- Chronic alcoholics
- Renal/liver failure
- CHF
- Severe lung disease
SGLT-2 inhibitors
examples and basic features
-gliflozins
1. Canagliflozin
2. Dapa-
3. Empa-
4. Ertu-
Oral drugs
Use:
polytherapy only for DM with metformin/ DPP 🅱️
SGLT-2 inhibitors
S/E common
1. 🔼 glucose in urine: M/C - UTI by M/C Candida (➡️ vaginal pruritis in females) 2. 🔼 Na+ in using: 🔼 water loss • diuretic effect • hypotension • dehydration
SGLT-2 inhibitors
rare side effects
1. Urosepsis: M/C cause: E. coli 2. Fourier gangrene 3. Osteoporosis ➡️ 🦴 fracture 4. Pancreatitis 5. DKA with euglycemia 6. Canagliflozin: 🔼 risk of limb amputation 7. Dapagliflozin: 🔼 risk of bladder and breast cancer
Beneficial effects of SGLT-2 inhibitors
- 🔼 CVS mortality (🔽 bp) like GLP1 agonist
2. Weight loss
Anti diabetic action of colesevelam
Use: T2 DM
Mechanism: bile acid binding resins 🔼 🔽 glucose absorption
Anti diabetic action of bromocriptine
D2 agonist
Use: T2 DM
Mechanism:
🔽 in hypothalamic drive for hyperglycemia
Dual PPAR agonist as anti diabetic drugs
Stimulates PPAR α, γ α: 🔽 TAG γ: 🔽 glucose Drugs: 1. Saroglitazar 2. Ragaglitazar
Iodides should be initiated after thioamide therapy or avoided if treatment with
radioactive iodine seems likely
Iodide therapy will increase the intraglandular stores of iodine. It delays the onset of action
of thioamide therapy. Increased intraglandular iodine stores will inhibit the uptake of
radioactive iodine into the gland. So the therapy will be ineffective
Amiodarone produces both hypo and hyperthyroidism.
Amiodarone has structural similarity with thyroid hormone and high iodine content. The
iodine content accumulated in thyroid will inhibit thyroid synthesis and release resulting in
hypothyroidism.
Amiodarone causes autoimmune thyroiditis and releases excess thyroid hormone into circulation. Iodine content can increase the thyroid hormone synthesis and release.
Meglitinide analogs are useful for controlling postprandial hyperglycemia
Meglitinide analogs (Repaglinide and Nateglinide) have rapid onset of action and the peak effect is observed within 1 hour of ingestion. Hence if taken just before a meal, they effectively suppress postprandial hyperglycemia
Non selective beta blockers should be avoided in diabetics.
Beta-adrenoceptor-blocking drugs may impair the sympathetically mediated release of glucose from the liver in response to hypoglycaemia and also reduce the adrenergically mediated symptoms of hypoglycaemia (except sweating). Insulin hypoglycaemia may thus be more prolonged and/or less noticeable.
Ideally, a patient with diabetes needing a b-adrenoceptor blocker should be given a b1-selective member, e.g. bisoprolol only and non selective beta blocker has to be avoided
