Pharmacology Flashcards
1
Q
What is eulers constant? (to the first 3 DP)
A
2.718
2
Q
What are tear away functions?
A
Exponential increasing functions
3
Q
In an exponentially decreasing function, what is an asymptote?
A
A line that the curve approaches as it heads towards infinite on the X axis, but never actually meets
4
Q
Compare the function of an exponential decreasing function to a rectangular hyperbolic function?
A
Exponential decreasing: y = e^(-x)
Rectangular hyperbolic function: y = 1/x
5
Q
Compare exponential decreasing function and rectangular hyperbola in terms of meeting the Y axis?
A
Exponential decreasing function meets the Y- axis
Rectangular hyperbola asymptotes the Y axis
6
Q
Natural exponential functions describe processes where the variable changes at a rate proportional to its own …
A
magnitude
7
Q
What are the 3 constants in first order pharmacokinetics?
A
1) 1/2 life
2) Time constant (t)
3) Rate constant (k)
8
Q
How is the time constant (t) described? (3)
A
1) Time taken for process to complete if continued at initial rate of fall
2) Time taken for magnitude to fall to 37% of its value
3) Time taken for magnitude to fall to 1/e of its value
9
Q
Which is shorter - the half life or the time constant?
A
Half life
Fall to 50%, compared to time constant which is fall to 37% (1/e)
10
Q
What is the formula for the rate constant?
A
1/t
Where t = tau, time constant
11
Q
What are the units of the rate constant (k)?
A
per second (1/s)
12
Q
What is the equation for first order kinetic drug elimination?
A
C(t) = C(0) . e ^(-kt)
C(t) = conc at time t
C (0) = conc at time 0
e = Eulers constant
k = rate constant
t = time
13
Q
At how many elimination half lives do we consider a process as ‘complete?’ what percentage is gone?
A
5 half lives = 96.875%
14
Q
What is the relationship between half life and time constant?
A
Half life (t1/2) = 0.693 x time constant (T)
15
Q
Describe the 2 patterns of hyperbaric oxygen toxicity?
A
Smith effect - accelerated pulmonary changes
Bert effect - CNS toxicity
16
Q
At FiO2 of 1.0, compare how long it takes to develop oxygen-related pulmonary damage in the critically ill patient vs the well patient?
A
critically ill - 12 hours
well - 24 hours
17
Q
Above what FiO2 does oxygen related pulmonary damage become an issue at 1 atmospheric pressure?
A
Above FiO2 0.5
18
Q
Until how many weeks is the neonate at risk of oxygen associated retrolental fibroplasia?
A
44 weeks
19
Q
Describe the 5 main factors which determine the uptake of inhalational agents?
A
1) Alveolar fractional concentration
2) Blood: gas coefficient
3) Cardiac output
4) Alveolar: Venous gradient
5) Concentration / second gas effect
20
Q
What factors increase the alveolar fractional concentration? (FA) (3)
A
Increasing:
Inspired concentration (Fi)
Increasing alveolar ventilation
Decreasing FRC
21
Q
What does a higher alveolar fractional concentration (FA) do to the onset and equilibrium time of the gas?
A
Faster onset and equilibrium time
22
Q
As the blood: gas coefficient increases, what happens to
(1) the solubility in the blood
(2) the speed of onset/offset
A
As blood: gas coefficient increases the
1) Solubility in blood increases
2) Slower onset/offset (as partial pressure determines effect rather than solubility)
23
Q
When plotting volatile agents on a wash in curve, why does nitrogen have a faster onset time than desflurane despite a higher blood-gas partition coefficient?
A
Nitrogen additionally has the concentration effect
24
Q
How does cardiac output effect the onset time of inhalational agents?
A
Increased cardiac output, decreases onset speed (as the effective volume is increased and therefore equilibriates slowly)
25
What are the 2 inhibitory CNS receptors?
GABA
Glycine
26
What are the 3 excitatory CNS receptors?
5HT3
Neuronal nicotinic
Glutamate - NMDA/AMPA
27
What is the main cerebral inhibitory receptor?
GABA
28
Describe the structure of GABA receptors?
5 subunits,
30 different isomers, most commonly 2 alpha subunits, 2 beta subunits, 1 gamma subunit
29
Compare GABA A and GABA B receptors?
GABA A - post-synaptic: ionotropic
GABA B - pre-synapric - metabotropic
30
Where does GABA bind on the GABA receptors?
Alpha subunits
31
What ion-conducting pore opens when the GABA receptor is opened?
What does this cause?
Cl- conducting pore
Cl- influx
causes hyperpolarisation of the neuronal membrane thus inhibiting pathway transmission
32
How do anaesthetic agents activate GABA receptors?
Positive allosteric modulators
- Enhance function of receptor in presence of the agonist
33
Where do IV anaesthetic agents bind to GABA receptors?
Alpha subunits
34
Where do volatile agents bind to GABA receptors?
B subunit
35
Where do benzodiazepines bind to GABA receptors?
Alpha- beta subunit interface
36
How does ketamine bind to NMDA receptors?
non-competitive agonist
37
Are NMDA receptors ionotropic or metabootropic?
Ionotropic
38
What CNS receptor does magnesium bind to and what does this do?
