Treatment Flashcards
1
Q
what type of receptor is a nicotinic acetylcholine receptor
A
receptor-operated ion channel
2
Q
name the two competitive antagonists to the nicotinic acetylcholine receptor and state which one is reversible/irreversible
A
reversible:
tubocurarine and vecuronium
irreversible:
(a) bungarotoxin
3
Q
name two examples of non-competitive antagonists in a nicotinic acetylcholine receptor
A
lidocaine and tetrodotoxin
4
Q
what type of receptor is a GABAA receptor
A
receptor-operated ion channel
5
Q
to which superfamily of receptors do the adrenoceptor family and the muscarinic acetylcholine receptor family belong
A
superfamily 2
G-protein coupled receptors
6
Q
what enzyme is responsible for the turning on and off of a G protein coupled receptor
A
GTPase
7
Q
is it GTP or GDP when the G protein is switched on
A
GTP = on GDP= off
8
Q
describe the Role of G-proteins and second messengers in Superfamily 2 receptor-effector coupling (how G protein coupled receptors work)
A
- first messenger
- receptor
- transducer (G protein)
- effector (enzyme or ion channel)
- second messenger (regulate an internal target)
- cellular response
9
Q
how are second messengers generated within cells
A
- synthesis inside cell catalysed by enzymes whose activity is regulated by cell surface receptors
or
- influx of ions via channels whose activity is regulated (indirectly) by cell surface receptors
10
Q
what are the two key protperties of G proteins
A
Amplification:
- receptor remains active long enough to active several G-proteins (or the same one several times)
- effector remains activated by Ga subunit long enough to generate many molecules of second messenger
Specificity- different Ga subunits (>28):
- each encoded by a different gene or splice variant
11
Q
what are these effectors regulated by:
- adenylate cyclase (makes cyclic AMP)
- phospholipase C-b (makes IP3 and DAG)
- voltage-gated potassium channels
- voltage-gated calcium channels
A
effectors regulated by G - proteins
12
Q
how do allosteric modulators work
A
allosteric modulators cause shape change in channel protein on binding elsewhere on the protein
This affects properties of gate and influences time for which channel is open (and ions can move)
13
Q
what do inhibitor modulators do
A
↓amount of time channel open, ↓ion flux
14
Q
what do Facilitator Modulator (+ve) do
A
↑amount of time channel open, ↑ion flux
15
Q
what are the 5 factors that affect size of response to a receptor agonist
A
- concentration of drug in vicinity of receptor at a given time - influenced by dose given, route of administration,
distribution throughout the body, rate of elimination
(metabolism, excretion) - affinity - tendency to bind, strength of attraction between agonist and receptor
- ‘intrinsic efficacy’ - ability to activate a shape change leading to response
- nature of receptor-response coupling ‘signal transduction mechanism’
- total number of receptors present
16
Q
briefly describe receptor occupancy
A
-Theoretically, size of overall response varies with proportion of receptors occupied by agonist (occupancy)
- maximum response to agonist occurs when all receptors for that
agonist that are present in that tissue are occupied by agonist - proportion of total receptors available which are occupied depends on:
- agonist concentration
- strength of bonds formed
17
Q
what is the equation of occupancy
A
Occupancy = [XA]
__________________
[XA] + KA
KA = equilibrium constant* for agonist drug A
18
Q
what happens when KA = XA in the occupancy equation
A
occupancy = 50%
KA is numerically equal to the concentration of agonist when half of the total receptors present are occupied
19
Q
what does an increase and decrease in Ka mean in terms of occupancy
A
If KA is a very small value (e.g. picomolar, <10-9 M), the bonds formed between an agonist and its receptor are very strong
and it is easier to form complexes but more difficult to reverse or dissociate binding (↑affinity)
If KA is a very large value (e.g. micromolar, >10-6 M), the bonds formed between an agonist and its receptor are very weak and
it is more difficult to form complexes but much easier to reverse or dissociate binding ↓affinity
20
Q
what is the definition of EC50
A
EC50 : effective concentration
to produce 50% of maximum response
21
Q
how is EC50 used
A
EC50 is a practical, indirect, measure of Drug A’s potency, measured downstream of receptor – relates agonist drug A’s concentration to biological effect produced as a consequence of occupancy
22
Q
what is intrinsic efficacy
A
ability of an agonist on binding to a receptor to activate a change in shape or folding of that receptor
23
Q
what would the typical intrinsic efficacy values be of a full agonist and a partial agonist
A
full: +1 (or 100%)
- Evoke the maximum shape change/activation response of
which the receptor protein is capable
partial: between 0 and +1
- Evoke less than the maximum shape change/activation
response of which the receptor is capable
24
Q
briefly describe inverse agonists stating their possible efficacy value
A
- [-1 < efficacy <0]
- cause –ve shape change which stabilises inactive state of receptor and attenuates coupling/basal activity
- Make receptor less likely to activate signal transduction – negative efficacy value – make it even harder for receptor to be activated
25
state the equation of the size of response (R) to an agonist
see slide 30
| lecture 31 - treatment 2
26
