Pharmacology Flashcards
1
Q
what type of chemical compound is metformin ?
A
Biguanide
2
Q
What is the molecular mechanism of metformin?
A
- Inhibition of complex 1 of the mitochondrial respiratory chain
- Causes fall in cellular ATP (rise in ADP/ATP ratio)
- leads to rise in AMP:ATP ratio, activation of AMPK and reduction in gluconeogenesis
3
Q
how is metformin taken up into cells?
A
active transport via organic cation transporters (OCTs)
these channels are mainly found in the intestines, Liver and kidney
4
Q
what are the main physiological mechanisms of metformin?
A
- Lowers hepatic glucose production ( with patients who have diabetes)
- increases Guy glucose utilisation and metabolism
other mechanisms:
- increased intestinal GLP-1 secretion
- Altered gut microbiome
- Decrease lipogenesis
- reduced inflammation
5
Q
what effect does metformin have on HbA1c?
A
lowers it by approximately 18 mmol/mol from the intial value
6
Q
what is the usual and maximum dose of metformin?
A
500mg bd
maxi dose 1g bd
7
Q
what are the side effects of metformin?
A
- Metformin associated lactic acidosis (MALA) - metformin increases lactate production. bad if AKI is present as kidney is usually needed to remove lactate.
- GI intolerance :
Diarrhoea
bloating
abdominal pain
dyspepsia
metallic taste in mouth
8
Q
What should you reduce metformin by if eGFR is <45ml/min?
A
max dose should be 1g daily
metformin should be contraindicated if eGFR <30ml/min
9
Q
what is the first line therapy for Type 2 diabees?
A
Metformin and comprehensive lifestyle management
10
Q
Metformin is weight gaining drug true or false?
A
false
11
Q
Give examples of sulphonylureas (Sus)
A
- Gliclazide (most common SU in UK)
- Glipizide
- Glimepiride
- Glibenclamide
12
Q
How does a beta cell release insulin?
A
normal beta cell function:
- Glucose enters beta cell via GLUT 2 transporter
- Glycolysis occurs results in ATP formation
- Rise in ATP causes closure of sensitive K channel (KATP)
- rise in membrane potentials triggers voltage gated calcium channel
- Calcium influx causes insulin exocytosis
13
Q
what is the molecular mechanism of sulphonylureas?
ii. what effect does this mechanism have on insulin secretion?
A
- Sulphonylureas act on ATP k channel in the beta cell
- SUs boind to SUR1 which causes closure of K channel (Katp)
- rise in membrane potentials triggers voltage gated calcium channel
- Calcium influx causes insulin exocytosis
ii. SUs stimulation of insulin is glucose independent. therefore insulin is secreted when glucose is not increased
14
Q
what effect does SUs have on HbA1c?
A
lowers HBA1c by 18mmol/mol from initial value
15
Q
SUs is weight gaining true or false?
A
true - causes release of insulin which increases appetite and anabolic reactions which cause weight gain
16
Q
what are the side effects of SUs?
A
risk of hypoglycaemia - careful when given to elderly
weight gain
17
Q
what is the usual dosage of SUs?
A
40-80mg od
max dose 160mg bd
18
Q
when would you prescribe SUs for Type 2 diabetes?
A
after Metformin and where cost is a major issue (i.e. developing countries)
no longer mainline treatment
19
Q
where are sodium glucose transporters found (SGLT)?
A
kidneys
20
Q
give examples of SGLT 2 inhibitors?
A
dapagliflozin
Canagliflozin
Empagliflozin (most common in tayside)
21
Q
what effect do SGLT 2 inhibitors have?
A
Direct effects:
decrease uptake of sugar in kidneys (i.e. makes you pee sugar)
also leads to weight loss
urate excretion is increased
indirect effects:
glucose reduction: this causes reduce insulin and increase in glucagon
increase lipolysis: increase in fatty acids results in increase of ketones. ketones are good for cardiac myocytes
22
Q
what is the physiology of SGLT 2 inhibitors?
A
Glucose loss results in osmotic diuresis which also reduces Na reabsorption. Both result in a mild diuretic action
urate excretion is increased
23
Q
what are the side effects of SGLT 2 inhibitors?
