Pharmacology Flashcards
1
Q
examples of steroid hormones
A
cortisol
testosterone
2
Q
examples of tyrosine derivative hormones
A
thyroxine
epinephrine
3
Q
what does the ability to measure hormones depend on?
A
pattern of secretion presence of carrier proteins interfering agents stability of hormone absolute concentrations (determined by rate of secretion)
4
Q
four types of membrane-bound receptors
A
ligand-gated ion channels
GPCR
receptor tyrosine kinase (kinase-linked receptors)
steroid hormone receptors
5
Q
response time of ligand-gated ion channels
A
milliseconds
6
Q
describe how ligand-gated ion channels work?
A
- activated by neurotransmitters (can also be hormones)
- binding causes conformational change in channel structures allowing influx/efflux of ions
7
Q
example when membrane bound ion channel goes wrong?
A
myasthenic gravis
8
Q
examples of GPCR
A
- 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
9
Q
structure of GPCR
A
7 transmembrane spans across the cell membrane coupled with G-proteins that stimulate/inhibit various types of effector molecules or ion channels
10
Q
response time of GPCR
A
seconds due to enzyme activity and signal amplification
11
Q
what does a GPCR do?
A
binding causes conformation change where the G-proteins dissociate
12
Q
three G-proteins
A
alpha subunit
beta and gamma subunits
13
Q
role of the alpha subunit?
A
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
14
Q
what do the beta and gamma subunits do?
A
form a dimer
15
Q
describe signal amplification in GPCR
A
- continual conversion of ATP to cAMP until switched off
- increased number of enzymes activated and therefore responses
- switched off by GTP hydrolysis
16
Q
what binds to receptor tyrosine kinases?
A
hormones e.g. insulin
17
Q
how long do receptor tyrosine kinases take to act?
A
hours
18
Q
describe how receptor tyrosine kinases work?
A
- 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
19
Q
explain how the hormone insulin binding produces a divergent response?
A
produces a variety of responses:
- glucose transport channels
- inhibition of gluconeogenesis
- glycogen storage
20
Q
examples of substances that bind to steroid hormone receptors
A
glucocorticoids
21
Q
describe how steroid hormone receptors work?
A
- 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
22
Q
what two receptors do glucocorticoids bind to?
A
GR and MR
23
Q
what is the negative consequence of glucocorticoids binding to MR
A
triggers cutaneous adverse effects e.g. skin atrophy and delayed wound healing
24
Q
three types of signalling
A
- autocrine
- paracrine
- endocrine
25
define autocrine signalling
chemicals released bind to receptors on the cell that is releasing them
26
define paracrine signalling
chemicals are released from cells bind to receptors on adjacent cells
27
define endocrine signalling
chemicals are transported via circulatory system to act on distant cells
28
two types of feedback control
negative
| positive
29
two co-ordinated regulatory systems
- intrinsic
| - extrinsic
30
factors that cause homeostatic end points to vary
```
genetics
age
gender
health status
environment
```
31
actions of insulin
- induces glucose uptake and utilisation by cells (muscles and liver)
- promotes glycogenesis and lipogenesis
- stimulates amino acid uptake and protein formation
32
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)
33
aims of diabetes management
optimise blood glucose and decrease possible complications
34
non-pharmacological management of diabetes
```
lifestyle changes
smoking
diet
weight
exercise
```
35
two modes of action of pharmacological therapies
1. dependent upon insulin
| 2. independent upon insulin
36
dependent upon insulin therapy action
increase secretion/ decrease resistance and hepatic glucose output
37
independent upon insulin mode of action
slowing absorption from the GI tract/ enhancing excretion by kidney
38
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
39
define sulfonylureas (SUs)
insulin secretagogues
40
what do SUs require?
functional beta cells
41
what do SUs require?
functional beta cells, so efficacy can reduce with time
42
what do all agents in the SU class contain?
the sulfonylurea moiety (sulphur and oxygen)
43
action of SUs
displace ADP-Mg2+ from SUR1 closing KATP channels, stimulating insulin release
44
what do SUs do?
decrease fating and post-prandial blood glucose and long-term microvascular complications
45
how are SUs administrated?
orally
| peak release is 1-2 hours
46
short-acting SUs
tolbutamide
| gliclazide
47
long-acting SUs
glibenclamide
| glipizide
48
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)
49
when are SUs used?
first line for those intolerant to metformin or with weight loss
second line in conjunction with metformin
50
which drugs decrease the action of SUs?
thiazide diuretics
| corticosteroids
51
examples of glinides
repaglinide
| nateglinide
52
action of glinides
bind to SUR1 (benzamido site) to close KATP channel and trigger insulin release
53
how are glinides administered?
orally
rapid onset (30-60 minutes) and off set 4 hours
used in response to meals
54
role of glinides
reduce post-prandial glucose
| less likely to cause hypoglycaemia
55
when are glinides used?