Binds to NMDA receptors inhibiting current passage
39
Where are glycine receptors found and what is their action?
Brain stem and spinal cord
Function as the analogue of GABA
40
Do IV or inhalational anaesthetics potentiate the effect of inhibitory glycine receptors in the spinal cord more?
Inhalational anaesthetics
41
What is the relationship between MAP, CO and SVR?
MAP = CO x SVR
42
What is the relationship between SV, HR and CO?
CO = HR x SV
43
What are the determinants of stroke volume?
Preload
Contractility
Afterload
44
How does the sympathetic nerve system work to increase force and rate of myocardial contraction?
(Which receptors are involved? What does stimulation do?
B1 mainly (and lesser extent B2) adrenergic receptors
Stimulation of B-adrenergic receptors increases available cyclic- adenosine monophosphate (cAMP) to increase levels of intracellular calcium
45
Adrenaline causes positive action on which adrenergic receptors?
Compare low dose to high dose infusions.
Non- selective agonist at ALL receptors
at low dose has more B-adrenergic effects
at high dose has increasing A-adrenergic effects
46
Compare the Levo and Dextro adrenaline isomers?
L-adrenaline is the naturally occurring form ad 15x more active
47
Why can diastolic blood pressure fall when using adrenaline?
B2-adrenergic effects --> peripheral vasodilation
48
Compare low dose and high dose dopamine infusion in terms of receptor action?
Low dose - B1 adrenergic action
High dose - increasing alpha action
49
How does dopamine cause nausea and vomiting?
Chemoreceptor trigger zones via D2 receptors
50
What does dopamine do via D1 receptors at the renal and mesenteric beds?
Vasodilation
51
What does dopamine do to endogenous noradrenaline?
Stimulated noradrenaline release
52
Which receptors does Dobutamine work on?
Mainly B1 adrenergic agonist
some B2 and alpha action
53
Explain how dobutamine decreases LVEDP?
B2 action causing vasodilation, reduced venous return and SVR
54
Which receptors does Isoprenaline work on?
B1 and B2 adrenergic agonist
55
Which receptors does Dopexamine work on?
B2 adrenergic agonist and D1 agonist
56
How do phosphodiesterase inhibitors work for positive inotropy?
Inhibit phosphodiesterases (which typically break down cyclic Adenosine Monophosphate cAMP)
Therefore increase cAMP and so increase intracellular calcium
57
Which types of phosphodiesterases work within the myocardium?
III and IV
58
Enoximone and milrinone are selective inhibitors to which type of phosphodiesterase?
Phosphodiesterase III inhibitors
59
Why are phosphodiesterase inhibitors such as milirone and enoximone known as inodilators?
Cause peripheral vasodilation, often required a vasopressor to maintain BP
60
Aminophylline inhibits which type of phosphodiesterase?
Non-selective phosphodiesterase inhibitor
61
How does cAMP work to increase intracellular calcium in myocytes?
Activates protein kinase A
Activated protein kinase A phosphorylates L-gated calcium channels
Calcium influx causes calcium-induced-calcium-release from sarcoplasmic reticulum
62
What are the 3 classes of intotropic drugs?
1) Sympathomimetic (adrenergic effects)
2) Phosphodiesterase inhibitors
3) Others
63
How does levosimendan work to
1) Cause positive intotropy
2) Peripheral vasodilation
1) Binds to troponin-C to increase sensitivity to calcium
(doesn't increase intracellullar calcium)
2) Opens ATP-sensitive K channels causing peripheral vasodilation
64
How does digoxin work to cause positive inotropy?
Inhibits Na/K ATPase
Therefore increases intracellular Na in the myocyte
Therefore reduces action of the Na/Ca exchange pump (which works via electrochemical gradient to pump Na in and Ca out)
Increases intracellular calcium
65
How does glucagon cause positive inotropy?
Activation of glucagon receptors increases increacellular cyclic Adenosine MonoPhosphate (cAMP)
66
Glucagon is used in the management of overdose of which drug?
Beta blocker
67
In which 2 circumstances is calcium indicated in cardiac arrest?
1) Hyperkalaemia
2) Ca channel blocker OD
68
What receptors does noradrenaline work on?
Alpha 1 adrenergic agonist
Some B1 effects
69
Noradrenaline has some b1 adrenergic effects, so why does no significant inotropy take place?
Minor inotropic effects offset by baroreceptor reflex vagal response to increased BP
70
What receptors does ephedrine work on?
Mixed alpha and beta adrenergic agonists
71
Are ephedrines effects direct or indirect?
Both
Direct and Indirect by releasing noradrenaline storage granules
72
Why does tachyphylaxis occur with ephedrine?
Depletion of endogenous noradrenaline stores
73
Which receptors does phenylephrine work on?
Alpha1 adrenergic agonist, no beta
74
Why does bradycardia occur with phenylephrine?
Reflex bradycardia due to baroreceptor response to increased BP
75
Which receptors does metaraminol work on?
Mainly alpha1, some minor B
76
Does metaraminol have direct or indirect actions?
Both direct and indirect due to release of endogenous noradrenaline
77
What type of membrane receptors are alpha 1 adrenergic receptors?
