Endocrinology Flashcards
Insulin was discovered by …..
Secretion and structure of insulin
Banning and best in 1921.
Prepoinsulin (86 aa)
|
Proinsulin
| cleave
C peptide.
Human insulin- 51aa: 21A chain 30Bchain
What are the insulin preparations?
- Conventional preparation
- Highly purified preparation
- Human insulin
- Insulin analogues
What are the conventional insulin preparations?
Beef insulin: 3 aa
Pork insulin: 1 aa
Difference:
Pork: 30B chain : Ala instead of thre
Beef: A chain: 8th: Ala
10th: Val
B chain: 30: ALA
OHA that elevate both C peptide and Human insulin.
Importance of C peptide
Sulfonylureas
Insulinomas: both rise
Factious hypoglycemia: only insulin rise
Factious hypoglycemia + sulfonylureas: dx with high index of suspicion + drug level in plasma / urine .
Hormone that inhibits both insulin and glucagon
Hormone that evokes release of insulin + somatostatin
Somatostatin
Glucagon
Insulin receptor is …..
B subunit has…..activity
Tetrameric glycoproteins containing A and B chain attached together with disulphide bonds.
Tyrosine kinase activity.
How is highly purified forms of insulin made? (2)
From gel filtration
Ion exchange chromatography
Human insulin is produced by …..how?
Recombinant DNA technology
Isolate insulin gene from human DNA by restriction endonuclease.
Take a vector and cut it -also with same enzyme.- plasmid
Insulin + plasmid —-> inject it into Ecoli/yeast (transformation)
This will multiply to form more human insulin genes.
Benefits of human insulin (3)
- Rapidly absorbed
- Shorter duration of action
- Earlier and more defined peak
Insulin analogues on basis of onset and duration of action
Rapid : onset: 10mins, DOA: 3-5hrs
Short: onset: 30min-1hr DOA: 6-8 hrs
Intermediate : onset: 1-2hrs DOA: 20hrs
Long acting : onset: 2-4 hrs DOA: >24hrs
What are the rapid acting insulin analogues ? Structure differences
Lispro: B chain 28,29
lys, proline-interchanged
Aspart: 28 : lys-> aspartic acid
Glulisine: 23,29 :
Asparate—>lysine
Lys—>glutamic acid
Short acting: is …..
Structure
Regular insulin given iv & s/c
Small amount of zinc added to hexameric structure.
Disadvantages of regular insulin
So remedy?
Should be taken 1/2-1hr before meals and it’s tiresome.
To overcome that: intermediate acting :
Lente:
ultralente: large crystalline particle,insoluble, longer duration of a action
Semilente: smaller , shorter duration.
Together given in ratio : 7:3.
Structure of glargine
Disadvantages
B chain: 2 more aa is added
A chain: aspargine—->glycine at 21.
Provide background insulin coverage but not for meal time insulin spikes
Structure of insulin determir
Longest acting insulin
On B chain at 29aa, fatty acid myristol is added.
Degludec- >40hrs
Can be mixed with other insulin as it’s at neutral ph.
All insulin preparations are hexameric except?
All insulin prep is at neutral ph except
Aspart, lispro, glulisine- monomeric
Insulin glargine-thus can’t be combined with other insulins
All insulin contains phosphate buffer except ….(3)
Regular
Glargine
Glulisine
Regular insulin + lente =…….disadvantage
Shortest acting insulin ….
Lose rapidity of action
Aspart- resemble physiological insulin activity
Disadvantage of rapid acting insulin
Use of Glulisine
Injected 2-3 times a day.
Given s/c via continuous pump.
Sites of insulin administration (4)
How to give insulin ?
Abdomen
Arms
Thigh
Flanks
Massage the s/c area to increase blood flow and give it s/c.
Sms of hypoglycaemia
- Sweating, anxiety ,palpitation, tremor
- Decrease glucose in brain: dizziness,headache,fatigue ,weakness,behavioural changes
Hypoglycaemic unawareness
30% lose adrenergic stimulation after some time .
