Pharmacology Flashcards
examples of steroid hormones
cortisol
testosterone
examples of tyrosine derivative hormones
thyroxine
epinephrine
what does the ability to measure hormones depend on?
pattern of secretion presence of carrier proteins interfering agents stability of hormone absolute concentrations (determined by rate of secretion)
four types of membrane-bound receptors
ligand-gated ion channels
GPCR
receptor tyrosine kinase (kinase-linked receptors)
steroid hormone receptors
response time of ligand-gated ion channels
milliseconds
describe how ligand-gated ion channels work?
- activated by neurotransmitters (can also be hormones)
- binding causes conformational change in channel structures allowing influx/efflux of ions
example when membrane bound ion channel goes wrong?
myasthenic gravis
examples of GPCR
- adrenaline binding to beta2-adrenoceptors in the lungs
- adrenaline binding to alpha2-receptors leading to inhibition in the GI tract (K+ channels)
- adrenaline to alpha1-receptors causes vasoconstriction
structure of GPCR
7 transmembrane spans across the cell membrane coupled with G-proteins that stimulate/inhibit various types of effector molecules or ion channels
response time of GPCR
seconds due to enzyme activity and signal amplification
what does a GPCR do?
binding causes conformation change where the G-proteins dissociate
three G-proteins
alpha subunit
beta and gamma subunits
role of the alpha subunit?
GDP is attached and is exchanged with GTP to give the protein energy to activate another substance.
to stop this the GTP must be hydrolysed
what do the beta and gamma subunits do?
form a dimer
describe signal amplification in GPCR
- continual conversion of ATP to cAMP until switched off
- increased number of enzymes activated and therefore responses
- switched off by GTP hydrolysis
what binds to receptor tyrosine kinases?
hormones e.g. insulin
how long do receptor tyrosine kinases take to act?
hours
describe how receptor tyrosine kinases work?
- binding causes conformational change to the receptor which becomes a dimer
- autophosphorylation of tyrosine residues by ATP and relay proteins attach to residues which activates other proteins producing a divergent response
explain how the hormone insulin binding produces a divergent response?
produces a variety of responses:
- glucose transport channels
- inhibition of gluconeogenesis
- glycogen storage
examples of substances that bind to steroid hormone receptors
glucocorticoids
describe how steroid hormone receptors work?
- they bind and pass through the cell membrane and enter the nucleus
- as a dimer this binds to glucocorticoid response elements (GRE) in promoter sequence and activates transcription
- as a monomer it represses transcription
what two receptors do glucocorticoids bind to?
GR and MR
what is the negative consequence of glucocorticoids binding to MR
triggers cutaneous adverse effects e.g. skin atrophy and delayed wound healing
three types of signalling
- autocrine
- paracrine
- endocrine
define autocrine signalling
chemicals released bind to receptors on the cell that is releasing them
define paracrine signalling
chemicals are released from cells bind to receptors on adjacent cells
define endocrine signalling
chemicals are transported via circulatory system to act on distant cells
two types of feedback control
negative
positive
two co-ordinated regulatory systems
- intrinsic
- extrinsic
factors that cause homeostatic end points to vary
genetics age gender health status environment
actions of insulin
- induces glucose uptake and utilisation by cells (muscles and liver)
- promotes glycogenesis and lipogenesis
- stimulates amino acid uptake and protein formation
define type 2 diabetes mellitus
state of insulin deficiency caused by resistance to insulin’s actions at target tissues, abnormal insulin secretion, inappropriate liver gluconeogenesis and obesity (demand on pancreas)
aims of diabetes management
optimise blood glucose and decrease possible complications
non-pharmacological management of diabetes
lifestyle changes smoking diet weight exercise
two modes of action of pharmacological therapies
- dependent upon insulin
2. independent upon insulin
dependent upon insulin therapy action
increase secretion/ decrease resistance and hepatic glucose output
independent upon insulin mode of action
slowing absorption from the GI tract/ enhancing excretion by kidney
how is insulin secreted by the pancreatic beta cell?