Gq protein coupled
78
What type of membrane receptors are V1 (vasopressin) receptors?
G protein coupled
79
What does stimulation of V1 receptors by vasopressin cause in the vasculature?
Peripheral vasoconstriction
80
What is the first line vasopressor for septic shock?
Noradrenaline
81
What is the second line vasopressor for septic shock?
Vasopressin
82
What type of membrane receptors are b-adrenergic receptors?
Gs protein coupled
83
What is the relation between vasculature smooth muscle intracellular cAMP and cGMP and muscle contraction?
Increasing cAMP or cGMP causes relaxation/vasodilation
84
How does smooth muscle intracellular cAMP activation via beta-adrenerceptor action cause vasodilation?
cAMP activates protein kinase A
Activated protein kinase A inhibits phosphorylation of myosin light chain
Causing vasodilation (relaxation)
85
How does smooth muscle intracellular cGMP cause vasodilation? (4)
cGMP activated protein G
Activated protein kinase G
1) Activates potassium channels causing hyperpolarisation and relaxation
2) Decreases sensitivity of contractile elements to Calcium
3) Decreased calcium entry into cell
4) Dephosphorylates myosin meaning bridges between actin and myosin cannot form
86
What is the effect of central alpha 2 stimulation on smooth muscle within vasculature?
Alpha 2 agonism
Inhibition of noradrenaline release
Reduced alpha 1 stimulation
Reduced sympathetic tone
87
Which receptors do clonidine, methyl-dopa and dexmedetomidine work via?
Central alpha 2 adrenergic agonists
88
How does hydralazine work to reduce BP?
Hydralazine activates guanlyl cylase to increase cGMP
increased cGMP leads to smooth muscle relaxation within vasculature
89
How do nitrates work to reduce BP?
Concerts to nitrous oxide to increase gyanylyl cyclase, which increases cGMP
Increased cGMP leads to smooth muscle relaxation within vasculature
90
Why does tolerance occur with nitrates?
Depletion of sulphydryl groups
91
How does sodium nitroprusside work to reduce BP?
Broken down into nitrous oxide
NO increases guanyly cyclase
which increases cGMP
Increased cGMP causes smooth muscle relaxation
92
Why does sodium nitroprusside lead to rebound hypertension if stopped abruptly?
increases plasma catecholamines
93
How does sodium nitroprusside increase shunt?
Inhibits hypoxic pulmonary vasoconstriction (V/Q matching)
94
Why does sodium nitroprusside need to be kept away from light?
Exposure to light causes break down to cyanide
95
How does magnesium work in relaxing vascular smooth muscle? (3)
1) Blocks catecholamine receptors
2) Blocks influx of calcium via L-type calcium channels
3) Generation of cAMP via adenylate cyclase is magnesium dependent as magnesium is a co-factor, increased cAMP causes smooth muscle relaxation
96
What are the 3 main effects of calcium channel blockers?
1) Vasodilation
2) Decreased myocardial contractility
3) Decreased propagation of cardiac depolarisation
97
How do calcium channel blockers work?
Block influx of calcium via L-type calcium channels
98
What are the 3 subgroups of CCB?
Give examples
1) Dihydropyridines e.g amlodipine, nifedipine
2) Phenylalkylamines e.g verapamil
3) Benzothiazepines e.g diltiazem
99
How do thiazide diuretics work in
1) low doses
2) high doses
1) Activates K channels causing hyperpolarisation and relaxation of vasculature smooth muscle
2) Inhibits sodium and chloride ion reabsorption in the distal tubule of the kidney
100
How do ACE inhibitors work?
Competitive inhibition of Angiotensin Converting Enzyme, stopping production of angiotensin II
101
How do ARBs work?
Inhibition of Angiotensin II by binding to angiotensin II receptor (AT1)
102
What electrolyte abnormalities can ACE inhibitors and ARBs lead to? Explain why?
Hyponatraemia and hyperkalaemia
Due to reduced aldosterone
103
Why can ACE inhibitors cause a dry cough?
Due to accumulation of bradykinin
104
How is sodium nitroprusside broken down?
Non enzymatically within RBC
105
How many cyanide ions are produced per molecule of sodium nitroprusside?
5
106
What type of membrane receptors are alpha 2 adrenergic receptors?
Gi protein coupled
107
What endogenous catecholamines bind to adrenoreceptors? (2)
Noradrenaline
Adrenaline
108
Activation of a1 adrenoreceptors (Gq protein coupled receptors) causes activation of what enzyme?
Phospholipase C (PLC)
108
What does activation of phospholipase C within smooth muscle cells do?
Causes release of calcium from sarcoplasmic reticulum
Leads to phosphorylation of myosin light chain by myosin light chain kinase
Allows smooth muscle contraction
109
Where are most alpha 2 adrenoceptors (Gi-protein coupled) found?
Presynaptic membrane
110
What are the 2 main groups of a-adrenoceptor antagonists?
Selective a1 antagonists
e.g doaxazosin, prazosin, terazosin
Non selective
e.g phentolamine, phenoxybenzamine
111
Describe the infinity for alpha 1 and alpha 2 receptors with phentolamine? (Non-selective alpha competitive antagonist)
3x greater affinity for A1 than A2
112
Describe what the A1 and A2 blockade effects of phentolamine are?