what may cause a reduction in size of response during chronic exposure to an agonist drug (desensitisation)
- ↑ removal/metabolism of drug - ↑synthesis/activation of enzymes/transport proteins
- altered characteristics of agonist receptor complex - e.g. phosphorylation of amino acids in receptor proteins - influence affinity and/or efficacy (i.e. binding/activation)
- exhaustion, down-regulation of signal transduction mechanisms downstream from receptor
- ↓number of receptors - ↓synthesis and/or ↑ internalisation, degradation
27
what is an antagonist drug
‘any drug which reduces the response to another drug’
28
what would the intrinsic efficacy value be of a competitive antagonist
0
29
describe the action of competitive antagonists
compete with chemical mediator or agonist drug for binding
to similar or overlapping binding site on the same receptor but
without initiating a cellular response; reduce probability that
receptors will be occupied by chemical mediator or agonist drug
30
give an example of a competitive antagonist at B1 adrenoreceptors
atenolol
31
give an example of a reversible competitive antagonist
atenolol
32
describe reversible competitive antagonists
associate but can then dissociate again so effects can be overcome by adding more agonist (as this increases chance that receptor will be occupied by an agonist rather than antagonist molecule when antagonist dissociates to leave a free receptor)
33
what is the effect of a competitive reversible antagonist on the agonist log concentration response relationship
```
rightward
parallel shift
without reduction
in maximum
response to
agonist
```
see treatment 3 slide 7
34
what is the equation fir the dose ratio
see treatment 3 slide 7
35
give an example of an irreversible competitive antagonist
phenoxybenzamine
36
describe irreversible competitive antagonists
associate and remain associated with receptor indefinitely;
receptors are permanently blocked and increasing agonist
concentration will have no effect since the receptors remain
blocked and agonist molecules cannot get in to the binding site
to replace antagonist molecules
37
what is the effect of competitive irreversible antagonists
| on agonist log concentration-response curve
```
progressive
reduction in
maximum response
to agonist without
rightward parallel
shift in agonist
log concentration
response curve
```
38
describe non-competitive antagonist
- affects action of agonist at some point in chain leading to response but does not compete with agonist for binding to same site on receptor
- can be reversible or irreversible
- normally ↓ maximum response
39
give an example of a non-competitive antagonist
palonosetron
or lidocaine:
Ion channel blocker lidocaine antagonises the action of acetylcholine
at a point downstream in the chain leading to response
40
describe the two methods of action of non-competitive antagonists
- can involve binding to an allosteric site on an unoccupied receptor to cause conformational change which alters agonist binding elsewhere and/or initiation of signal transduction
- or can involve interference with a component of signal transduction pathway downstream from receptor
41
describe and give an example of Physiological (Functional) antagonist
has an opposite effect to the agonist but achieves its result by acting
as an agonist on separate cells or tissues or on different population of receptors/signal pathway in the same cell i.e. two systems are involved
e.g. parasympathetic and sympathetic nerves supplying heart - see T3 - slide 14
42
describe pharmacokinetic antagonist
one drug ↓ concentration of another drug by interfering with its absorption, distribution, metabolism or excretion (and hence concentration in vicinity of its molecular target)
43
give an example of a Pharmacokinetic Antagonist and describe how it works
antibiotic rifampicin induces expression of liver enzymes which metabolise anti-coagulant drug warfarin
anticoagulant protection is reduced
44
what is the difference between an alpha and beta adrenoreceptor
alpha: noradrenaline > adrenaline
beta:
adrenaline> noradrenaline
45
what receptor does diazepam work on
GABAA receptor /chloride channel
46
what are the two Pharmacological classification of cholinoceptors
nicotinic (NMJ)
Muscarinic (PNS)
47
what's the difference between stimulatory and inhibitory G-proteins
stimulatory G-proteins induce conformational change in effector protein (channel or enzyme) to more active state (enhanced activity)
inhibitory G-proteins induce conformational change in effector protein (channel or enzyme) to less active state (reduced activity)
48
name 5 processes regulated by cyclic AMP-dependent protein kinase
- smooth muscle relaxation
- cardiac muscle contraction
- ion transport via voltage-operated channels:
altered gating, neuronal excitability etc
- cell growth and differentiation:
↑ transcription factor activation (phosphorylation of cyclic AMP response element binding protein, CREB)
- cellular metabolism:
enzymes controlling lipolysis, glycogen synthesis and degradation
49
what is the function of theophylline
- ↓ metabolism of cyclic AMP;
prolongs/enhances cyclic AMP-dependent signalling events
Main actions:
- relaxes bronchial smooth muscle
- some anti-inflammatory effects
- stimulates respiratory centre in brain
Therapy for asthma and COPD
- now rarely used clinically due to numerous side-effects
- narrow therapeutic index
50
what is IP3
IP3 is a second messenger which causes release of pre-stored