- elevation of blood glucose leads to increased facilitated diffusion through GLUT2 into the beta cell
- glucose is phosphorylated by glucokinase
- glycolysis of glucose-6-phosphate in mitochondria yields ATP
- increased ATP closes ATP-sensitive K+ channels leading to membrane depolarisation
- opens Ca2+ channels and increased intracellular Ca2+ triggers insulin release
define sulfonylureas (SUs)
insulin secretagogues
what do SUs require?
functional beta cells
what do SUs require?
functional beta cells, so efficacy can reduce with time
what do all agents in the SU class contain?
the sulfonylurea moiety (sulphur and oxygen)
action of SUs
displace ADP-Mg2+ from SUR1 closing KATP channels, stimulating insulin release
what do SUs do?
decrease fating and post-prandial blood glucose and long-term microvascular complications
how are SUs administrated?
orally
peak release is 1-2 hours
short-acting SUs
tolbutamide
gliclazide
long-acting SUs
glibenclamide
glipizide
adverse of SUs
hypoglycaemia (increased risk in long-acting agents, elderly, reduced hepatic/renal function CKD)
undesirable weight gain (anabolic effect of insulin and appetite increased with urinary loss of glucose decreased)
when are SUs used?
first line for those intolerant to metformin or with weight loss
second line in conjunction with metformin
which drugs decrease the action of SUs?
thiazide diuretics
corticosteroids
examples of glinides
repaglinide
nateglinide
action of glinides
bind to SUR1 (benzamido site) to close KATP channel and trigger insulin release
how are glinides administered?
orally
rapid onset (30-60 minutes) and off set 4 hours
used in response to meals
role of glinides
reduce post-prandial glucose
less likely to cause hypoglycaemia
when are glinides used?
in conjunction with metformin and TZDs
how is repaglinide metabolised?
hepatic metabolism and thus safer in CKD
what is the incretin effect
insulins has a greater response to oral glucose than IV
what happens with oral glucose?
- ingestion stimulates release of GLP-1 and GIP from enteroendocrine cells
- GLP-1 and GIP enter the portal blood
- enhance insulin release from beta cells and delay gastric emptying
- GLP-1 decreases glucagon release from alpha cells and decreases glucose production
two classes of drugs that work based on the incretin effect
DPP-4 inhibitors
Incretin analogues
examples of DPP-4 inhibitors
sitagliptin saxagliptin vildagliptin linagliptin alogliptin
is the incretin effect reduced in T2DM?
yes
how can the incretin effect be restored in T2DM
reducing breakdown of endogenous incretins
administering exogenous incretins resistant to breakdown
what terminates the action of GLP-1 and GIP within minutes?
enzyme dipeptidyl peptidase- 4
action of gliptins?
competitively inhibit DPP4, causing insulin secretion to be preserved
when are gliptins used?
in combination with SU or metformin, but can be used as monotherapy
adverse of DPP4-inhibitors (gliptins)
nausea
no hypoglycaemia
weight is neutral as they are weak drugs
examples of incretin analogues
extenatide
liraglutide
role of incretin analogues
mimic the action of GLP-1 but resist breakdown by DPP-4
agonists of GPCR GLP-1 receptors that increase intracellular cAMP concentration stimulating insulin release, also suppress glucagon, slow gastric emptying and decrease appetite
positives of incretin analogues
weight loss
reduce hepatic fat accumulation
how are incretin analogues administered?
SC weekly
adverse of incretin analogues
nausea
rarely pancreatitis
examples of alpha glucosidase inhibitors
acarbose
miglitol
voglibose
describe alpha glucosidase
brush border enzyme that breaks down starch and disaccharides to glucose (glycogenolysis)
when are alpha glucosidase inhibitors taken?
with a meal to delay absorption of glucose and reduce postprandial increase
adverse of alpha glucosidase inhibitors
flatulence
loose stools
diarrhoea (undigested carbohydrate and colonic bacteria)
which drug is infrequently used in the UK?
alpha glucosidase inhibitors
example of biguanides
metformin
which drug is first line in T2DM?