A1 blockade - vasodilation and reduction in SVR
A2 blockade - increased norad release leading to increased HR/CO
113
Why can phentolamine (non-selective competitive alpha blocker) lead to bronchospasm in some asthmatics?
sulphites in the preparation
114
Why can phentolamine (non-selective competitive alpha blocker) lead to hypoglycaemia?
Raises insulin levels
115
Compare phentolamine and phenoxybenzamine in terms of duration of action?
Both non-selective alpha blockers
Phentolamine - short acing
Phenoxybenzamine - long acting
116
Explain why the half life of phenoxybenzamine is 24 hours?
Irreversibly binds to alpha receptors
Therefore effects last until new receptors are produced (24hrs)
117
Describe phenoxybenzamine's affinity for A1 vs A2 receptors?/
More affinity for alpha 1
118
Compare alpha 1 blockers vs non-selective alpha blockers in terms of reflex tachycardia?
Non-selective alpha blockers have a reflex tachycardia due to blocking alpha 2 leading to increase norad release
No reflex tachycardia with selective alpha 1 blockers
119
Which beta blockers are cardioselective B1 vs non-selective beta blockers?
Atenolol
Bisoprolol
Carvedilol
Esmolol
Labetalol
Metoprolol
Nebivolol
Propranolol
Timolol
Cardioselective (b1) blockers:
Atenolol
Bisoprolol
Esmolol
Metoprolol
Nebivolol
Non-selective beta blockers:
Carvedilol
Labetolol
Propranolol
Timolol
120
Explain the concept of intrinsic sypmathomimetic activity with some beta blockers?
Some beta blockers have partial agonism at beta-adrenoceptors if the enodgenous catecholamine levels are low
If the catecholamine levels are high, the beta blocker will have typical antagonistic action
121
Which 4 beta blockers have showed benefit in congestive cardiac failure?
Recommended by nice:
Carvedilol (most benefit)
Bisoprolol
Nebivolol
Not recommended but demonstrated benefit:
Metoprolol
122
What are the indications for a trial of beta bloclers in patents with cardiac failure?
Clinically stable NYHA II or III
Not recommended if class IV/decompensated
Start once already established on ACE I
123
Describe the adrenoreceptors targeted by Labetalol?
Alpha-1 agonist
Non-selective Beta agonist
124
Compare oral and IV administration of labetalol in terms of alpha1 to beta antagonism?
A1: B antagonism
1:3 if oral
1:7 if IV
125
Where is labetalol metabolised?
Liver
126
What is a phaeochromocytoma?
A tumour of chromaffin cells in the adrenal medulla or in the other paraganglia of the sympathetic nervous system
127
What is neurotransmitters/hormones are produced by a phaeochromocytoma?
What does each cause?
Noradrenaline: Severe refractory hypertension
Adrenaline and Dopamine: Episodic palpitations
128
What is the treatment of a phaeocyromocytoma?
Manage hypertension and tachycardia with
1) Alpha blocker 1st - can be a1 selective or non-selective
2) THEN beta blocker if required for tachycardia
Ultimately treatment is surgical
129
In the management of a phaeochromocytoma why is alpha blockade required prior to beta blockade?
Beta blockade removes the protective action of B2 peripheral vasodilation --> risk of increasing peripheral vasoconstriction and hypertensive crisis
130
Describe the pros (1) and cons (3) of the use of phenoxybenzamine in the peri-op management of phaeochromocytoma?
Non-selective alpha blocker
Pros:
Long half life (24hrs)
Cons:
- Also blocks alpha 2, therefore increases norad causing tachycardia - more likely to require addition of beta blocker
- Even when stopping 24-48hr pre surgery there can be some residual block, so once tumour is removed and catecholamine levels return to normal, can be hypotensive unrepsonsive to alpha-agonists
- Crosses BBB - sedation
131
Describe the pros (3) and cons (2) of doxazosin in the peri-op management of phaeochromocytoma?
Competitive alpha-1 blocker
Pros:
- Long half life (once daily preparation
- No alpha 2 effects so doesn't cause tachycardia, less need for beta blockade unless tumour secretes adrenaline/dopamine as well
- Doesn't cross BBB so less sedation
Cons:
- Severe postural hypotension at onset of therapy
- Massive catecholamine surges during surgery can displace drug from receptor
132
How do 3rd generation beta blockers (carvedilol, nebivolol etc) cause vasodilation?
Through alpha1 blockade or nitrous oxide release
133
Which adrenoceptor causes platelet aggregation?
Alpha 2
134
Which adrenoceptor causes lipolysis?
B1
135
Which adrenoceptor causes increased renin secretion?
B1
136
Which adrenoreceptor causes mydriasis?
Alpha1
137
Describe the racemic mixture of atropine?
Which isomer is active?
D- hyoscyamine and L- hyoscyamine
Only L- hyoscamine is active
138
What is the total dose of atropine needed for complete vagal blockade in adults?
3mg atroping
139
What is the elimination half life of atropine?
2.5 hours
140
How does atropine work at receptor level?
