Pharmacology Flashcards
Action of ACTH
- act on adrenal glands to stimulate glucocorticoid release
2. also has a trophic effect on adrenal cortex
Effects of glucocorticoids
Metabolic: protein, CHO metabolism and adipose distribution
Anti-inflammatory
Resistance to stress
Effects of mineralocorticoids
Water and electrolyte homeostasis
Corticosteroid mechanism of action
- Plasma cortisol - bound to CBG
- Lipophilic molecule → crosses PM &
binds cytoplasmic receptor (GR) - (Cortisol also binds MR)
- GR dimerises & translocates to nucleus
- Dimeric GR binds GREs to alter transcription of target genes
- GR is a ligand-activated transcription factor
- Transcriptional activation → most GC metabolic effects
- Transcriptional repression → pro-inflammatory genes e.g. IL-2
Primary deficiency of corticosteroids
Addison’s disease
Secondary deficiency of corticosteroids
- exogenous steroid use
leads to HPA axis suppression
Glucocorticoid XS
Cushing’s syndrome
Common signs of Cushing’s
Catabolic: -thin skin and striae -bruising -muscle wasting - thin arms & legs Fat redistribution/deposition: -moon facies -buffalo hump -abdominal Cushingoid changes don’t only occur with systemic steroid administration → 2 years inhaled fluticasone
Clinical uses of GC’s
- replacement therapy
2. anti-inflammatory therapy (GC only)
Hyperthyroidism treatment strategies
- remove gland and T4
- inhibit thyroperoxidase
- prevent peripheral deiodination of T4
- interfere with sympathetic nervous system facilitating action of T3 and 4
Iodide as a treatment for hyperthyroidism
- alpha and beta-emitter
- Taken orally as an iodide salt
- Actively incorporated by thyroid epithelium • -emission leads to death of thyroid tissue • t1⁄2~8days
- Patient ultimately becomes hypothyroid
- Then needs T4 replacement
What are some thiourylenes and how do they act?
- carbimazole and methimazole
- propylthiouracil
They inhibit thyroperoxidase - prevents iodination of tyrosine residues and prevents conversion of T4 to T3
They deplete the follicle contents over 3-4 weeks
Action of potassium iodide in hyperthyroidism
Suppresses release of stored thyroid hormone
Inhibits peripheral conversion of T3-T4
For fast and temporary suppression of hyperthyroidism
What is important in monitoring T4 replacement and anti-thyroid drugs?
TSH level most generally useful
High TSH = needs more T4 or less anti-thyroid
Low TSH = needs less T4 or more anti-thyroid
Free T4 measurement appropriate in some specific clinical situations
Action of beta adrenergic blockers in hyperthyroidism
Antagonises thyroid hormone facilitation of sympathetic activity.
Adjunct in managing hyperthyroid-related tachyarrhythmias
Suppresses sympathetic manifestations • Tachycardia
• Tremor
• Eyelid retraction
3 Zones of adrenal cortex and what they produce
- Zone glomerulosa = mineralocorticoids
- Zona fasciculate = glucocorticoids
- Zona reticularis = sex hormones
Rate limiting step in adrenal steroidogenesis
Side chain cleavage of cholesterol
How is insulin stored in the pancreas?
Stored as pro-insulin in beta cell granules and is then proteolytically cleaved into mature insulin + C-peptide
What stimulates insulin release?
- glucose increase
- amino acids and fatty acids
- peptide gut hormones - incretins (GLP1, GIP, CCK)
What does insulin activate?
- GLUT4 transporter - glucose enters cells
- Glycogen synthase - converts glucose to glycogen
- cell growth and gene expression pathways
Presenting symptoms in diabetes
o Polyuria o Polydipsia – thirst o Polyphagia – hunger o Weight loss catabolism o Tiredness, confusion, irritability o Poor healing and infections
Difference between type 1 and 2 diabetes
Type 1: absolute insulin deficiency / autoimmune destruction of B cells
Type 2: relative insulin deficiency / peripheral insulin resistance
Microvascular complications in the eyes and kidneys
Eyes
• Diabetic retinopathy
- ↑ vascular permeability
- haemorrhages
• lipid exudates • neovascularisation • 25x↑ in blindness • cataracts, glaucoma Kidneys • Diabetic nephropathy • Glomerular disease
• ↓ GFR & albuminuria
Treatment of diabetes type 1
- insulin
- diet, exercise and lifestyle
- regular monitoring
Importance of HbAc1 in diabetes monitoring
HbA1c: • covalent modification of Hb - • long term measurement of glucose levels • 4 - 6% - normal range • <7% - good control • >8% - poor control
How is insulin administered normally and in emergency?
Normally S.C
Emergency I.V
Side effects of insulin therapy
Hypoglycemia
Weight gain
Injection site - scarring, lipoatrophy/hypertrophy
Treatment for type 2 diabetes
Aim: lower blood glucose levels to prevent microvascular complications
- Lifestyle measures
- oral hypoglycaemic agents
- insulin
- Treat associated conditions
Hypoglycemic agents for T2DM
- Metformin
- Sulfonylureas
Also
- Thiazolidinediones
- α-Glucosidase Inhibitors
- Incretin based therapies
- SGLT2 inhibitors
Mechanism of action of metformin
- Mainly reduces hepatic gluconeogenesis
- May also cause GLP1 release – incretin effect
- Additional benefits – no hypoglycaemia, no increase in appetite, no weight gain, improved lipid profile, reduced CRC rates?
Mechanism of action of slufonylureas
Mechanism of action: insulin secretagogues
• Bind SU receptor (SUR1) on beta cells to block K+ channel insulin release
• Need functional beta cells
Side effects of metformin
- GI 30% but transient – helps with weight control
- Lactic acidosis – extremely rare
- Vitamin B12 deficiency (reduced absorption?) – screen your patients!