Due to diabetic neuropathy, which abolishes the nerves,they are unable to recognise the hypoglycaemic changes.
Rx of hypoglycaemia in insulin rx
- Glucose
- Glucagon=0.5-1mg / adrenaline =0.2mg s/c where glucose is n/a.
Local reactions of insulin
Sweating,stinging,erythema
Lipodystrophy -multiple inj on same site
Allergy reaction of insulin injection (3)
Urticaria
Angioedema
Anaphylaxis
When does Edema occur?
Short lived, due to Na+ retention in early insulin rx.
What is NPH?
Isophane/ neutral protamine hagedorn
Instead of zinc, protamine is added 1:1 with regular insulin.
Interactions of insulin (4)
- B2 receptor blocker- masks warning signs, only rise in BP due to a stimulation by ADR.
- Thiazide,furosemide ,CS, OCP, salbutamol, nifedipine
- Acute ingestion of alcohol
- Lithium, aspirin,theophylline.
Regimen of insulin (2)
- Split mixed regimen:
Regular + lente=30:70
Bbf, before dinner - Basal bolus regimen
3-4 inj rapid acting daily + glargine
Isophane insulin has ……structure
Cloudy insulin is …..
6 molecules of insulin with 1 protamine
NPH insulin
Afreeza was used for …..
Rx of only post prandial hyperglycaemia - 30mins before meal.
Pharmacodynamics of afreeza
Mc side effect is ……
Absorption rapid
Peak insulin level- 15 mins
Declines to baseline after 3 hrs
Cough
C/I of afreeza (3)
Smokers
Asthma
Copd
Define term insulin’s resistance
When >100 units insulin is needed to keep blood glucose within normal limits
Causes of insulin resistance (14)
LOW PRACs
Leprechaunism
Lipodystrophy
Obesity
Werger syndrome
PCOD
Pineal hyperplasia
Rabson Mendenhall syndrome
Acute and chronic Renal failure
Anti insulin Ab
Acromegaly
Asian origin
Alstrom syndrome
Ataxia telangiectasia
Cystic fibrosis
Clinical markers of insulin resistance (6)
- Acanthosis nigricans
- Multiple skin tags- acrochordons
- Acromegaloid features
- Hyperandrogenism-acne,hirsuitism,oligomenorrhoea
- Central obesity: high waist-hip ratio
- High BMI >30kg/m2.
Functions of insulin anabolic hormone (8)
Decrease gluconeogesis
Increase glycogenesis
Increase glucose transport in muscle,ad tis
Increase glycolysis
Increase lipogenesis (TG,cholesterol)
Increase protein synthesis
Increase sodium retension in kidney
Increase cellular uptake of K+
Functions of glucose as catabolic hormone (4)
Increase glycogenolysis
Increase gluconeogenesis
Increase ketogenesis
Increase lipolysis
Organs that don’t need insulin for glucose uptake
L-BRICK
Liver
Brain
RBC
Intestine
Cornea
Kidney
Insulin physiology
Blood glucose increases >70mg/dl—> goes to beta cells of pancreas-> enter via GLUT2, glucose —>g6p by enzyme Glucokinase
1atp is released—> inhibits K+ channel —> membrane depolarizes—> calcium channel open, calcium comes in, and throws out insulin from the cell.
Insulin binds on a subunit of insulin receptor found on the target cell—> b subunit gets activated—>TK released. Series of phosphorylation takes place inside the cell , GLUT4 is expressed on the surface of target cell, and glucose gets inside.
Classification of OHA
- Enhance insulin secretion from pancreas
a. K+ channel inhibitors:
Sulfonylureas, meglinitide
b. GLP-1 agonist
c. DDP4 inhibitor - Decrease insulin resistance
Biguanides
Thiazolidindiones - Miscellaneous
a. A-glucosidase inhibitors
b. Amylin analogue
c. DA against
d. SGLT2 antagonist
MOA of sulfonylureas
Extrapancreatic action of sulfonylureas
Similar to release by normal glucose, they inhibit K+ channel activity
At least 30% fn cells should be present for its action to take place.