Competitive antagonist of muscarinic receptors
(minimal nicotinic receptor action)
141
Describe the Bezold-Jarish reflex in response to low dose atropine?
Bradycardia
142
What does atropine do to physiological dead space? Why?
Causes bronchodilation which increases physiological dead space
143
Describe the structure of glycopyrrolate?
Charged quaternary amine
144
How does glycopyrrolate work at receptor level?
Compatitive antagonist at peripheral muscarinic receptors
145
Describe atropins vs glycopyrrolate in terms of ability to cross BBB and placenta?
Atropine can cross BBB and placenta
Glyco can cross placenta but not BBB
146
What is the elimination half life of glycopyrrolate?
0.6 - 1.1 hours
147
What is the dose of atropine?
0.015-0.02mg/kg IV or IM
0.2 - 0.6mg PO
500mcg as per ALS for adults up to 3mg
148
What is the dose of glycopyrrolate?
200mcg to 400mcg IV or IM adults
4-10mcg/kg paeds
149
Why can BP drop with Isoprenaline?
B1 and B2 agonist
B2 action can lead to vasodilation and reduced SVR
150
What kind of receptors are glucagon receptors?
How does this affect intracellular cAMP
Gs - protein coupled receptors
Increases intracellular cAMP
151
What type of compound is amiodarone?
Benzofuran derivative
152
What anti-arrhythmic class does amiodarone belong to?
How does it work and what phase of the AP is involved?
Class III anti-arrhythmic
Blocks K channels so prolongs phase III increasing refractory period
153
Amiodarone blocks K channels, in very high doses, what other channels can be depressed?
Na and Ca
154
Where does amiodarone slow the conduction rate?
SA node, AV node
Does not slow conduction through bundle of his/ ventricles
155
What is the IV dose of amiodarone?
Loading -
5mg/kg over 1hr (300mg in adults)
Then -
15mg/kg over 24h (900mg in adults)
156
What is the oral dose of amiodarone in adults?
200mg TDS for 1 week,
200mg BD for 1 week, then 200mg OD
157
How does amiodarone potentiate the action of anticoagulants, digoxin, beta blockers and CCB?
Amiodarone is highly protein bound and so displaces those other drugs from proteins
158
What is the elimination half life of amiodarone?
4 hours to 52 days
159
Why does amiodarone impact thyroid function?
As amiodarone resembles thyroxine
160
What receptor does adenosine work on?
What type of receptor is this?
A1 receptors
Gi-protein coupled receptors
161
Where are the A1 receptors that adenosine works on?
SA node and AV node
162
What is the dose of adenosine?
3mg IV then 6mg IV then 12mg IV in adults
0.0375-0.25mg/kg in paediatrics
163
Why does atropine increase myocardial blood flow?
Causes direct smooth muscle relaxation of coronary arteriesW
164
Why can atropine lead to AF or A flutter?
Reduces the atrial refractory period
165
Risk of digoxin toxicity is increased in the presence of? (7)
1) Hypokalaemia
2) Hypomagneseamia
3) Hypernatraemia
4) Hypercalcaemia
5) Hypoxaemia
6) Renal failure
7) Drugs - amiodarone, verapamil, diazepam
166
How does flecanide work?
What anti-arrhythmic class does it belong to?
Blocks fast Na channels and slows depolarisation
Class 1c anti-arrhythmic
167
Describe the direct and indirect action of digoxin?
Direct - blocks Na/K/ATPase to increase refractory period of AV node
Indirect - Increases ACh release which slows conduction and prolongs refractory period
168
Where is tissue factor present? (2)
1) Injured endothelium
2) Fibroblasts and monocytes
169
What are the 3 stages of coagulation?
1) Initiation
2) Amplification
3) Propagation
170
What important compound is formed during the initiation phase of coagulation?
Prothrombinase
171
What is the key process in the amplification stage of coagulation?
Activation of platelets - thrombin plays a key role in this
172
What factors is thrombin?
Factor IIa
173
What is the key process in the propagation stage of coagulation?
Massive thrombin burst Thrombin converts fibrinogen to fibrin forming fibrin clot
174
What factors in prothrombinase made from?
Xa/Va complex
175
What it the effect of prothrombinase?
Convers prothrombin (II) into thrombin (IIa)
176
How many molecules of thrombin can be generated from 1 prothombinase complex?
Known as 'thrombin burst'
1000 molecules of thrombin
177
What factors and proteins does warfarin inhibit?
Factors II, VII, IX, X
Protein S and C
178
How do precursors of factors II, VII, IX, X and proteins C, S become the active forms?
Carboxylation of precursor proteins
By the active hydroxy form of vit K
179
What happens to active hydroxy vitamin K in order to produce factors II, VII, IX, X and proteins C and S from precursors?
Active hydroxy vitamin K is oxidised to inactive vitamin K epoxide
180
What enzyme does warfarin inhibit?
What reaction does this prevent?
Warfarin inhibits vitamin K epoxide reductase
This prevents reduction of inactive vitamin K epoxide into active hydroxy vitamin K
181
How much of warfarin is plasma protein bound?
99% plasma protein bound
182
Where is warfarin metabolised and excreted?