| calcium from intracellular organelles into the cytoplasm
51
what does elevated cytoplasmic calcium ion concentration regulate
- activity of contractile proteins in smooth and cardiac muscle
- secretion from exocrine and endocrine glands
- release of neurotransmitters
- activity of many enzymes and ion channels
52
Processes regulated by phosphorylation of cellular proteins by PKC include:
- contraction of smooth muscle
- neurotransmitter release
- release of hormones from endocrine glands
- receptor desensitization (reduced activity)
- ion transport across membranes
- inflammation
53
what is DAG
DAG is a second messenger which activates a phosphorylating
| enzyme called Protein Kinase C
54
give two examples or receptors that are coupled to Phospholipase C-b by G-proteins
a1 adrenoceptors (blood vessels)
M3 muscarinic cholinoceptors (airway smooth muscle)
55
what are the agonists and antagonists for a1 adrenoreceptors
agonists are vasoconstrictors (noradrenaline, phenylephrine)
antagonists are vasodilators (prazosin, doxazosin)
56
what are the agonists and antagonists for M3 muscarinic cholinoceptors
agonists are bronchoconstrictors (acetylcholine)
antagonists are bronchodilators (ipratropium bromide, tiotropium)
57
describe the phospholipase C-b signalling pathway: termination of response
- cytoplasmic calcium leaves cell or is returned to organelle stores
- dephosphorylation of proteins that were phosphorylated by PKC is undertaken by phosphoprotein phosphatases
58
give two examples of SH-2 domain-containing proteins
glucose transporter proteins (GLUT4) responsible for glucose uptake across cell membrane
MAPK enzyme involved in cell proliferation, differentiation and survival pathways
59
describe the JAK/STAT pathway
when agonist (cytokine) binds, receptor dimerizes and associates with cytosolic tyrosine kinase (Jak)
Jak phosphorylates receptor dimer
phosphorylated receptor dimer is a binding site for transcription factor, STAT (SH-2 domain containing protein)
STAT is phosphorylated, travels to nucleus and alters gene expression
60
give two examples of drugs that target tyrosine kinase-linked receptors
renal cancer drug - sunitinib
breast cancer drug - trastuzumab (herceptin)
61
what are the main types of receptors linked to tyrosine kinase
- insulin receptor - insulin-like growth factor receptor - epidermal growth factor receptor - (cytokine receptors)
62
what are the main receptors linked to granulate cyclase
- receptors for natriuretic peptides - receptors for guanylin peptides
63
describe the action of ANP Receptor/Guanylate Cyclase
1. first messenger interacts with ANP receptor/
guanylate cyclase
2. phosphorylated
precursor (GTP) converted to 2nd messenger (cyclic GMP)
3. acts on cyclic GMP-activated protein kinase (internal target)
4. protein phosphorylation
and cellular response (relaxation/vasodilatation)
64
describe the Mechanism of action of nuclear receptors
enhance or suppress gene expression
- agonist (hormone) binds to
intracellular receptor
- zinc finger domain opens up, binds to hormone responsive element located upstream from gene promoter region
- ↑ ↓ activity of RNA polymerase
- ↑ ↓ gene transcription
- ↑ ↓ translation of mRNA
- ↑ ↓ synthesis of new protein altered cell response
65
give 3 examples of drugs that act on nuclear receptors
```
Aldosterone receptor (MR) antagonists - Spironolactone:
- oppose sodium, fluid retention and potassium loss by antagonising aldosterone receptor-dependent gene expression
```
Glucocorticosteroid receptor (GR) agonists -
budesonide, beclometasone:
- not bronchodilators- do not relieve acute bronchospasm
- prevent inflammation/resolve established inflammation
- ↓ expression of inflammatory mediators
Peroxisome proliferator-activated receptors (PPAR) for fatty acids - PPARy agonists such as pioglitazone:
- oral anti-diabetic agent
- modulate transcription of insulin-sensitive genes involved in control of glucose and lipid metabolism in muscle, adipose, liver
66
what is the functional effects of adrenoreceptors in the heart and what is the primary receptor
increase rate of contraction
increase cardiac conductivity
increase force of contraction
primary receptor: beta 1
67
what is the functional effects of adrenoreceptors in blood vessels (arteries, skeletal muscle, veins) and what is the primary receptor
arteries: constriction and alpha 1
skeletal muscle: dilation and beta 2
veins: constriction and alpha 1
68
what is the functional effect of a1 and B2 adrenoreceptors on smooth muscle
Generally a1 constrict/b2 relax smooth muscle
69
what is the functional effect of adrenoreceptors in the kidney and what is the primary receptor
increased renin secretion
B1
70
what is the functional effect of adrenoreceptors in the airways and what is the primary receptor
relax (dilate)
B2
71
what is the functional effect of adrenoreceptors in the peripheral sympathetic nerves and what is the primary receptor
increased release - B2
decreased release - a2
72
what is the functional effect of adrenoreceptors in the brainstem and what is the primary receptor
decreased sympathetic outflow
a2
73
what is the definition of Adrenoceptor Antagonists and what type of drugs would they include
drugs which occupy adrenoceptors and prevent the action of adrenaline (epinephrine) and noradrenaline (norepinephrine)
Includes:
- beta blockers (-lol)
- alpha1 blockers (-osin)
74
how can B adrenorecptor antagonists differ from one another