A
Thrush - main (more common in women)
fournier gangrene ( rare)
Hypovolemia and hypotension
Diabetic ketoacidosis
24
Q
What are SGLT 2 inhibitors?
A
specific inhibitors of renal sodium glucose transporter 2
25
what are Sulphonylureas?
insulin secretagogues which act directly on pancreatic beta cells to increase secretion
26
what effect do SGLT2 inhibitors have on HbA1c?
reduces it by 11 mmol/mol
27
whys should SGLT2i be omitted in prolonged fasting or acute illness?
as there is a risk of DKA and hypovolaemia( loss of ECF)
28
when should you prescribe SGLT2 inhibitor for T2DM?
After metformin:
```
1.give to HF or CKD patients
or
2. patients who need to minimise hypoglycaemia
and/or
3. or patients who want to lose weight
```
29
what is the incretin effect?
describes the greater response to rise in glucose and the subsequent release of insulin when glucose is taken in via the oral route rather than intravenously
30
Give examples of Incretin hormones
ii. which cells secrete them?
1. Gastric inhibitory peptide (GIP) - K cells
| 2. Glucagon like peptide (GLP-1) - L cells
31
what is the molecular mechanism of incretins?
amplifying pathway of the beta cell
1. GLP-1/GIP binds to GLP-1/GIP receptor which is G protein coupled rising to increase in cAMP
2. more Insulin is released
3. needs glucose or SUs to trigger this pathway otherwise this does not occur.
32
what effects does GLP-1 have?
1. increase in insulin secretion/ decrease glucagon secretion
2. Decrease beta cell apoptosis
3. increase glucose uptake and storage in muscles and fat
4. decrease glucose production in liver
5. delays gastric emptying
33
what are Dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors) also known as?
Gliptins
34
what is the effect do DPP4i have?
inhibit breakdown of incretin hormones
promote insulin secretion
helps incretin pathway so it is glucose dependent and wont cause hypoglycaemia
35
what effect do DPP4i have on HbA1c levels?
causes it to decrease by 5-8 mmol/mol
36
what are the side effects of DPP4i?
pancreatitis
37
Give examples of GLP-1 Receptor agonists?
Liraglutide
Lixisenatide
Dulaglutide
Albiguitide
semaglutide (oral version allowed in scotland only type)
38
what is the difference between GLP -1 and GLP-1 RA?
GLP-1 RA are modified to avoid breakdown by DPP4
39
what is the effect of GLP-1RA?
promote insulin secretion (insulin secretagogues) in a glucose dependent mechanism
lowers glucose
reduce gastric emptying
40
what effect do GLP 1RA have on Hba1c?
reduces it by 11-15 mmol/mol
41
Does GLP-1 RA cause weight loss true or false
true
42
what are the side effects of GLP-1RA?
nausea and vomiting
Gallstones
weight loss
43
when would you prescribe GLP-1RA in patients with T2DM?
first metformin:
1. Given to patients with high risk for ASVD,CKD or heart failure
2. needed to minimise hypoglycaemia
3. promote weight loss?
44
when would you prescribe DDP4i in patients with T2DM?
first metformin
then
1. patients needed to minimise hypoglycaemia
45
what is the molecular mechanisms of thiazolidinediones (TZDs)
they are PPARγ ligands
ligand binding results in formation of a complex with a co-activator
increase transcriptional activation of PPARv target genes
46
what is the physiological mechanism of TZDs?
main effect is on adipose tissue
1. increases differentiation from pre adipocytes to adippocytes
2. increases fat mass of subcutaneous fat which is good
3. Fatty acid is removed from viscera e.g. liver, pancreas and muscle which reduces lipotoxcitiy
4. adiopnectin - insulin sensitising peptides which acts on liver adipnectin receptors - increases insulin sensitising in the liver
47
what effect do TZDs have on inflammatory cytokines?
reduces them e.g IL 6
48
what effect do TZDs have on HBA1c?
reduces it by 15-20 mmol/mol
especially effective in obese women
49
TZDs cause weight gain true or false?
true - increase fat mass and fluid retentio n
50
what effect do TZDs have on blood pressure?
reduces it:
SBP by 4.7 mmHg
DBP 3.8 mmHg
51
give an example of TZD?
pioglitazone
52
what are the side effects of TZDs?
weight gain
fluid retention - causes peripheral oedema and increased risk of HF
fracture risk - fat accumulation in bone marrow and reduction in bone density
53
when would you prescribe TZDs for T2DM??
first metformin:
prescribed to minimise hypoglycaemia
prescribed if cost is a major issue
54
What occurs in ligand gated ion channels?