When the insulin releasing activity from pancreas is decreases , they synthesize target tissues to increase action of insulin.
Due to increase sensitivity of insulin receptors
Advantages of repaglinide, nateglinide
Shortest acting miglitol
Decrease post prandial hypoglycemia as they are short acting.
Nateglinide
S/e of miglitol (4)
Headache, dyspepsia, arthralgias, weight gain
S/e of chlorpropamide (3)
- Cholestasis
- Dilutional hyponatremia -ADH like
- Intolerance to alcohol-disulfiram like
Longest acting sulfonylureas
Drugs that displace sulfonylureas from protein binding (4)
Chlorpropamide
- Phenylbutazone
- Sulfinpyrazone
- Salicylates
- Sulfonamides
Drugs that prolong sulfonylureas actions (5)
1 salicylates
2. Propanolol
3. Lithium
4. Theophylline
5. Alcohol
Hypoglycemia is most with ….sulfonylureas
Lowest risk,low potency sulfonylureas
Chlorpropamide
Tolbutamide
Non specific symptoms of sulfonylureas (5)
N/V
Flatulence
Constipation
Diarrhea
Headache
Max insulinotropic action of Su
T1/2 of glyburide
Lowest hypoglycemia with su is with …
Approved in Japan
Glyburide
1-2hrs
Glimepride
Mitiglinide
Drug that binds to SUR-1 receptor binder and beta cell sequestration
Glyburide
What are the egs of incretins?
2 types :
GIP: present on K cells of prox intestine
GLP-1: present on L cells of terminal ileum and colon.
MOA of incretins
food into stomach —-> glucose into blood—> directly stimulate pancreatic cells to release insulin.
—> decrease glucagon
—-> delay emptying
Thus there is a feeling of satiety.
What inhibits incretins ?
DDP4 resistant incretins
Disadvantage
Long acting GLP-1 against
DDP4— degrade the incretins.
Exenatide
Coz it’s
peptide, can’t be taken orally .
Liraglutide
S/e of GLP-1 agonist
DPP4 inhibitors are ……
S/e…..
Nausea
Competitive and selective
Nasopharyngitis
Cough
URTI
—due to inhibition of substance P degradation.
MOA of biguanides
Metformin—> enters target cell via Oct-1 channel—-> inhibit mitochondrial ATP. AMP activated —> activated AMPk —> more vesicles to enter the cell, decreasing insulin resistance.
Action of metformin
Intestine
Liver
Skeletal muscle
- Increase glycolysis
- Inhibit gluconeogenesis
Increase lipogenesis -> decrease hyperlipidemia - Increase glucogenesis
Advantages of metformin. (4)
Non hypoglycemic
Reduces both macro and micro vascular complications
Weight loss
Combined with other drugs
C/I of metformin.
- Hypotension
- Heart failure , renal failure,liver failure
- Alcoholics
MOA of TZD
Glitazones—> go to nuclear PPAR gamma of target cell—> enhance transcription of insulin responsive gene —> increase GLUT-4 expression to the surface of the cell.
OHA safer in renal disease, but c/I in ….
Rosiglitazone was banned because….
TZD
Liver disease
MI/stroke
S/e of TZD
Weight gain , pedal edema , macular edema, hepatotoxicity
MOA of Acarbose
Food —> intestine —>polysaccharide—> monosaccharides by enzyme a glucosidase and is absorbed.
Acarbose blocks a glucosidase. Polysaccharide goes into the large intestine, acted upon by bacteria and cause bloating, flatulence.
……strong inhibitor of sucrose
MOA of pramlintide
Miglitol
It’s an amylin analogue
Causes : 1. Decrease glucagon from pancreas
2. Acts on the brain , cause satiety
3. Delays gastric emptying
Only drug other than insulin that can be given for type 1 and type 2 DM
Pramlintide
MOA of SGLT2 inhibitors
S/e
All the glucose that is filtered from the bowman’s capsule is absorbed in the PCT via SGLT2 .