Pharmacodynamic properties:
- selectivity
- partial agonist activity
- additional actions
Pharmacokinetic properties:
- solubility in water vs. lipid
- ability to enter CNS
- route of elimination
75
describe the pharmacokinetic aspects of water soluble B-blockers and lipid soluble B-blockers
give examples of each
```
Water Soluble:
- little metabolism (mainly eliminated by kidney)
- long half lives/less frequent
administration
- reduce dose in renal impairment
- less likely to cross
blood-brain barrier
- less sleep disturbance
- Examples = atenolol and stall
```
```
Lipid Soluble:
- extensive metabolism
(> variation)
- short half lives/more frequent administration
- reduce dose in hepatic impairment
- more likely to cross
blood-brain barrier
- poor quality sleep and nightmares
- examples = propranolol and oxprenolol
```
76
what are the cardiovascular actions of b blockers
- reduce heart rate, cardiac conductivity and force of contraction
- decrease cardiac work and oxygen demand
- reduce blood pressure
- [reduce skeletal and peripheral blood flow]
77
Why do beta-blockers lower blood pressure
Initial fall in cardiac output:
- antagonise b1 adrenoceptors in heart
- but soon compensated by rise in peripheral vascular resistance via noradrenaline action on vascular a1 adrenoceptors so fall in BP modest
Delayed indirect fall in peripheral vascular resistance (with continued reduction in cardiac output), BP ↓ :
- due to ↓renin secretion (blockade of b1 receptors in kidney)
- and ↓ central sympathetic outflow and blockade of facilitator pre-synaptic b2 receptors on sympathetic nerve terminals
78
Name 2 clinical uses of B blockers
- [uncomplicated hypertension]
- arrhythmias
- angina pectoris
- post myocardial infarction
- [stable] heart failure
- migraine
- glaucoma
- physical effects of anxiety
79
what are the anti-arrhythmic effects of B-blockers
- attenuate sympathetic effects on automaticity and conductivity
- management of supraventricular tachycardias
- management of atrial fibrillation
80
why are B-blockers used in prophylaxis of stable angina
- blunt sympathetic response to exercise
- reduce myocardial oxygen demand by reducing heart rate and contractility
- (reduced peripheral vascular resistance, ↓BP also reduces after-load and oxygen demand)
- prolonged diastole also improves perfusion of sub-endocardial myocardium and oxygen supply
81
why are B-blockers used as secondary prevention post MI and what are the reasons for these benefits
- reduce morbidity and mortality post MI
- [some*] ↓ recurrence of myocardial infarction
Due to:
- ↓ cardiac work, oxygen demand
- attenuate ventricular remodelling
- ↓incidence of supraventricular tachycardias
- ↓ incidence of ventricular dysrhythmias (caused by sympathetic nervous stimulation)
82
Describe when B-blockers are used in heart failure patients
contra-indicated in acute/worsening unstable heart failure
some* [carvedilol, bisoprolol, metoprolol] useful in chronic stable heart failure
83
what are the reasons for benefit in heart failure after using B-blockers
Reduce heart rate
- prolong diastole, improve chamber filling
- reduce ischaemia (improved coronary blood flow during diastole, and ↓ cardiac work ↓ oxygen demand)
↓ Activation of renin-angiotensin-aldosterone system (↓ pre-load and after-load)
Attenuate adverse remodelling/myocyte loss
Anti arrhythmic effects (major)
- reduced risk of sudden cardiac death
84
what are some adverse effects of B-blockers
- bradycardia
- heart block (atrioventricular block)
- fatigue, nightmares, confusion, depression, insomnia
b2 -adrenoceptor antagonism:
- poor tissue perfusion in peripheral vascular disease, intermittent claudication (cramping of skeletal muscles in calf, thigh)
- exacerbation of Raynaud’s disease
- cold hands and feet (less marked with partial agonists)
- bronchospasm in asthmatics/ COPD
- adverse metabolic effects
- weight gain in some patients
- diarrhoea, nausea
- impotence
85
Contra-indications for B blocker use
- bradycardia and heart block
- asthma
- [acute decompensated heart failure]
- [Type 1 diabetes mellitus]
- [claudication]
[ ] = possible contraindications
86
why is it when someone is on B-blockers and you decide to discontinue the medication must you withdraw the medication gradually
Sudden discontinuation of B-blockers may cause:
- hypertension
- angina pectoris/myocardial ischemia
- acute myocardial infarction
this is because:
rebound sympathetic stimulation of heart following prolonged beta receptor blockade
87
what are the Cardiovascular effects of a* adrenoceptor antagonists
reduce peripheral vascular resistance
BUT cause rebound increase in heart rate, cardiac work and oxygen demand
88
3 clinical uses of a adrenoceptor
- management of resistant hypertension
- hypertension secondary to phaeochromocytoma
- relieve urinary retention in prostate hyperplasia
89
adverse effects of a adrenoceptor antagonists
- postural hypotension, dizziness and fainting
- headache
- nasal congestion
- stress incontience
90
what is the ending of names of drugs that are beta blockers
what is the ending for alpha blockers
beta blockers, -lol
alpha blockers, -osin
91
describe the action of nitrates as vasodilators
- Nitrates bind to receptor in vascular smooth muscle
- A NO group is formed which stimulates enzyme guanylate cyclase to produce cyclic GMP
- Calcium entry is inhibited or calcium exit enhanced and vasodilatation occurs
- Process requires SH groups.