Metabolised in the liver
Metabolites excrete in urine/faeces
183
Which inhibit warfarin due cytochrome p450 induction?
SCRAP GP
Sulfufonylureas, smoking
Carbamazepine, Corticosteroids
Rifampicin
Alcohol (chronic)
Phenytoin
Griseofulvin
Phenobarbitol
184
Which drugs potentiate warfarin due to cytochrome P450 inhibition?
VIDEO CASE
Valproate
Isoniazide
Disulfiram
Erythromycin, clari
Omeprazole
Cimetidine
Allopurinol
Sulfonamides
Ethanol (acute)
185
How is warfarin monitored?
Using prothrombin time
INR - Ratio of Prothrombin time to normal sample
186
What factors is prothrombin time sensitive to?
factors II, VII, X
187
What factor does not rise if using FFP following warfarin OD/high INR?
Factor IX does not rise
188
What are the 2 methods of complete reversal of warfarin OD or high INR?
1) vitamin K
2) prothrombin complex
189
What should warfarin be substituted with in pregnancy?
LMWH
190
Compare warfarin and LWMH in terms of ability to cross the placenta?
Warfarin crosses placenta
LMWH doesn't
191
What is the mechanism of action of hepatin?
Reversibly binds to and potentiates antithrombin III which then inhibits mainly factors II, IX and X
192
What is the half life of unfractionated hepatin?
30-60 mins
193
What enzyme metabolises unfractionated heparin?
Hepatic heparinase
194
How are the metabolites of heparin excreted?
In the urine
195
Why is there significant individual variation in UFH anticoagulation efficacy?
UFH highly bound to plasma proteins, this has individual variation
196
Which factors do LMWH target?
Full anti Xa action
(Less anti-IIa action tan UFH)
197
Why do LMWH have 2-3x longer half lives than UFH?
Due to lower affinity for hepatin-binding proteins
198
How do you monitor the effects of LMWH?
Antix Xa assays
199
How do you monitor the effects of LMWH?
APTT and Anti Xa assays
200
Why do you not need to monitor APTT with LMWH compared to UFH?
More reliable anticoagulation with LMWH
201
Why is there a smaller risk of bleeding with LMWH than UFH?
Less interaction wiht platelets
202
What is hepatin induced thrombocytopaenia?
Immune mediated thrombocytopaenia, where antibodies are formed
203
Typically, with HIT when does the platelet count fall?
5-14 days
204
What alternative anticoagulants can be used in patients who develop heparin-induced thrombocytopaenia to heparin?
Danaparoid
Fondaparinux
Rivaroxaban
205
What factor does danaparoid inhibit?
Factor Xa inhibitor
206
What are the adverse effects of danaparoid?
Low platelets
Asthma exacerbation
207
What factor does fonadparinux inhibit?
Factor Xa inhibitor
208
What is the half life of fondaparinux?
21hours
209
How is fondaparinux excreted?
Renally
210
What factor does rivaroxaban inhibit?
Factor Xa innhibition
211
Heparin has some indirect anti-platelet effects mediated through what factor?
Fibrin (Ia)
212
Compare the effects of protamine on UFH vs LMWH?
Explain why?
Completely reverses UFH
Partially reverses LMWH
Protamine fully reverses anti-IIa activity
only partially reverses anti-Xa activity
213
What are the 3 most common reactions after heparin?
Haemorrhage
Hypotension
Thrombocytopaenia
214
Gliclazide, amiodarone and NSIADs do not effect the P450 pathway, but potentiate the effects of warfarin - how?
Displace warfarin from proteins
215
What is the % of peak anti-Xa activity 12 hours after administration of LMWH?
50
216
During platelet adhesion, fibrinogen binds to which receptor leading to platelet aggregation?
GPIIb/IIIa
217
Which molecules activate the GPIIb/IIIa receptor?
Thromboxane A2 (TXA2) and ADP
218
How is thromboxane A2 (TXA2) produced?
Platelet activation initiates: the arachnidonic acid pathway inside the platelet
COX-1 converts arachnidonic acid into TXA2
219
What are the 2 main functions of Thromboxane A2 (TXA2)?
1) Activation of GPIIb/IIIA receptor (with ADP) for platelet aggregation
2) Vasoconstriction
220
How does aspirin work within the platelet?
COX-1 inhibitor
Prevents production of thromboxane A2
Results in reduced activation of GPIIb/IIIa receptor and reduced vasoconstriction
221
How does clopidogrel work?
Blocks ADP-induced platelet activation
Reduces activation of GP IIb/IIIA receptor
222
How do GPIIb/IIIa antagonists work?
Block the GPIIb/IIIa receptor
preventing binding of receptor to fibrinogen
223
Is aspirin more effective agains COX 1 or COX 2?
50-100x more effective against COX 1
224
Compare COX1 and COX2 in terms of function?
COX 1 - homeostatic function
COX 2 - inducible inflammatory response
225
Why does aspirin take 7-10 days for effects to wear off?
Irreversibly inhibits COX1 within platelets
Platelet function will only return to normal once new platelets are formed
226
Describe the metabolism and excretion of aspirin?