Glifloxcins inhibit SGLT2 transporter.
Vaginal candidiasis
UTI
Leg and foot amputations seen with ……OHA
Breast and bladder cancer seen with ….
Canagliflozin
Dapagliflozin
Drug that can decrease TG
Type 2 DM regimen
Dual PPAR agonist -Saroglitazar
Type 1: insulin
Type 2: diet, exercise , metformin
If uncontrolled = metformin + add 1 drug
If uncontrolled = metformin + 2 drugs
If uncontrolled = metformin + 3 drugs / insulin + metformin .
Pregnant: insulin +_ metformin
OHA with max decrease in HbA1C
OHA with min decrease in HbA1C
Sulfonylureas
Acarbose
Essential meds of WHO list
Shortest acting SU
Longest acting SU
Shortest acting OHA
Metformin, glimenclamide
Tolbutamide
Chlorpropamide
Nateglinide
Eg of Aldose reductase inhibitor MOA
Epalrestat
Delay sorbitol accumulation in sciatic and other nerves
Delay progression of Diabetic neuropathy
GLP2 agonist Eg
Use
Teduglutide
Rx of short bowel syndrome
Main source of GLP-1 in the body is …
Hormone that remain stable with aging
Intestinal L cells - secrete GLP-1 as gut hormone
GLP.
Insulin analogue that changes both A and B chains
Antidiabetic drug with insulin independent action …..
Glargine
SGLT2 inhibitor
S/e of SGLT2 inhibitors (6)
- Vaginal Candida
- UTI
- Hypotension
- Weight loss
- Fourniers gangrene
- DKA
OHA causing weight loss, weight gain and neutral
Weight loss: GSP
GLP-1 agonist
SGLT2 inhibitor
Pramlintide
Weight gain: SIT
SU, Insulin, TZD
Weight neutral: DPP4 inhibitor, Metformin
OHA that decrease ASCVD mortality (3)
- Metformin
- SGLT2 inhibitor
- GLP-1 agonist
Rx of hypothyroidism
Difference between T3 , T4. (3)
Levothyroxine T4.
T4: levothyroxine. T3: liothyronine 1. Less potent. More potent
2. Longer DOA. Less plasma t1/2
3. Decrease arrhythmias. More
Rx for myxedema coma
- T4
2 T3- add on drug
Drugs for hyperthyroidism (4)
- Damage NIS
- TPO inhibitors
- Inhibit Iodine release
- Radioactive I 131
Actions where TPO is required (3)
Oxidation : I - to I+
Organification: I+ + TG —> MIT/DIT
Uncoupling: T3,T4 bound to TG- release
Difference between methimazole and PTU (5)
Methimazole. PTU
1. More potent. Less potent
2. More plasma t1/2. Less plasma t1/2
Sustained action
3. Teratogenic. Less placental tx
4. More PC. Less peripheral C
5. Less problem. Increased S/e
Action of iodide (3)
- Fast acting anti thyroid drug
Inhibit T3,T4 release -thyroid constipation
Rx: thyroid storm - Decrease blood flow to gland-shrink size, used before thyroid surgery
- High dose/ chronically
Inhibit proteolysis/organification. Inhibit thyroid synthesis.
S/e of action of iodide (3)
- Fetal goiter
- Iodism = mucosal I.F -> conjunctivitis,
Painful swollen parotid gland
Beta blocker use.
Drugs that decrease peripheral conversion of T4——>T3 (5)
Given as add on rx, symptomatic Rx:
Tremor, arrhythmia
- PTU
- Propanolol
- Prednisolone
- Amiodarone
- Lithium.
What is thyroid storm? DOC
Life threatening condition. Cause seizures,arrhythmias—> death.
DOC:
1. PTU
2. Iodide (given 1-2hrs after PTU)
3. Beta blocker-propanolol
DOC for hyperthyroidism
What is carbimazole?
Methimazole
Prodrug—>methimazole
Where is PTU useful?