92
What contributes to tolerance of nitrates as vasodilators
Tolerance is thought to be due to depletion of SH groups
93
when should nitrates be prescribed to a patient
Angina - acute and prophylactic
Acute heart failure (with good BP)
- Acute effort angina (GTN)
- Angina prophylaxis (ISMN)
- Angina at rest
- Acute myocardial infarction – with heart failure
- Severe acute congestive failure (with good BP) especially with right-sided failure
94
name 4 adverse effects of all vasodilators
Flushing
Headache
Tachycardia
Hypotension
95
what is the suffix for dihydropyridines (calcium channel antagonist)
-dipine
96
how do calcium channel antagonists work
Calcium antagonists block the entry of calcium through the calcium channel in vascular smooth muscle and myocardium
Less calcium is available for the contractile apparatus causing:
- Vasodilatation
- Negative inotropic effect (reduces force of contraction)
97
describe the selectivity of calcium channel antagonists (dihydopyridines and then diltiazem and verapamil)
Dihydropyridines favour depolarised closed Ca++ channels most commonly found in the vascular smooth muscle cells
Diltiazem and Verapamil favour the hyperpolarised Ca++ channels more commonly found in cardiac muscle cells
98
what is the main use of dihydopyridines
Dihydropyridines mainly vasodilator effects so main use is hypertension
99
what is the main use of Diltiazem and verapamil
Diltiazem and verapamil have rate-limiting activity so may be used more for anti-anginal or anti-arrhythmic
100
name a major and some minor adverse effects of nifedipine
minor:
- Headache
- Flushing
- Tachycardia
- Peripheral oedema
major:
Rare but can cause heart failure in patients with poor left ventricular function
101
name a major and some minor adverse effects of diltiazem
minor:
- Headache
- Flushing
- Tachycardia
- Peripheral oedema
- constipation especially in the elderly
major:
May cause heart block in ‘at risk’ patients and those on digoxin and beta blockers
102
name a major and some minor adverse effects of verapamil
minor:
- Headache
- Flushing
- Tachycardia
- Peripheral oedema
- constipation especially in the elderly
major:
May cause heart block in ‘at risk’ patients and those on digoxin and beta blockers
103
why might a drug be given buccal or sublingual
- goes directly into systemic circulation
- really quick absorption
- good vascular supply
104
Describe the pharmacodynamic effects of ACE inhibition and how these may benefit patients with hypertension and heart failure
peripheral vasodilatation, ↓ BP:
- reduces AngII constrictor action in arteries and veins
- more pronounced in hypertensives than normal volunteers
- esp. when renin secretion enhanced due to salt/volume depletion
```
decreased aldosterone (and vasopressin) secretion:
- decreased Na+ /water retention, blood volume
```
↓ sympathetic activation:
- ↓ facilitation of neuronal noradrenaline release by angiotensin II
↑ bradykinin / PG vasodilatation:
- prevent metabolism of bradykinin, helps ↓ BP
- improved endothelial function, ↓risk of cardiovascular events in atheromatous disease
↓ angiotensin mediated generation of ROS:
- inhibition of NADPH oxidase, oxidative stress-related injury
decreased glomerular filtration rate:
- esp. useful in diabetic nephropathy
↓ hypertension-related remodelling:
- in vasculature, heart and kidney
105
Outline precautions that should be taken when introducing ACE inhibitor therapy
- use a low dose when starting the drug in patients with heart failure – monitor blood pressure and renal function
- avoid starting the drug in established renovascular disease unless guided by renal physicians
- watch for rising K+ and avoid potassium supplements and potassium sparing diuretics
- probably contraindicated in severe aortic stenosis (all vasodilators- > risk of hypotension)
- DO NOT GIVE IF PREGNANCY PLANNED
106
what is the suffix for AT1 Receptor Antagonists (ARBs)
-sartan
107
what are some Contraindications/Cautions for ARBs
generally similar to ACE inhibitors
contra-indicated in bilateral renal artery stenosis
caution in unilateral disease, history of renal impairment or generalised atherosclerosis, elderly:
- monitor renal function / serum K+ (U+E) before and after
avoid in aortic stenosis
contra-indicated in pregnancy
108
what are some adverse effects of AT1 Receptor Antagonists
generally mild and better tolerated than ACEI
1st dose hypotension:
- esp. in volume-depleted /in combination with diuretics
- less marked than for ACE inhibitors
acute renal failure
hyperkalaemia:
- especially with K+ sparing diuretics
rarely angio-oedema
109
give an example of an osmotic diuretic
mannitol
110
describe how osmotic diuretics work, when they may be used, and some side effects
(mode of action for mannitol)
- freely filtered, act on parts of nephron most water-permeable (PCT and early Loop of Henle)
- reduce H2O reabsorption (water retained in filtrate due to osmosis)
- reduce electrolyte reabsorption (leak back into tubule down concentration gradient)
Infused i.v. mainly for raised intracranial pressure (cerebral oedema) and intraocular pressure (works by drawing fluid out)
Side-effects (uncommon): hypotension, fluid and electrolyte disturbance
111
give an example of a carbonic anhydrase inhibitor
Acetazolamide
112
describe how Carbonic Anhydrase Inhibitors work, when they may be used, and some side effects
Mode of action: - Inhibits carbonic anhydrase in PCT
- enzyme interconverts CO2 /H20 and H+/HCO3- (controls acid-base balance)
- Acetazolamide (example of a carbonic anhydrase inhibitor) reduces Na+ and HCO3- reabsorption
- Weak diuretic (action partially compensated by greater Na+ reabsorption in DCT)
Clinical indications: glaucoma and acute altitude sickness
Adverse effects: metabolic acidosis, hypokalaemia, renal stone formation (due to alkaline urine)
113
give 3 examples of loop diuretics
furosemide, bumetanide, torasemide
114
describe how loop diuretics work, when they may be used, some side effects and some interactions
Mode of Action:
- inhibit Na+/K+/2Cl- co-transporter in ascending limb of Loop of Henle (impermeable to water)
- decrease osmolarity of medullary interstitium (relative to that of tubule lumen) leading to decreased reabsorption of water from collecting duct