- C/I in severe renal, hepatic or cardiac failure
Mechanism of action of Thiazolidinediones
- PPARγ nuclear receptor expressed in many tissues
- PPARγ agonists activate gene transcription
- Increase in insulin sensitivity (30%) – effects take weeks to months to develop
- Also improve lipid profiles
What are incretins and how are they involved in diabetes and management?
Incretin: gut peptide that increases insulin release after food (oral glucose not IV)
Incretin response is decreased in T2D
Incretin based therapies: increase insulin release in a glucose dependent manner
- GLP1 receptor agonists
- DPP-4 inhibitors
Which drugs are really eliminated and have a narrow therapeutic range?
- Aminoglycoside antibiotics (eg gentamicin)
- Factor Xa & Prothrombin Inhibitors (-gatran’s & -aban’s)
- Digoxin, atenolol, some ACE-inhibitors, eg ramipril
- Lithium
• Hypoglycaemics: metformin, insulin - some sulphonylureas (glibenclamide)
- Methotrexate
- Allopurinol (in people genetically predisposed to immune-mediated toxicity)
- Nitrofurantoin (urinary antibacterial)
Antiviral“cyclovirs”(egaciclovir,ganciclovir)
Why is it important to measure creatinine clearance?
- get a good idea of renal function
- track changes in renal function over time
- roughly estimate renal clearance for common drugs
Really eliminated toxic metabolites
¥ Morphine 6-glucuronide sedation
¥ Pethidine norpethidine seizures (part of the reason why pethidine is never a drug of choice)
Drugs which have altered pharmacokinetics in renal disease
Reduced efficacy
- diuretics
Increased toxicity
- K+ sparing diuretics
- Anticoagulants
- CNS depressants more sedating
- Diuretics, NSAIDs and ACE inhibitors or Angiotensin receptor blockers more likely to affect GFR
How do MR tissues respond to aldosterone not cortisol?
They express 11-beta-steroid hydrogenase which converts cortisol to cortisone (not active)
What does GC and MC deficiency affect in Adison’s?
GC: CHO metabolism = reduced glucose and impaired stress tolerance = Adisonian crisis
MC: reduced BP, low sodium, high potassium
What is preserved in secondary deficiency of corticosteroids?
MC secretion = normal RAAS / normal BP / normal NA+/K+ balance
Differentiating between primary and secondary adrenal insufficiency
Secondary has normal K+/Na+, ACTH is low normal so no pigmentation change, rapid ACTH test will differentiate
Causes of cushion’s syndrome
- Cushing’s disease = raised ACTH from ALP
- Raised ACTH from ectopic source
- Increased GC from adrenal carcinoma/adenoma
- Increased GC from prescribed GC = iatrogenic
Treatment of adrenocortical insufficiency
MEDICAL EMERGENCY
- IV hydrocortisone
- then hydrocortisone to replace diurnal rhythm
- during times of stress - double the dose of hydrocortisone
Corticosteroid AEs
- Iatrogenic cushion’s syndrome
- Very common with systemic GC use, patents look cushingoid and children have growth suppression - Suppression of HPA axis
- adrenal atrophy may occur and abrupt GC withdrawal may result in Adisonian crisis
Action of TSH
- increase BF to thyroid
- Increase uptake of iodine into thyroid
- Increase iodination of tyrosine on thyroglobulin
- Increases formation of thyroglobulin-associated T3 + T4
- Increases release of stored T3 + T4
Effects of thyroid hormones
Growth and maturation
Increased metabolic rate
Adrenergic facilitation
Causes of hypothyroidism
- AI thyroid disease
- iodine deficiency
- surgical removal or radio-iodine treatment
- drug induced
Causes of hyperthyroidism
- Grave’s disease
- Thyroid adenoma
- Thyroid hypertrophy
- Overproduction of TSH - rare
Which hormones increase and decrease blood glucose levels?
Increase: glucagon, adrenaline, glucocorticoids, growth hormone
Decrease: insulin
Action of insulin on carbohydrates in the liver, muscle and fat
Liver: increase glycolysis and glycogenesis. Decrease gluconeogenesis and glycogenolysis.
Muscle: increase glucose uptake and glycolysis
Fat: increase glucose uptake and glycerol synthesis
Diagnosis of Diabetes
Fasting glucose >7mmol/L
2hr post prandial >11.1mmol/L
What causes diabetic foot ulcers?
Neuropathy: sensory can’t feel pain OR motor - foot deformities
PVD - ischaemic ulcers
Immunosuppresion - infections
Metformin mechanism of action
Hypoglycemic agent - Reduces hepatic gluconeogenesis
Mechanism of action of sulfonylureas
Insulin secretagogues:
Binds SUR1 receptor on beta cells to block K+ channel which stimulates insulin secretion
–> Requires functional beta cells
Action of thiazolidinediones
PPAR-gamma agonist - activates gene transcription
Results in increased insulin sensitivity and improves lipid profiles
Mechanism of action of alpha-glucosidase inhibitors
Competitive inhibitor of intestinal alpha-glucosidase
Inhibits breakdown of maltose into glucose
Delay CHO absorption –> controls post prandial hyperglycaemia
Regularly prescribed with metformin and sulfonylureas
Action of SGLT2 inhibitors: Dapagliflozin
> 90% of glucose is reabsorbed by SGLT2 in PCT
Inhibitor prevents glucose reabsorption/ and salt
Results in:
- glycosuria
- reduced BGL
- Reduced BP
- Reduced weight