- Pregnancy
- Thyroid storm
S/e of PTU
Carbimazole causes ……s/e (3)
Hepatotoxicity
Agranulocytosis
- Aplasia cutis
- Choanal atresia
- Fetal goiter
Drugs that inhibit iodide trapping ? (2)
……..contains thiocyanate,avoid in patients with thyroid disease
Percholates
Thiocyanates
Inhibit sodium iodide cosymporter
Cabbage 🥬
Drugs that inhibit hormone release? (2)
- Lugol’s iodine
- Potassium iodide
What is lugol’s iodine?
Use.
5% iodine + 10% potassium iodide
Used in thyroid storm- as it causes decrease T3,T4 release—>thyroid constipation.
T1/2 of radioactive I 131.
Indication
8 days
Elderly,unfit for surgery coz of Mi/stroke
Uses of various rays of
radioactive I 131. (2)
- Gamma rays - thyroid scan
- Beta particles- destroy thyroid gland.
Slow acting -3 weeks
Until then, give methimazole,or beta blocker.
Contraindications of radioactive iodine. (3)
Pregnancy
<25 years
Graves opthalmopathy
Drugs causing hypothyroidism (8)
Lithium
Amiodarone
Sulfonamides
Phenobarbitone
Phenytoin
Para-amino salicylic acid
Carbamazepine
Rifampin
What is dronedarone?
Amiodarone - Iodide = dronedarone
It does not cause thyroid abnormality.
Define osteoporosis. (3)
Reduction in bone mass
Normal bone mineralization
Sparse trabeculae
What are the types of osteoporosis?
Type 1: postmenopausal- due to decreased estrogen.
Type 2: senile osteoporosis (>70yrs)
Features of vertebral crush fracture (3)
Acute back pain
Loss of height
Kyphosis
What are the fractures that occur in osteoporosis? (3)
Vertebral crush fractures
Colle’s fracture - distal radius fracture
Vertebral wedge fracture
Prophylaxis of osteoporosis (3)
ALP is ……..in osteoporosis
Exercise
Calcium
Low dose estrogen rx
Normal
Dose of calcium and vit d for rx of osteoporosis
Calcium : 1200mg/d
Vitamin D: 400-800IU/d
MOA of denosumab
RANK ligand inhibitor.
Prevents bone resorption
MOA of romosozumab
Inhibits sclerostin
Increases new bone formation
Calcitonin is given as …..route for osteoporosis
MOA of teriparatide
It’s withdrawn from market .why?
Nasal spray
Teriparatide,abaloparatide given as PTH analogue
Stimulates formation of new collagen matrix, so mineralized can take place with calcium and vit D supplements.
C/I Paget’s disease and osteosarcoma
Causes hypercalcemia
DOC for osteoporosis
MOA
Bisphosphonates
Inhibit osteoclast bone resorption by inhibiting farnesyl pyrophosphate synthetase
Drugs that decrease bone resorption (3)
Denosumab
Bisphosphonates
Calcitonin
Drugs that increase bone formation (2)
Teriparatide
Romosozumab
Dosing frequency of alendronate, risedronate,ibandronate, zolindronate
Alendronate,risendronate: once weekly
Ibandronate: once a month
Zolindronate: once a year
Most potent bisphosphonates
S/e (4)
Zolindronate
S/e:
1. Acute phase reaction-fever,chills,myalgia etc
2. Acute renal failure
3. Atrial fibrillation
4. Uveitis
Fracture that occurs with zolendronate
X ray shows:…….
Chalk stick fracture of femur -aka insufficiency fracture
Lateral cortical fracture
Osteonecrosis of …..take place with bisphosphonates.
Risk of ……..cancer
Jaw
Esophageal cancer
Bone mineral changes first seen in immobilization osteoporosis is in ….
Immobilization osteoporosis occurs in….&…..patients
Proximal humerus
Stroke
Hemiplegic
…….bone density is reliable for predicting risk of hip fracture
……….bone density to monitor response to rx .