```
(1) Loop diuretics block Na+ /K+ /2Cl-
transporter preventing absorption
and promoting tubular excretion of Na+ and Cl-
(2) Loop diuretics also ↓ potential
difference across tubule cell which is
generated by recycling of K+
(3) As a result, ↑ excretion of Ca2+
and Mg2+ occurs because of inhibition
of paracellular diffusion
```
```
uses:
- used for oedema
as Loop diuretics are
good at getting rid of
excess water:
> Congestive heart failure
> Resistant hypertension
> Liver ascites
> Nephrotic syndrome
- Acute hypercalcaemia
```
Adverse effects:
- Hypovolaemia and dehydration
- Hypokalaemia (cramps, arrhythmias)
- Hypomagnesaemia
- Hyponatraemia
- Hyperuricaemia (gout)
- Oto and renal toxicity (high doses)
- Allergic reactions to skin and kidney (rare)
interactions:
- Increased risk of electrolyte disturbance when combined with thiazide diuretics (see later)
- Increased oto and nephrotoxicity when combined with aminoglycoside antibiotics (e.g. gentamicin)
- > risk of hypotension when combined with ACE inhibitors and other vasodilator drugs (but can often be combined for therapeutic benefit)
- Impaired diuresis when combined with non-steroidal anti-inflammatory drugs (NSAIDs) (reduce vasodilatory prostaglandin dependent renal blood flow)
115
what is the suffix for thiazides
-thiazide
116
give two examples of thiazides
Bendroflumethiazide,hydrochlorothiazide
117
give three examples of thiazide-like drugs
Chlortalidone, Indapamide and Metolazone
118
describe how thiazides work, when they may be used, some side effects and some interactions
Mode of action in the early distal convoluted tubule:
(1) thiazide diuretics increase
excretion of Na+ and Cl- by
inhibiting Na+ /Cl- cotransporter (bind to Cl- site)
(2) (3) reabsorption of Ca2+ is increased due to stimulation of Na+ /Ca2+ counter-transport as consequence of increased concentration gradient for Na+ across basolateral membrane
Clinical indications:
- Now relegated to 2nd or 3rd line in uncomplicated hypertension (indapamide, chlortalidone) in UK
> often tolerated less well than calcium channel modulators esp. due to electrolyte and metabolic disturbance, gout
> but consider 1st or 2nd line instead of calcium channel modulator if oedema present or (high risk of developing) heart failure, very elderly
- occasionally in resistant oedema in heart failure (in combination with loop – with caution) or other causes of oedema but loop diuretics still first line
- protective in osteoporosis and for prevention of renal calcium stones?
> promote calcium retention
Adverse effects:
Same as loop diuretics except:
- associated with > urate retention
- > increase in cholesterol and hyperglycaemia (at high dose)
- reduced calcium excretion (hypercalcaemia)
- less oto and nephrotoxicity in combination with aminoglycosides
Interactions:
Same as loop diuretics except:
- hypotension is less likely in combination with ACE inhibitors and other vasodilators
- more likely to cause lithium toxicity when co- prescribed with lithium
- more likely to cause hyponatraemia when co-prescribed with SSRI antidepressants (especially elderly)
119
describe how potassium-sparing diuretics work, when they may be used, some side effects and some interactions
action localised to late DCT/early collecting duct
weak natriuretic, diuretic action
Mode of action of amiloride and triamterine in late distal tubule and collecting duct:
- block apical Na+ channels
- ↓ potential difference across
principal cell
- ↓ driving force for K+ secretion from principal cell and H+ from intercalated cell
- leading to ↑ Na+ excretion and ↓K+ and H+ excretion
Mode of action of aldosterone
antagonists in late distal
tubule and collecting duct:
- Aldosterone is a steroid hormone acting
on a nuclear receptor to ↑ synthesis
of proteins (AIPs) which activate silent Na+
channels, ↑ synthesis of K+ channels,
Na+ K+ATPase, Na+ /H+ counter-transporter,
H+ ATPase, ATP production by mitochondria
- i.e. ↑ potential for Na+ retention, K+/H+ loss
- Spironolactone and eplerenone block effects
of aldosterone leading to ↑ Na+ excretion
and ↓K+ and H+ excretion
Clinical indications:
- Potassium sparing diuretics are occasionally still used to prevent thiazide or loop diuretic- induced hypokalaemia
- Spironolactone is prescribed in conditions associated with primary (Conn’s syndrome) and secondary hyperaldosteronism (heart failure, liver ascites)
- Spironolactone is a useful add on 4th agent in resistant hypertension (patients already receiving A+C+D)
Adverse effects:
- Hyperkalaemia (K+ retention)
- Metabolic acidosis (H+ retention)
- Gynaecomastia, impotence and testicular atrophy, menstrual irregularities (spironolactone only)
```
Interactions:
- Hyperkalaemia when combined with:
> ACE inhibitors
> Angiotensin II receptor antagonists
> Renin inhibitors
> Beta adrenoceptor antagonists
> Non steroidal anti-inflammatory drugs
```
120
what are the two types of potassium-sparing diuretics
| give two drugs from each categories
sodium channel blockers (aldosterone independent):
- amiloride
- triamterene
aldosterone receptor antagonists:
- spironolactone
- eplerenone
121
how does aspirin work as an anti platelet drug
Low dose (75mg) aspirin selectively and irreversibly inhibits cyclo-oxygenase (COX-1) which catalyses production of thromboxanes and prostaglandins
- irreversible COX-1 inhibitor
- reduced levels of TXA2 result in reduced platelet aggregation, increased bleeding time, vasodilatation
- Platelets do not contain nuclei and cannot regenerate new COX-1
- Anti-aggregatory effect is irreversible for lifespan of platelet (7-10 days)
- Daily generation of 10-14% new platelets so recovery of most of the platelet function by 4 days after drug cessation
122
what are the clinical indications for aspirin
secondary prevention in those with:
- ischaemic stroke/TIA
- acute coronary syndrome (reduce mortality)
- post myocardial infarction (long-term)
- following coronary bypass/stents (prevents occlusion)
- angina pectoris (prevention of ischaemic events)
- peripheral arterial disease/claudication
- atrial fibrillation (only if warfarin contra-indicated)?