metformin
can metformin be used in kidney disease
no as it accumulates
action of metformin (biguanide)
reduces hepatic gluconeogenesis by stimulating AMP-activated protein kinase (AMPK), increasing glucose uptake and utilisation by skeletal muscle (increasing insulin signalling), reducing carbohydrate absorption and increasing fatty acid oxidation
desirable effects of metformin
reduces microvascular complications
administered orally
can be combined with other agents e.g. insulin, TZDs and SUs
prevents hyperglycaemia but doesn’t cause hypoglycaemia
causes weight loss
adverse of metformin (biguanide)
GI upset
rarely lactic acidosis (hepatic/renal disease and excess alcohol)
role of thiazolidinediones (TZDs)
enhance insulin action at target tissues, without affecting insulin secretion (reduce insulin resistance)
what do TZDs act on?
PPAR-gamma (nuclear receptor) which associates with RXR
largely confined to adipocytes
activated complexes act as transcription factors promoting expression of genes encoding several proteins involved in insulin signalling and lipid metabolism
desirable effects of TZDs
promote fatty acid uptake and storage in adipocytes rather than skeletal muscle and liver
reduce hepatic glucose output
enhance peripheral glucose uptake
do not cause hypoglycaemia
adverse of TZDs
weight gain fluid retention (promote Na+ reabsorption by the kidney)
specific drugs in TZDs class
ciglitzone
troglitzone
pioglitzone
what is the only TZD used and why?
pioglitzone as ciglitzone and troglitzone cause serious hepatotoxicity
what can TZDs be used in combination with?
metformin or SUs
what patients is TZDs used in?
obese people as it shifts fat from visceral and liver
do SGLT2 inhibitors require insulin
no
what does sodium-glucose cotransporter-2 inhibitors act on?
selectively block the reabsorption of glucose by SGLT2 in proximal tubule of the kidney nephron to deliberately cause glucosuria
benefits of SGLT2i
decrease blood glucose with little risk of hypoglycaemia
calorific loss and water accompanying glucose (osmotic diuresis) contributes to weight loss
agents in SGLT2i
dapaliflozin
canagliflozin
empagliflozin
adverse of SGLT2i
increased risk of thrush
what other diseases benefit in SGLT2i?
CVS
renal
define insulins somogyi effect
taking insulin at night causes on waking very high blood glucose levels due to blood sugar being lowered too much
what provides the highest level of endocrine control?
the hypothalamus
how does the hypothalamus integrate endocrine and nervous system?
- secretes regulatory hormones which control activity of anterior pituitary cells
- synthesises hormones and transports them to the posterior pituitary via the infundibulum
- hypothalamic autonomic control centres control secretion of adrenaline and NA by the adrenal medulla
describe the diurnal (circadian rhythm) control of hormone levels
- external cues (light/dark) evoke fluctuations in hormone secretions
- hormone levels are influences by the rate at which they are eliminated from the body
example of a female steroid hormone?
oestrogen
what are steroid hormones made of?
lipids derived from cholesterol
are steroid hormones stored?
no, once they are synthesised they are secreted
how are steroid hormones transported?
hydrophobic and transported in the blood plasma by binding to carrier proteins
when are steroid hormones biologically active?
when they are unbound
they pass through the membrane forming an activated hormone-receptor complex which binds to DNA and activates specific genes to produce specific proteins
example of an amine hormones
adrenaline
three classes of hormones
steroid
amine
peptide and protein
describe how catecholamines are transported?
hydrophilic and transported unbound in blood plasma
describe how thyroid amines are transported?
bound to carrier proteins
two types of amine hormones
thyroid amines
catecholamines
what are amine hormones made of?
amino acids
are amine hormones stored?
yes in vesicles until needed and they bind to membrane bound receptors
examples of peptide hormones
oxytocin
ADH
examples of protein hormones
GH
insulin
how are peptide and protein hormones transported?
they are hydrophilic and transported unbound in blood plasma
how are protein and peptide hormones synthesised?
precursor molecules and stored in secretory vesicles and cleaved by enezymes
what does the binding to carrier proteins facilitate?
hormone transport
increased half-life
reservoir of hormones
specific carrier proteins
cortisol-binding globulin (CBG)
thyroxine-binding globulin (TBG)
sex steroid-binding globulin (SSBG)