Hip bone density
Spine bone density
T score for :
1. Normal bone:
2. Osteopenia
3. Osteoporosis
4. Severe osteoporosis
- > -1
- -1 to -2.5
- Less than -2.5
4 less than -2.5 + presence of non traumatic fracture
Mgt of acute hypercalcemia
- Iv saline + furosemide
- Iv pamidronate
- Calcitonin iv
Given last, onset within hrs (fastest acting)
S/e: tachyphylaxis
Vit D synthesis physiology
Skin by UV rays —-> cholecalciferol
Cholecalciferol—->liver—-> 1(OH) D3
1(OH)D3——> kidney—-> 1,25(OH) D3
Order: skin-liver-kidney
Rx for rickets
Type 1: deficiency of 1,hydroxylase
Rx: calcitriol
Can also give alpha calcidiol, 1(OH) vit D3—> liver—-> 1,25(OH) vit D3
GH effect on blood sugar
Via IGF-1: hypoglycemia
Directly via liver: increase gluconeogenesis—> increase RBC
Rx for acromegaly (4)
- Doc: Octreotide
- DA agonist : cabergoline
- GH antagonist: pegvisomant
- Tamoxifen- decrease IGF-1 level
Action of DA in normal and acromegaly patients
Normal: increase GH
Acromegaly: decrease GH
Side effects of GH rx (4)
- Edema
- Slipped capital epiphysis
Carpal tunnel syndrome
Scoliosis - Increased ICP
- Hypothyroidism-unmask TSH def
Long acting analogue of somatostatin is …..
…….times more potent than somatostatin
Ocreotide
45
Uses of ocreotide (4)
- Decrease GH: acromegaly
- Decrease insulin: insulinomas
- Decrease Gi secretion: secretary diarrhoea
- Vasoconstriction splanchnic vessels- Rx of bleeding varices
S/e of ocreotide (2)
Hyperglycemia
Gall stones
Somatostatin analogue for Rx thyroid tumors
GH antagonist for rx acromegaly
Lanreotide
Pegvisomant
Recombinant GH for Rx GH deficiency (2)
Somatropin
Somatrem
Rx for Laron’s syndrome (2)
Dwarfism
Rx: 1. Somatrem (im)
2. No benefit —> rIGF-1 : mecasermin
What is mecasermin? Use
Recombinant IGF-1 + recombinant IGFBP-3
For rx short stature
Define mecamylamine
Hexamethionium ganglion blocker
DA against drugs (4)
- Bromocriptine
- Cabergoline
- Pergolide
- Quinagolide
Most potent glucocorticoid
Glucocorticoid similar efficacy to prednisone but lesser s/e
Dexamethasone
Deflazacort
Glucocorticoid antagonist
GC synthesis inhibitors (4)
Mifepristone
Metyrapone
Aminogluthimide
Mitotane
Ketoconazole
What are anabolic steroids? Eg?
(4)
Used to reduce virilization while maintaining anabolic effects.
Eg:
Methandienone
Oxymetholone
Nandrolone
Stanozolol
Betamethasone preferred over hydrocortisone why?
They have zero mineralocorticoid action
Rx for adrenal cortex insufficiency
GC+ MC =
hydrocortisone + fludrocortisone
Corticosteroid with maximum A/E potential
Any CS given long term as it decrease the HPA axis
In a patient taking long term CS gets a trauma or stress. Next course of action.
Increase the dose of GC.
Chronic use suppresses HPA axis-ongoing dose can’t produce enough cortisol to control the stress related condition.
Rx of Cushing syndrome.MOA of drugs
11 beta hydroxylase inhibitors—> inhibit formation of CS.
Metyrapone
Ethomidate
Ketoconazole
Mitotane
Drug that acts on CS receptor and inhibit it.
CS not suitable for alternate day Rx
Mifepristone
Betamethasone t1/2- >36hrs
DOC for child born with adrenal cortex hyperplasia
Doc for pregnant female with in utero child with CAH:
Hydrocortisone + fludrocortisone
Dexamethasone- prevent virilization of female fetus.
Better placental transfer