primary prevention of fatal and non-fatal cardiovascular events in patients at very high cardiovascular risk?- use declining (even in diabetes)
- unproven benefit, risk (bleeding) > benefit
123
what are some of the adverse effects of aspirin
- gastric irritation /bleeding
> interactions with NSAIDs, corticosteroids, anticoagulants, other anti-platelet agents increase risk
- hypersensitivity reactions [skin, airways]
- Reye’s Syndrome in children
> rash, vomiting, with damage to brain, liver
- lack of response in some patients (aspirin resistance)
> rare, often related to poor drug adherence
- irreversible platelet inhibition
> continued bleeding risk for some time after stopping the drug
124
what is the mechanism of action for clopidogrel
pro-drug given orally, metabolised by liver
active metabolite is selective and irreversible inhibitor of ADP-dependent platelet activation
125
what are the clinical indications of clopidogrel
secondary prevention in patients intolerant of aspirin
with aspirin for 3-12 months after acute coronary syndrome and after procedures to coronary arteries [such as CABG, stenting] to prevent thrombosis
126
what are some adverse effects of Clopidogrel
gastro-intestinal irritation and bleeding
- especially with aspirin
dyspepsia, gastrointestinal upset
hypersensitivity reactions
- skin, liver
127
give two examples of thienopyridines and what is their action
(clopidogrel and prasugrel) selectively and irreversibly inhibit ADP-mediated platelet activation and aggregation
128
what is the difference between Ticagrelor with Clopidogrel and Prasugrel
cyclopentyl-triazolo-pyrimidine that does not bind to ADP binding site but a separate site on P2Y12 receptor to inhibit G-protein signalling
reversible inhibitor of platelet P2Y12 receptor with rapid onset and offset of action
not a prodrug
129
what is the mechanism of action of Dipyridamole
- thromboxane synthase inhibitor, may also enhance prostacyclin synthesis
- phosphodiesterase inhibitor [↑cAMP]
- inhibits reuptake and metabolism of adenosine
- collectively these mechanisms attenuate platelet adhesion and aggregation, and promote vasodilatation
130
what are the clinical indications for dipyridamole
given with oral anticoagulants for prevention of thromboembolism in patients with prosthetic heart valves
given with aspirin for secondary prevention of ischaemic stroke, TIA
131
what are some adverse effects of dipyridamole
- gastro-intestinal irritation /bleeding
> interaction with other anti-platelet agents and anticoagulants increases risk
- dizziness, flushing and headache
- myalgia
- chest pain
- hypersensitivity reactions [skin, kidney]
132
what are the general side effects of anti-platelet drugs
- bleeding is the most important side-effect
> less so with low dose aspirin than other antiplatelet agents
> risk of bleeding increases with use of drugs that also influence platelet function or haemostasis (such as warfarin, NSAIDS)
- need to stop drugs before elective procedures
> usually 1 week for clopidogrel, 4-5 days for aspirin, preferably 2 days for ticagrelor, see specific protocols/guidance
- other common class side-effects
> dyspepsia, altered bowel habit, headache, dizziness
- hypersensitivity reactions, bone marrow suppression, thrombocytopenia, hepatic damage
> more likely with other agents than with low dose aspirin
133
give three examples of Anti-coagulant Drugs
Heparin
unfractionated (UFH)
low molecular weight (LWMH)
Coumarins (Warfarin)
Non-Vitamin K (direct) oral anticoagulants (NOACS/DOACS)
134
what are Anti-coagulant Drugs mainly used for
*Anticoagulants are of greater use in preventing thrombus formation in veins than arteries, for in faster-flowing vessels such as arteries thrombi are composed mainly of platelets with little fibrin
135
what is the mechanism of action of heparin
- binds to and activates anti-thrombin III (ATIII)
- UFH-ATIII complex then inactivates thrombin (IIa) and Xa
- LMWH not long enough to inactivate thrombin (IIa) so main effect is to inhibit Xa
136
describe the pharmacokinetics of heparin
large, highly charged molecules so cannot be absorbed by the GIT
UFH given intravenously (and subcutaneously)
> immediately active, T½ 40-90 minutes (> at higher dose as metabolic pathways in liver saturate)
LMWH given subcutaneously
> longer T½ , once or twice daily dosing
> renal excretion, caution/dose adjustment in renal failure
137
what are the uses of heparin
Treatment of:
- thromboembolic disease (DVT /PE) initially together with warfarin (and instead of warfarin in pregnancy)
- (acute coronary syndrome)
- (acute peripheral arterial occlusion)
() = less useful in arterial circulation
Prevention of thromboembolic disease (DVT/PE):
- esp. before surgery in high risk patients
Extracorporeal circuits
(haemodialysis)
138
what are the adverse effects of heparin
haemorrhage (bleeding gums)
> avoid in bleeding disorders, gastric ulcer
