thr patient Flashcards
give a feature of steroid hormones
lipophillic
Lipophillic; can readily enter into the cell. Usually transported
in plasma via carrier proteins
what is a ligand
Ligands are molecules that bind to receptors, enzymes, or other molecular targets, often with high specificity.
Ligands for nuclear receptors
Glucocorticoids,mineralocorticoids, sex hormones
Thyroid hormones
Retinoic acid
Endogenous lipids (act on the PPARs)
Foreign chemicals (act on PXRs)
what is a nuclear receptor
A nuclear receptor is a class of proteins found within cells that are responsible for sensing and responding to various molecules, including hormones, vitamins, and other signaling molecules. These receptors play a crucial role in regulating gene expression and controlling numerous physiological processes such as metabolism, development, and reproduction.
what is chromosome puffing
blood fly salivary gland - large chromosomes - identify in light microscope
when you add a steroid / insect hormone, there was swelling in certain regions in the chromosome. PUFFING
+ steroid
+ inhibitor of mRNA
synthesis - add both you got rid of the swelling / puffing
steroids work increasing MRNA synthesis, interact with DNA of chromosomes
describe the structure of a nuclear receptor
N-C
N
A/B - variable region
C - DNA binding zinc fingers
D - hinge region
E/F ligand binding
C
what two domains do receptors have
hormone binding domain
DNA binding domain
what does a mineralcorticoid do
Binds Aldosterone
Produces transport proteins
what does a glucocorticoid do
Binds cortisol
Inhibits COX-2 production
what is a chimeric receptor
Binds aldosterone
Inhibits COX2 production
BUT
has a hormone binding domain from mineral corticoid and DNA bindin domain from glucocorticoid
describe hormone binding to receptor
hormone bypassed cemm membrane as its lipophillic
proteins are bound to receptor and hold it in an inactive form
when hormone binds protiens fall off
receptor usually usually moves into nucleus
binds to dimer
mrna synthesis
binding of DNA to a monomer usually inhibits mrna
tethering when receptor binds to TF -m inhibition of mrna
what are type 2 nuclear receptors
Not associated with heat shock proteins
what is a heat shock protein
Heat shock proteins (HSPs), also known as stress proteins, are a diverse group of proteins found in virtually all living organisms. They are synthesized in response to various stressors, including heat shock, oxidative stress, exposure to toxins, infection, and other cellular insults. Heat shock proteins play crucial roles in maintaining cellular homeostasis, protecting cells from damage, and facilitating cellular recovery under stressful conditions.
what are zinc fingers
Zinc fingers are small protein structural motifs that can bind to specific sequences of DNA or RNA. They are characterized by the coordination of one or more zinc ions in a finger-like structure, which stabilizes the protein’s fold and allows it to interact with nucleic acids.
tell me about dna binding sites and inverted repeats
Some response elements lack the repeat (eg GATC rather than GATCCTAG).
In this case only a single receptor binds. For glucocorticoids, this receptor then
binds a protein that makes it harder for RNA polymerase to bind, causing
inhibition of RNA synthesis
ensure receptors bind as dimers
Drugs acting on nuclear receptors
Anti-inflammatory agents
Clofibrate PPARa (cholesterol lowering)
Thiazolidines PPARg (type II diabetes)
where else can some steroids also act
Some steroids can also act via membrane bound receptors to produce very rapid responses
Steroid transport proteins exist to facilitate steroid entry into cells and may be important in signalling
describe transcription
steroid receptor hormone binds (usually dimer)
Dna unwinds from chromosome
steroid receptor dimer and RNA polymerase get close together and make contact
Stages of development and timing of exposure P&B
Potential harm influenced by timing of exposure
– < 17 days = Pre-embryonic period (All or nothing)
– 18-56 days = Embryonic period (Organ development)
– Weeks 8 – 38/40 = fetal stage (Growth)
* Different defects occur with drugs in different
periods of pregnancy (Phenobarbital)
* Time period crucial
– Spina Bifida (Valproate, Carbamazepine)
– Cleft Palate (Methotrexate, Valproate)
– Pulmonary Hypertension PPHN (NSAID’s)
Teratogenicity what is teratogen
Teratogen is an agent that interferes with the normal
growth and development of the fetus.
effects of teratogen
Potential effects include
– Chromosomal abnormalities
– Structural malformations
– Inter Uterine Growth Retardation
– Fetal death
– Behavioural or intellectual abnormalities
incidents of teratogen
2-3% Incidence of spontaneous malformations in newborn
babies in Europe
Pharmacokinetic changes P&B
Volume of distribution
– ⇑body water and fat
– ⇑cardiac output
* Protein Binding
– ⇓albumin
* Clearance
– ⇑GFR by 50% in first weeks of pregnancy
* = Need for Increased monitoring in some drugs
Sodium Valproate P&B
Pregnancy Prevention Programme
* Smaller pack sizes to ensure original box given
with warnings
* Annual acknowledgement of Risk Form - specialist
* Patient alert card issued with every prescription
* Contraception – considerations and compliance
* Regular pregnancy tests
role of placenta
nutrient uptake,
waste elimination & gas
exchange
what medicines cross placenta quicker as the placenta is not a barrier
Lipid soluble, unionised
medicines cross placenta
quicker
Principle of medicine use
Medicines should only be prescribed
when BENEFITS to the mother >
RISK to the fetus
* Simple Rules:
Preferably use agents extensively used before
Use lowest effective dose
* To aid compliance all risks and benefits should be discussed
with mothers for each medication and their importance.
prescribing in pregnancy things to consider
Trimester/
number of
weeks?
Past pregnancies?
Previous
exposure?
Necessity for
therapy?
Duration of
therapy
Drug
properties i.e
half life,
Teratogenicity
risk
Nutrition in pregnancy
Folic acid supplementation
– Essential vitamin to ensure neural tube closure
– Low risk; 400microgram OD pre conception to week12
– High risk; 5mg OD before conception to week12
* Vitamin D (10mcg per day)
* No Alcohol government advice
* Vitamin A (restrict to 700mcg)
* Vitamin K supplementation
– May be required
Medication use effect to the fetus depends upon
many factors
Timing of exposure
– Dose
– Maternal Disease
– Genetic Susceptibility
* Teratogenicity can be dose dependent.
* Can get incidence of spontaneous malformations in
normal population.
National Recommendations on Breastfeeding
World Health Organisation (WHO)
Initiate breastfeeding within 1st hour of life and
continue exclusively for first 6 months of life
* Breast fed “on demand” – eg led by the baby, not
at specific times
* No bottles or dummys should be used to avoid
latching on issues