Hormones bind to ligand-gated ion channel receptor
They conduct ions into and out of the cell when activated via depolarisation and hyperpolarisation of the membrane
response occurs in milliseconds
55
What occurs in G protein coupled receptors?
A First example: adrenaline binding to beta 2 adrenoceptor
1. Beta 2 adrenoceptor is connected to three G proteins (G alpha subunit -separate and G beta gamma which form a dimer) also attached is GDP
2. Adrenaline binds to beta 2 adrenoceptor which causes conformational change making the receptor bind to G alpha subunit
3. GDP is exchanged for GTP
4. G alpha subunit with the GTP goes to activate
adennylyl cyclase to convert ATP to cAMP
Response occurs in seconds
2. There is a different response if the G coupled receptor has a different G alpha subunit e.g. G alpha i:
example: adrenaline binding to alpha 2 adrenoceptor
1. Adenylyl cyclase is already activated
2. Adrenaline binds to alpha 2 adrenoceptor
3. Conformational change allows for G alpha subunit which is activated when GDP is exchanged for GTP
4. G alpha i with GTP moves to adenylyl cyclase to inhibit it
5. G beta gamma interact with adjacent ion channels. If Gamma alpha i is present G beta gamma most likely has an inhibitory effect on adjacent ion channels
3. G protein coupled receptors e.g. arenaline bidning to alpha 1 adrenoceptor - has G alpha q
1. Adrenaline binds to alpha 1 adrenoceptors causing conformational change allowing for G coupled proteins to bind to it
2. GDP connected to G alpha q is exchanged for GTP and activates it
3. activated G alpha q moves to phospholipase C which converts PIP2 to DAG and IP3 which increases release of calcium ions
ALL G coupled receptor mechanisms stop when GTP turns to GDP which deactivates the G alpha subunit. Hormone disassociates from receptor causing conformational change
56
what type of ligand are hormones?
agonist
57
How do G proteins coupled receptors cause signal amplification?
cAMP is produced by adenylyl cyclase
cAMP interacts with PKA causing it to become phosphorylated
phosphorylate protein kinase A interacts with multiple enzymes leading to numerous products being made.
58
what do all beta adrenoceptors mainly cause?
all have G alpha s subunits which will lead to stimulation of adenylyl cyclase - increases cAMP
59
what is an adrenoceptors?
receptors bound and activated by the neurotransmitters/ hormones adrenaline and noradrenaline
60
what occurs in Kinase linked receptors?
1. Hormone causes receptors to dimerisation of the receptor
2. the receptors contain tyrosine residues in the intracellular section
3. The tyrosine residues are phosphorylated by ATP
4. Relay proteins bind tot he phosphorylated tyrosine residues
5. Varied cellular response can occur
response occurs in hours
61
what are the three main receptors activated by hormones?
1. Ligand gated ion channels
2. G protein coupled receptors
3. Kinase linked receptors
62
what are the three main ways in which cells communicate with each other?
1. Autocrine regulation - chemicals released from cells bind to receptors on or in the cell that is releasing them
2. Paracrine - chemicals released from the cells bind to receptors on adjacent cells
3. Endocrine - chemicals released from the secretory cells are usually transported through the circulatory system
63
what are the major endocrine glands?