Aspirin is a pro-drug
Intestinal and hepatic esterases hydrolyse into acetic acid and salicylate
Hepatic metabolism into salicyluric acid and glucuronide for excretion in urine
227
Explain the acid-base disturbance with aspirin overdose?
Resp alkalosis (Direct stimulation of resp centres)
Metabolic acidosis (impaired aerobic metabolism)
228
What is the treatment of aspirin OD?
1) Activate charcoal to reduce GI absorption
2) IV fluid resus to maintain UO 1-2ml/kg/hr
3) Alkalinisation of urine with sodium bicarb
4) Haemodialysis if severe
229
How do you reverse the effects of clopidogrel?
Platelet transfusion
230
How does dipyridamole work?
1) Inhibits platelet adhesion to vessel wall
2) Vasodilation (esp. coronary arteries)
231
How is dipyramidole metabolised and excreted?
Metabolised in the liver
Excreted biliary tree
232
What side effect significantly limits the use of dipyridamole?
headache in 25%
233
What are the 2 main mechanisms of anti-epileptic actions?
1) action on CNS Na channels
2) Potentiation of GABA
234
What are the 2 main ways anti-epileptics act on CNS Na channels?
- Inhibit fast Na channels
- Stablisie pre-synaptic Na channels by inhibiting release of excitatory neurotransmitted
235
How does phenytoin work?
Inhibits inactive fast Na channels
- higher affinitiy for Na channels which are opening and closing rapidly, don't interfere with normal neuronal transmission
236
How does lamotrigine?
Inhibits release of excitatory neurotransmitters and so stabilises the presynaptic Na channels
237
How do benzodiazepines and barbituates work as anti-epileptics?
Facilitates GABA by opening Cl- channels leading to Cl- influx and hyperpolarisation
Cell becomes less excitable
238
What type of agonists are baclofen and acamprosate?
GABA agonists
239
How does sodium valproate work as an anti-epileptic?
1) Inhibit GABA transaminase to prevent breakdown of GABA
2) Stabilises inactive Na channels
240
Where is phenytoin metabolised and excreted?
Metabolised in the liver to inactive metabolites
Excreted renally
241
What order kinetics does phenytoin exhibit?
1st order kinetics at therapeutic concentrations, zero order kinetics at high concentration due to enzyme saturation
242
How is valproate metabolised and excreted?
Liver metabolism
Renal excfretion
243
How does gabapentin work?
GABA analogue
244
What is the half life of phenytoin?
24 hours
245
Why should FBC be checked with sodium valproate?
Risk of thrombocytopaenia
246
What class of anti-arrhythmic is phenytoin?
Class 1b - Na channel blockers
247
What class of anti-arrhythmic is lidocaine?
Class 1b - Na channel blockers
248
Describe the random blood glucose cut off for diabetes?
>11mmol
249
Describe the fasting blood glucose cut offs for pre-diabetes and diabetes?
5.6 - 6.9 pre-diabetes
>7.0 diabetes
250
Describe the OGTT cut offs for impaired glucose tolerance and diabetes?
7.8 - 11.0 impaired
>11 diabetes
251
What cells is insulin produced from ?
Beta cells of the islets of langerhan in the pancreas
252
How does pro-insulin become insulin?
Removal of C-peptide
253
How do sulfonylureas work?
Increase insulin secretion from beta cells
Decrease insulin resistance long term
254
How are sulfonylureas metabolised and excreted?
Metabolised in liver
Excreted renally
255
Why is metformin called a biguanide?
structure containes 2 guanide rings
256
How is metformin metabolised and excreted?
Excreted UNCHANGED in the urine
--> Increased duration of action in renal failure
257
How does metformin work? (2)
Increases peripheral insulin utilisation
Delays glucose GI uptake
258
How does acarbose work?
Delays glucose absorption
259
How do thiazolidinediones eg pioglitazone work?
Improves insulin sensitivity
260
What is the difference between gram positive and gram negative bacilli?
Gram positive - thick outer peptidoglycan wall, retain crystal violet stain, appear dark blue/violet
Gram negative - don't have outer wall, so don't retain crystal stain
Stain pink/red with counterstain (safarin red stain)
261
Describe the difference between:
1) Obligate aerobes
2) Obligate anaerobes
3) Faculative anaerobes
1) Obligate aerobes need oxygen to survive
2) Obligate anaerobes cannot survive in the presence of oxygen
3) Faculative anaerobes can survive with or without oxygen
262
Why can obligate anaerobes not survive in presence of oxygen?
Oxygen is toxic, these organisms do not have the enzymes to detoxify oxygen waste products
263
How are staphyloccocci subdivided?
Coagulase positive (S. aureus)
Coagulase negative (S. epi)
264
How are streptococci subdivided?
Alpha - haemolytics (S. pneumonia, viridans)
Beta - haemolytic (S. pyogenes)
Gamma - haemolytic (non -haemolytic - enterococci)
265
What are the 3 mechanisms of action of antibacterials?
1) Act on cell wall synthesis
2) Inhibit protein synthesis
3) Inhibit nucleic acid synthesis
266
How do beta-lactams work?
Act on cell wall synthesis
Inhibit the enzyme which catalyses cross linking between peptidoglycan polymer chains in the cell wall
Leads to weakening then cell lysis
267
Are beta-lactams bacteriocidal or bacteriostatic?