in conjunction with metformin and TZDs
56
how is repaglinide metabolised?
hepatic metabolism and thus safer in CKD
57
what is the incretin effect
insulins has a greater response to oral glucose than IV
58
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
59
two classes of drugs that work based on the incretin effect
DPP-4 inhibitors
| Incretin analogues
60
examples of DPP-4 inhibitors
```
sitagliptin
saxagliptin
vildagliptin
linagliptin
alogliptin
```
61
is the incretin effect reduced in T2DM?
yes
62
how can the incretin effect be restored in T2DM
reducing breakdown of endogenous incretins
| administering exogenous incretins resistant to breakdown
63
what terminates the action of GLP-1 and GIP within minutes?
enzyme dipeptidyl peptidase- 4
64
action of gliptins?
competitively inhibit DPP4, causing insulin secretion to be preserved
65
when are gliptins used?
in combination with SU or metformin, but can be used as monotherapy
66
adverse of DPP4-inhibitors (gliptins)
nausea
no hypoglycaemia
weight is neutral as they are weak drugs
67
examples of incretin analogues
extenatide
| liraglutide
68
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
69
positives of incretin analogues
weight loss
| reduce hepatic fat accumulation
70
how are incretin analogues administered?
SC weekly
71
adverse of incretin analogues
nausea
| rarely pancreatitis
72
examples of alpha glucosidase inhibitors
acarbose
miglitol
voglibose
73
describe alpha glucosidase
brush border enzyme that breaks down starch and disaccharides to glucose (glycogenolysis)
74
when are alpha glucosidase inhibitors taken?
with a meal to delay absorption of glucose and reduce postprandial increase
75
adverse of alpha glucosidase inhibitors
flatulence
loose stools
diarrhoea (undigested carbohydrate and colonic bacteria)
76
which drug is infrequently used in the UK?
alpha glucosidase inhibitors
77
example of biguanides
metformin
78
which drug is first line in T2DM?
metformin
79
can metformin be used in kidney disease
no as it accumulates
80
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
81
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
82
adverse of metformin (biguanide)
GI upset
| rarely lactic acidosis (hepatic/renal disease and excess alcohol)
83
role of thiazolidinediones (TZDs)
enhance insulin action at target tissues, without affecting insulin secretion (reduce insulin resistance)
84
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
85
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
86
adverse of TZDs
```
weight gain
fluid retention (promote Na+ reabsorption by the kidney)
```
87
specific drugs in TZDs class
ciglitzone
troglitzone
pioglitzone
88
what is the only TZD used and why?
pioglitzone as ciglitzone and troglitzone cause serious hepatotoxicity
89
what can TZDs be used in combination with?
metformin or SUs
90
what patients is TZDs used in?
obese people as it shifts fat from visceral and liver
91
do SGLT2 inhibitors require insulin
no
92
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
93
benefits of SGLT2i
decrease blood glucose with little risk of hypoglycaemia
| calorific loss and water accompanying glucose (osmotic diuresis) contributes to weight loss
94
agents in SGLT2i
dapaliflozin
canagliflozin
empagliflozin
95
adverse of SGLT2i
increased risk of thrush
96
what other diseases benefit in SGLT2i?
CVS
| renal
97
define insulins somogyi effect
taking insulin at night causes on waking very high blood glucose levels due to blood sugar being lowered too much
98
what provides the highest level of endocrine control?
the hypothalamus
99
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
100
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
101
example of a female steroid hormone?
oestrogen
102
what are steroid hormones made of?
lipids derived from cholesterol
103
are steroid hormones stored?
no, once they are synthesised they are secreted
104
how are steroid hormones transported?
hydrophobic and transported in the blood plasma by binding to carrier proteins
105
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
106
example of an amine hormones
adrenaline
107
three classes of hormones
steroid
amine
peptide and protein
108
describe how catecholamines are transported?
hydrophilic and transported unbound in blood plasma
109
describe how thyroid amines are transported?
bound to carrier proteins
110
two types of amine hormones
thyroid amines
| catecholamines
111
what are amine hormones made of?
amino acids
112
are amine hormones stored?
yes in vesicles until needed and they bind to membrane bound receptors
113
examples of peptide hormones
oxytocin
| ADH
114
examples of protein hormones
GH
| insulin
115
how are peptide and protein hormones transported?
they are hydrophilic and transported unbound in blood plasma
116
how are protein and peptide hormones synthesised?
precursor molecules and stored in secretory vesicles and cleaved by enezymes
117
what does the binding to carrier proteins facilitate?
hormone transport
increased half-life
reservoir of hormones
118
specific carrier proteins
cortisol-binding globulin (CBG)
thyroxine-binding globulin (TBG)
sex steroid-binding globulin (SSBG)