1. Pineal gland - releases melatonin
2. Hypothalamus - manages the pituitary releases TRH and Cortico hormone releasing hormone
3. Pituitary - releases GH, TSH , FSH oxytocin, ADH
4. Thyroid - releases T3 and T4
5. Parathyroid - releases parathyroid horomone
6. Thymus
7. Adrenal gland - releases cortisol and adrenaline
8. Pancreas - releases insulin and glucagon
9. testes- testosterone
10. ovaries - oestrogen and progesterone
64
what is a hormone?
any substance elaborated by one cell to regulate another cell. May be delivered by autocrine, paracrine or endocrine routes
the biological response of a hormone to a receptor generally results in the amplification of a signal transduction cascades
most have effects on multiple targets in the body
65
Why is the Hypothalamus described as the endocrine director?
It intergrates activities of nervous and endocrine system by:
1. Secretion of regulatory hormones - which control activity of anterior pituitary cells
2. Synthesises hormones and transports them to the posterior pituitary via the infundibulum
3. Direct neural control - hypothalamic autonomic centres control secretion of adrenaline and noradrenaline by the adrenal medulla
66
Give an example of hormones performing complementary actions.
1. Stress/ exercise stimulates releases of adrenaline and cortisol
2. adrenaline causes stimulation of pancreatic alpha cells
3. cortisol causes gluconeogenesis which also increases blood glucose levels. This in turn also leads to stimulation of pancreatic alpha cells
4. Glucagon is released which is going to increase blood glucose too via glycogenolysis
67
give an example of hormones performing antagonistic actions against each other.
Dietary intake increases blood glucose leads to stimulation of pancreatic beta cells - insulin
Metabolism -decreases blood glucose levels leads to stimulation of pancreatic alpha cells - glucagon
Insulin causes glucose to be taken up by adipose and muscle tissue whereas glucagon causes more glucose to be made via glycogenolysis
68
what are the three hormonal structures?
Steroids - testosterone, cortisol and progesterone
Amine derived
Proteins
69
where do steroid hormone derive from?
lipids from cholesterol
70
how are steroid hormones transported in the blood?
carrier proteins (90%)
free (10%) - biologically activated
71
what is the steroid hormone action?
steroid hormones are hydrophobic/lipophilic
1. activated hormone receptor complex forms within the cell
2. Complex binds to DNA and activates specific genes causes gene activation leads to production of key proteins
72
where do amine hormones derive from?
amino acids
73
where are steroid hormones mainly released from?
Adrenal cortex - cortisol
Gonads - testosterone
Placenta - oestradiol
74
how are amine hormones transported in the blood?
Thyroid amine hormones - carrier proteins
catecholamine amine hormones - unbound in blood plasma. these are hydrophilic
75
Where are amine hormones secreted from?
Thyroid
adrenal medulla
76
what is the amine hormone action?
bind to membrane bound receptors to evoke cellular responses -mainly G protein
77
How are peptide hormones transported in the blood?
Transported unbound - they are hydrophililc
78
where are peptide hormones secreted from?
main type of hormones produced
pituitary
parathyroid
heart
stomach
liver
kidneys
synthesised as precursor molecules and stored in vesicles
79
where do peptide hormones derive from?
amino acids
80
what are the effects of thyroid and steroid hormones (which are insoluble in plasma) when they bind to carrier protiens?
1. Allows them to be transported
2. Increases half-life of hormone
3. A reservoir of the hormone
81
what is the mechanism for the insulin secreation of pancreatic beta cells?
1. Elevation of blood glucose concentration
2. Increased diffusion of glucose into beta cell by facilitated transport GLUT 2
3. Phosphorylation of glucose by glucokinase
4. Glycolysis of glucose - 6 - phosphate in mitochondria yielding ATP
5. Increased ATP/ADP ratio within cells closes TP -sensitive K+ channels cauisng membrane depolarisation
6. opening of bolatage activated ca 2+ increases intracellular ca2+ which triggers insulin secretion
82
Give examples of specific carrier proteins.
Cortisol binding globulin (CBG)
Thyroxine-binding globulin (TBG)
Sex steroid binding globulin (SSBG) - binds mainly to testosterone and oestradiol
83
Name the hormones released in the hypothalamus
ii. what is their class
iii. what is their main target and function?
Thyrotropin Releasing Hormone (TRH)
Corticotrophin Releasing Hormone (CRH)
ii. Both peptide
iii.
