S5 Insulin and Sex Steroid Hormones Flashcards
Diabetes mellitus
A group of metabolic disorders characterised my chronic hyperglycaemia due to insulin deficiency, insulin resistance or both. It is associated with elevated glucose levels in urine.
Diagnosis of DM
Diabetes is diagnosed in the presence of symptoms i.e. polyuria, polydipsia and unexplained weight loss, plus venous plasma glucose concentration:
• normal range 3.3-6mmol/L plasma glucose
• fasting ≥7.0mM, random ≥11.1mM both indicate DM
Also need to do laboratory tests to confirm;
• HbA1c - Glucose in the blood reacts with Hb to produce HbA1c. Poorly controlled diabetics can have HbA1c value >6.5%.
Type 1 diabetes is insulin deficiency, type 2 is insulin resistance.
What is the role of insulin?
Stimulates uptake of glucose into liver, muscle and adipose tissue. Decreases hepatic glucose output via inhibition of gluconeogenesis. Inhibits glycogenolysis.
Types of insulin
Animal Porcine & Bovine. Recombinant DNA technology allows development of analogues; by modifying insulin (B26-30 region) to alter pharmacokinetic properties such as absorption. 6 main insulin categories, all absorbed into blood stream via subcutaneous injection;• Ultrafast acting (e.g aspart) fast onset
• Rapid acting (novorapid), lasts 4-6h
• Short acting (actrapid), lasts 8-10h
• Intermediate acting (isophane), lasts 12-20h
• Long acting & very long acting (glargine), slow onset, lasts 50+h
Insulin adverse effects
Hypo (too much) & hyperglycaemia (too little), lipodystrophy (death of fat cells), Painful injections, Insulin allergies
Oral hypoglycaemic agents
Blood glucose can rise due to insulin deficiency (beta cell failure) or resistance.
Treatment of type 2 diabetes
Lifestyle plus non-insulin therapies e.g sulphonylureas. Weight gain and hypoglycaemia can affect drug adherence. Target is HbA1c 6.5 to 7.5%.
Metformin
- Reduces Insulin resistance leading to increased glucose uptake by tissues
- Reduces hepatic glucose production (gluconeogenesis)
- Limits weight gain
- Side effects include GI symptoms
Sulphonylureas (gliclazide)
- Stimulate beta cells to release insulin
* Side effects: Weight gain, Hypoglycaemia
Acarbose: α glucosidase inhibitor
- Inhibits breakdown of carbohydrates to glucose by blocking action of the enzyme α Glucosidase.
- Side effects: flatulence
Glitazones
- E.g Pioglitazone, Rosiglitazone
* Increase insulin sensitivity in muscle and adipose tissue and decrease hepatic glucose output by binding PPARs
Glucagon Like Peptide 1 Therapies
- E.g Exenatide, Liraglutide
- Increase insulin secretion from the beta cells
- Decreases Glucagon production from alpha cells
- GLP1 agonist side effects: nausea, GORD
Gliptins or DPP-4 inhibitors
- E.g Linagliptin, Sitagliptin
- Inhibit enzyme (DPP4) that breaks down GLP1
- Side effects: GI upset
Glifozins
- Selectively inhibits SGLT2 (Na glucose cotransporter) in proximal tubule
- Prone to UTI due to peeing out glucose
- Side effects: increased risk of LUTS, polyuria
Different sex steroid hormones
All synthesised from cholesterol; cholesterolpregnenoloneprogesterone17-hydroxyprogesteronetestosteroneoestrogen.
sex steroid hormone: Oestrogen
- Effects: Stimulates growth of the endometrium and breast
- Action: mild anabolic, Na & H2O retention, decrease bone resorption
- Side effects: breast tenderness, nausea, water retention
Progesterone
- Effects: Stimulates growth of the endometrium and breast; maintains pregnancy
- Action: anabolic, increases bone density
- Side effects: weight gain, acne, fluid retention
Testosterone
- Effects: Stimulates male characteristics e.g pubes, deep voice
- Action: anabolic, male characteristics
- Side effects: acne, aggression, high LDL
Contraceptive Routes of Administration
Oral, transdermal patch, implants, nasal, vaginal
Sex steroid hormone transport and pharmacokinetics
- Transport bound to SHBG (sex hormone binding globule, production upregulated by oestrogen) and albumin
- Liver metabolism: progesterone & oestrogen metabolised in one passage through liver
- Sex steroids stored in fatty tissue which increases half life
- Metabolites excreted in faeces and urine
- Bind to nuclear receptors: ER alpha & beta, PR A&B, AR 1&2
Oral contraceptive pills
Combined oral contraceptive pill
• Oestrogen (ethinyloestradiol) + progesterone (levonorgestrel)
• Monophasic: fixed amount of oes and prog
• Biphasic: fixed oes, increasing prog
• Triphasic: variable oes, increasing prog
• Mechanism: prevents ovulation (inhibits FSH LH), thickening of cervical mucous and endometrium (prevents sperm entry)
• Adverse effects: Venous thromboembolism, MI, Hypertension
o Metabolised by CP450, so there efficacy is reduced by enzyme inducing drugs;
Phenytoin, Carbamazapine, Rifampicin, Rifabutin (as all increase CP450)
o Broad-spectrum antibiotics can reduce efficacy of COCP as they affect flora reducing uptake of COCP
o Soya protein products enhance oestrogen absorption and reduce its storage
Progestin-only pill
- Thickens cervical mucus so impenetrable to sperm.
- E.g: levonorgestrel, norethisterone, medroxyprogesterone
- Adverse effects: menstrual problems common
Missed pill advice
Take last pill immediately and continue others as normal. May need extra contraception for next 7 days.
Emergency contraception
Levonorgestrel (72h after sex), ulipristal acetate (120h after sex).
NB Remember: for the drugs to work, receptor needs to be present and because progesterone receptor expression is dependent upon oestrogen action, the oestrogen must be supplied either continuously or prior to the progestin.
Postmenopausal Hormone Replacement Therapy
Can have unopposed oestrogen (E)RT or opposed oestrogen HRT. Help reduce menopausal symptoms e.g hot flushes, sweats, dyspareunia, osteoporosis.
Risks: can develop endometrial or ovarian cancers (ERT), breast cancer & thromboembolism (HRT), heart disease.
However can increase HDL and decrease LDL.
Administration routes: Oral, transdermal patch, implants, nasal, vaginal
Inhibitors & antagonists
Weak oestrogens that block receptors.
Clomiphene
• Ovulation induction: inhibits oestrogen to its receptor in the anterior pituitary, inhibits negative feedback, so results in increased FSH, LH expression
Tamoxifen
• Reduces risk of breast cancer: Binds to oestrogen receptor in breast tissue and blocks oestrogen-stimulated myoepithelial cell division
Anti-progestins
• E.g mifepristone: Partial agonist to progesterone receptor; inhibits progesterone action. Sensitises the uterus to prostaglandins, is used for termination of pregnancy and induction of labour
Anti-androgens
• E.g Cyproterone: Partial agonist at progesterone receptor, that competes with DHT. Used to treat prostate cancer.
Mixed agonists/antagonistsSelective estrogen receptor modulators (SERMs)
• E.g raloxifene; Protects against osteoporosis. Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis
Androgen replacement therapy
Implants – Testosterone/ Finasteride (prevent hair loss)
Can also be oral or intramuscular.