> reversed with protamine sulphate (chemical antagonism) [Lecture 1]
reduced aldosterone secretion / hyperkalaemia
rarely osteoporosis and alopecia (>6months treatment)
hypersensitivity reactions (to animal heparins)
thrombocytopenia (reduced platelet count):
- transient early, relatively common (~25% patients)
- rarely severe, potentially fatal, immune-mediated HIT, >50% drop in platelet count seen 5-10 days after treatment onset (~1% patients), accompanied by rash, thrombosis
- routinely monitor platelet count, measure heparin-platelet antibodies, switch to another anticoagulant if required (consult haematologist)
139
what is the mechanism of action of warfarin
inhibitor of Vitamin K epoxide reductase, preventing regeneration of reduced Vitamin K needed for clotting factor synthesis
blocks synthesis of Vitamin K-dependent clotting factors (prevents post-translational gamma-carboxylation of II, VII, IX, X)
onset of anti-coagulant effect delayed for a few days until already formed active factors degraded
LMWH used as initial therapy to cover this delay
duration of action 2-5 days
140
what are the uses of warfarin
Prophylaxis and treatment of thrombo-embolic disease (DVT / PE)
Prophylaxis in atrial fibrillation (to reduce risk of stroke)
Prophylaxis with prosthetic heart valves fitted (prevent valve emboli)
141
what are some of the adverse effects of warfarin
- Haemorrhage / High INR
> including gingival bleeding
- Gastrointestinal upset
> including mouth ulcers, taste disturbance
- Teratogen (avoid in pregnancy) – use heparin
- Alopecia
- Skin necrosis
142
what are some contraindications for warfarin
- Pregnancy
- Active bleeding
- Peptic ulcer (recent)
- Uncontrolled severe hypertension
- Bacterial endocarditis
Relative contraindications:
- Recent surgery
- Liver / renal impairment
143
what is the use of Direct Acting Oral Anticoagulants
- treatment of DVT/PE
- prophylaxis of DVT/PE (including after orthopaedic surgery)
- prophylaxis of stroke in non-valvular atrial fibrillation
144
what are some of the side effects of Direct Acting Oral Anticoagulants
gastrointestinal upset, abdominal pain, dyspepsia, thrombocytopenia, haemorrhage
145
what are some drug interactions with Direct Acting Oral Anticoagulants
avoid concomitant prescribing of
> other anticoagulants
> significant enzyme inhibitors (-azole antifungals)
additional drug interactions with
> NSAIDs and aspirin
> P-gp1 or enzyme inhibitors (clarithromycin, SSRIs, verapamil) or inducers (rifampicin, carbamazepine)
146
what are some of the advantages and disadvantages of using Direct Acting Oral Anticoagulants
Advantages:
- orally available
- no need for monitoring INR (but still need to monitor patient and other blood tests!!)
- less toxicity, fewer drug interactions?
Disadvantages:
- lack of INR means no way of confirming drug adherence – important as NOACs have direct action and short half-life
- less known yet about efficacy and safety
- lack of reversal agents?
147
when should QRISK2 not be used to assess CVD risk for primary prevention
- Pre-existing CVD
- Type 1 Diabetes Mellitus
- Estimated glomerular filtration rate (eGFR) <60mL/min or albuminuria
- Familial hypercholesterolaemia
148
why might the QRISK2 underestimate a value for CVD risk
Gives approximate value for CVD risk:- may underestimate if:
- HIV (human immunodeficiency virus)
- Drugs (steroids, antipsychotic drugs, immunosuppressants
- Systemic lupus erythematosus
- People taking antihypertensive or lipid lowering drugs
- Severe obesity (BMI >40)
149
what is the mechanisms of action of statins
Statins are hydroxy methylglutaryl CoA (HMG CoA) reductase inhibitors that competitively inhibit the activity of HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis
This causes a transient modest decrease cellular cholesterol concentration
The decrease in cellular cholesterol activates sterol regulatory element binding protein (SREBP), a transcription factor, that up-regulates the gene encoding for the LDL-receptor
Increased LDL-receptor expression (70% in hepatocytes) increases uptake of plasma LDL thus decreasing plasma LDL concentration
150
what is the mode of action of salbutamol
Target: B2 adrenoceptors in bronchial smooth muscle
Action: agonist
Effect: activation of B2 adrenoreceptors stimulates adenylate cyclase enzymes to increase production of cyclic AMP (cAMP)
Overall effect: bronchial smooth muscle relaxation and bronchodilation
151
what might be some adverse effects of BETA-ADRENOCEPTOR AGONISTS
TREMOR
Beta-2 selectivity dose dependent – tachycardia at high dose
Arrhythmias
Hypokalaemia
Loss of responsiveness from excessive use
152
what is the ending for Short acting muscarinic antagonists (SAMA) and what is the ending for Long acting muscarinic antagonists (LAMA)
SAMA= -tropium
LAMA = -ium
153
what is the ending for LEUKOTRIENE Receptor ANTAGONISTS - LTRA
-lukast