TRH - Anterior pituitary - stimulates release of TSH and prolactin
CRH - Anterior Pituitary stimulates release of ACTH
84
Name the hormones released in the pituitary gland
ii. what is their class
iii. what is their main target and function?
Thyroid Stimulating Hormone (TSH)
Adrenocorticotrophic Hormone (ACTH)
Luteinizing Hormone (LH)
Follicle Stimulating Hormone (FSH)
Growth Hormone (GH)
Prolactin
Melanocyte Stimulating Hormone (MSH)
Oxytocin
Antidiuretic Hormone (ADH)
ii. All peptide
iii.
Thyroid Stimulating Hormone (TSH) - thyroid, growth and metabolism
Adrenocorticotrophic Hormone (ACTH) - adrenal cortex causes metabolism pathways
Luteinizing Hormone (LH) - Gonads - reproduction
Follicle Stimulating Hormone (FSH) - gonads - reproduction
Growth Hormone (GH) - liver, bones and muscle - growth
Prolactin - mammary glands - reproduction
Melanocyte Stimulating Hormone (MSH) - Melanocytes - homeostasis
Oxytocin - mammary glands and uterus - reproduction
Antidiuretic Hormone (ADH) - kidney homeostasis
85
Name the hormones released in the pineal gland
ii. what is their class
iii. what is their main target and function?
Melatonin
Amine derived hormone
iii. Hypothalamus - homeostasis
86
Name the hormones released in the thyroid/parathyroid
ii. what is their class
iii. what is their main target and function?
T4 - amine - most tissues - growth and metabolism
T3 - amine - most tissues - growth and metabolism
Calcitonin - peptide - bone and gut - homeostasis
parathyroid hormone (PTH) - peptide- bone and gut - homeostasis
87
Name the hormones released in the adrenal medulla
ii. what is their class
iii. what is their main target and function?
Adrenaline - amine - multiple tissues - homeostasis and metabolism
Noradrenaline - Amine - Multiple tissue Homeostasis and metabolism
88
Name the hormones released in the Adrenal cortex
ii. what is their class
iii. what is their main target and function?
DHEA - steroid - CNS - growth
Aldosterone - steroid- kidney - homeostasis
Glucocorticoids - steroid - mutliple - homeostasis and metabolism
89
Name the hormones released in the testes
ii. what is their class
iii. what is their main target and function?
Testosterone
ii. Steroid
iii. Testes - reproduction
90
Name the hormones released in the pancreas
ii. what is their class
iii. what is their main target and function?
Insulin - protein - liver muscle and adipose tissue - growth metabolism and homeostasis
Glucagon - protein - liver, muscle and adipose tissue - growth metabolism and homeostsais
Somatostatin - gut - growth metabolism and homeostasis
91
Name the hormones released in the ovaries
ii. what is their class
iii. what is their main target and function?
Oestradiol - steroid - ovaries and uterus- reproduction
Oestriol - steroid - ovaries and uterus-reproduction
Progesterone - steroid - ovaries and uterus-reproduction
Testosterone - steroid - testes- reproduction
92
Name the hormones released in the Placenta
ii. what is their class
iii. what is their main target and function?
hCG - human chorionic gonadotrophin
Oestradiol
ii. hCG - peptide
Oestradiol - steroid
iii. hCG - uterus - reproduction
Oestradiol - - ovaries and uterus - reproduction
93
Name the hormones released in the Mammary glands
ii. what is their class
iii. what is their main target and function?
Oestrogen
Steroid
Ovaries and uterus - reproduction
94
What receptor does insulin use?
Tyrosine linked receptors
95
insulin increases DNA synthesis true or false?
true
96
how does the antipyretic effect of NSAIDs work?
reducing the production of prostaglandin E2 (PGE2)
NSAIDs inhibit the enzyme cyclooxygenase (COX). COX is required to convert arachidonic acid into thromboxanes, prostaglandins, and prostacyclins. Therefore, inhibiting COX can reduce the production of thromboxanes, prostaglandins, and prostacyclins. One of the prostaglandins reduced is PGE2, which acts on the thermoregulation centre, and therefore, decreases fever.
97
what are the side effects of NSAIDs?
gastric ulcer
acute kidney injury
indigestion
an increased risk of heart failure.
