Pharmacology Flashcards
1
Q
Action of ACTH
A
- act on adrenal glands to stimulate glucocorticoid release
2. also has a trophic effect on adrenal cortex
2
Q
Effects of glucocorticoids
A
Metabolic: protein, CHO metabolism and adipose distribution
Anti-inflammatory
Resistance to stress
3
Q
Effects of mineralocorticoids
A
Water and electrolyte homeostasis
4
Q
Corticosteroid mechanism of action
A
- 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
5
Q
Primary deficiency of corticosteroids
A
Addison’s disease
6
Q
Secondary deficiency of corticosteroids
A
- exogenous steroid use
leads to HPA axis suppression
7
Q
Glucocorticoid XS
A
Cushing’s syndrome
8
Q
Common signs of Cushing’s
A
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
9
Q
Clinical uses of GC’s
A
- replacement therapy
2. anti-inflammatory therapy (GC only)
10
Q
Hyperthyroidism treatment strategies
A
- remove gland and T4
- inhibit thyroperoxidase
- prevent peripheral deiodination of T4
- interfere with sympathetic nervous system facilitating action of T3 and 4
11
Q
Iodide as a treatment for hyperthyroidism
A
- 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
12
Q
What are some thiourylenes and how do they act?
A
- 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
13
Q
Action of potassium iodide in hyperthyroidism
A
Suppresses release of stored thyroid hormone
Inhibits peripheral conversion of T3-T4
For fast and temporary suppression of hyperthyroidism
14
Q
What is important in monitoring T4 replacement and anti-thyroid drugs?
A
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
15
Q
Action of beta adrenergic blockers in hyperthyroidism
A
Antagonises thyroid hormone facilitation of sympathetic activity.
Adjunct in managing hyperthyroid-related tachyarrhythmias
Suppresses sympathetic manifestations • Tachycardia
• Tremor
• Eyelid retraction
16
Q
3 Zones of adrenal cortex and what they produce
A
- Zone glomerulosa = mineralocorticoids
- Zona fasciculate = glucocorticoids
- Zona reticularis = sex hormones
17
Q
Rate limiting step in adrenal steroidogenesis
A
Side chain cleavage of cholesterol
18
Q
How is insulin stored in the pancreas?
A
Stored as pro-insulin in beta cell granules and is then proteolytically cleaved into mature insulin + C-peptide
19
Q
What stimulates insulin release?
A
- glucose increase
- amino acids and fatty acids
- peptide gut hormones - incretins (GLP1, GIP, CCK)
20
Q
What does insulin activate?
A
- GLUT4 transporter - glucose enters cells
- Glycogen synthase - converts glucose to glycogen
- cell growth and gene expression pathways
21
Q
Presenting symptoms in diabetes
A
o Polyuria o Polydipsia – thirst o Polyphagia – hunger o Weight loss catabolism o Tiredness, confusion, irritability o Poor healing and infections
22
Q
Difference between type 1 and 2 diabetes
A
Type 1: absolute insulin deficiency / autoimmune destruction of B cells
Type 2: relative insulin deficiency / peripheral insulin resistance
23
Q
Microvascular complications in the eyes and kidneys
A
Eyes
• Diabetic retinopathy
- ↑ vascular permeability
- haemorrhages
• lipid exudates • neovascularisation • 25x↑ in blindness • cataracts, glaucoma Kidneys • Diabetic nephropathy • Glomerular disease
• ↓ GFR & albuminuria
24
Q
Treatment of diabetes type 1
A
- insulin
- diet, exercise and lifestyle
- regular monitoring
25
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
```
26
How is insulin administered normally and in emergency?
Normally S.C
| Emergency I.V
27
Side effects of insulin therapy
Hypoglycemia
Weight gain
Injection site - scarring, lipoatrophy/hypertrophy
28
Treatment for type 2 diabetes
Aim: lower blood glucose levels to prevent microvascular complications
1. Lifestyle measures
2. oral hypoglycaemic agents
3. insulin
4. Treat associated conditions
29
Hypoglycemic agents for T2DM
1. Metformin
2. Sulfonylureas
Also
- Thiazolidinediones
- α-Glucosidase Inhibitors
- Incretin based therapies
- SGLT2 inhibitors
30
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?
31
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
32
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
33
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
34
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
35
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)
36
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
37
Really eliminated toxic metabolites
¥ Morphine 6-glucuronide sedation
| ¥ Pethidine norpethidine seizures (part of the reason why pethidine is never a drug of choice)
38
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
39
How do MR tissues respond to aldosterone not cortisol?
They express 11-beta-steroid hydrogenase which converts cortisol to cortisone (not active)
40
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
41
What is preserved in secondary deficiency of corticosteroids?
MC secretion = normal RAAS / normal BP / normal NA+/K+ balance
42
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
43
Causes of cushion's syndrome
1. Cushing's disease = raised ACTH from ALP
2. Raised ACTH from ectopic source
3. Increased GC from adrenal carcinoma/adenoma
4. Increased GC from prescribed GC = iatrogenic
44
Treatment of adrenocortical insufficiency
MEDICAL EMERGENCY
- IV hydrocortisone
- then hydrocortisone to replace diurnal rhythm
- during times of stress - double the dose of hydrocortisone
45
Corticosteroid AEs
1. Iatrogenic cushion's syndrome
- Very common with systemic GC use, patents look cushingoid and children have growth suppression
2. Suppression of HPA axis
- adrenal atrophy may occur and abrupt GC withdrawal may result in Adisonian crisis
46
Action of TSH
1. increase BF to thyroid
2. Increase uptake of iodine into thyroid
3. Increase iodination of tyrosine on thyroglobulin
4. Increases formation of thyroglobulin-associated T3 + T4
5. Increases release of stored T3 + T4
47
Effects of thyroid hormones
Growth and maturation
Increased metabolic rate
Adrenergic facilitation
48
Causes of hypothyroidism
1. AI thyroid disease
2. iodine deficiency
3. surgical removal or radio-iodine treatment
4. drug induced
49
Causes of hyperthyroidism
1. Grave's disease
2. Thyroid adenoma
3. Thyroid hypertrophy
4. Overproduction of TSH - rare
50
Which hormones increase and decrease blood glucose levels?
Increase: glucagon, adrenaline, glucocorticoids, growth hormone
Decrease: insulin
51
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
52
Diagnosis of Diabetes
Fasting glucose >7mmol/L
| 2hr post prandial >11.1mmol/L
53
What causes diabetic foot ulcers?
Neuropathy: sensory can't feel pain OR motor - foot deformities
PVD - ischaemic ulcers
Immunosuppresion - infections
54
Metformin mechanism of action
Hypoglycemic agent - Reduces hepatic gluconeogenesis
55
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
56
Action of thiazolidinediones
PPAR-gamma agonist - activates gene transcription
| Results in increased insulin sensitivity and improves lipid profiles
57
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
58
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