Bacteriocidal
268
How do glycopeptide antibiotics work? (vancomycin, teicoplanin)
Act on cell wall synthesis
Bind to the peptidoglycan chains preventing formation of peptide cross linking
269
How do macrolides work?
Inhibit protein synthesis
Bind to ribosome 50s subunit
Inhibits peptide chain translocation
270
Are macrolides bacteriocidal or bacteriostatic?
Bacteriostatic
271
How do tetracyclines work?
Inhibit protein synthesis
Bind to ribosome 30S subunit and inhibit binding of aminoacyl-tRNA
272
Are tetracyclines bacteriocidal or baceriostatic?
Bacteriostatic
273
How do aminoglycoside (e.g gentamicin) work?
Inhibit protein synthesis
Bind to 30s subunit causing misreading of mRNA
274
Are aminoglycoside (e.g gentamicin) bacteriostatic or bacteriocidal?
Bacteriocidal
275
How do lincosamide antibiotics (e.g clindamycin) work?
Inhibit protein synthesis
Disrupt the function of the ribosome 50S subunit
276
How does chloramphenicol work?
Inhibits protein synthesis
Inhibits peptidyl transferase activity of the ribosome 50S suunit stopping transpeptidation
277
Are lincosamides (e.g clindamycin) bacteriostatic or bacteriocidal?
Bacteriostatic
278
Is chlormphenicol bacteriostatic or bacteriocidal?
Bacteriostatic
279
How does trimethoprim work?
Inhibits nucleic acid synthesis
Inhibits dihydrofolate reductase
280
Is trimethoprim bacteriostatic or bacteriocidal?
Bacteriostatic
281
How do quinolones work?
Inhibit nucleic acid synthesis
Inhibit DNA gyrase
282
Are quinolones bacteriocidal or bacteriostatic?
Bacteriocidal
283
How does metronidazole work?
Inhibits nucleic acid synthesis
Unclear mechanism
284
Is metronidazole bacteriostatic or bacteriocidal?
Bacteriocidal
285
How does rifampicin work?
Inhibits nucleic acid synthesis
Inhibits RNA polymerase
286
Is rifampicin bacteriostatic or bacteriocidal?
Bacteriocidal
287
In general, all antibiotics are bacteriocidal except which 5 groups?
1) Macrolides
2) Tetracyclines
3) Lincosamides (e.g clinda)
4) Chloramphenicol
5) Tetracyclines
288
Why do narrow-spectrum penicillins have little gram -ve cover, but broad-spectrum penicillins have better gram -ve cover?
Narrow-spectrum penicillins cannot get passed outer phospholipid membrane
Broad-spectrum penicillins are more hydrophobic and so can pass through pores in phospholipid membrane
289
What can you add to penicillins to make them b-lactamase resistant?
b-lactamase inhibitor
e.g clavulanic acid, tazobactem
290
Why is flucloxacillin a good choice of antibiotic for Staph?
Most staph produce penicillinase (a b-lactamase)
Fluclox is penicillinase resistant
291
Does penicillin cross the BBB?
Only if the meninges are inflamed
292
Compare penicillin, cephalosporins and carbapenems in terms of susceptiability to beta-lactamases?
B-lactam ring of cephalosporins are typically less sensitive to beta-lactamases than penicillins
Carbapenems are highly b-lactamases resistant
293
With cephalosporins, what happens to the gram +ve and gram -ve cover as the generation increases?
Gram +ve cover remains
Gram -ve cover increases
with every successive generation
294
Explain why there is b-lactam antibiotic resistance with MRSA?
Due to changes in penicillin binding proteins
(NOT due to beta lactamases)
295
Which 3 main groups of organisms are not covered by carbapenems such as meropenem?
MRSA
E. faecalis
Some pseudomonas
296
Which beta-lactam antibiotics are effective against MRSA?
None
due to changes in penicillin-binding protein NOT due to beta-lactamases.
297
Explain why glycopeptides (vanc, teicoplaning) have limited gram negative cover?
Large molecules and so unable to penetrate the outer phospholipid membrane of gram -ve bacteria
298
What causes red man syndrome with vancomycin?
How do you prevent this?
Histamine release
Slow IV administration
299
Which antibiotic class are indicated for mycoplasma and legionella?
Macrolides
300
Where are macrolides metabolised and excreted?
Liver
301
Are macrolides cytochrome p450 inhibitors or inducers?
Inhibitors
302
Explain why aminoglycosides work synergistically with betalactams and glycopeptides?
beta-lactams and glycopeptides break down the cell wall
allows aminoglycosides better cellular access
(otherwise needs active transportation into the cell)
303
How are aminoglycosides excreted?
Renally
304
Why is gentamicin contraindicated in myasthenia gravis?
Decrease pre-junctional release of ACh and reduce post-junctional sensitiviy to ACh
305
Macrolides have a similar spectrum of activity to penicillin, so why can they not be used in the treatment of meningitis?
Penetrate the CNS poorly
306
Compare the reversibility of ototoxicity and nephrotoxicity with aminoglycosides (eg gent)?
Ototoxicity tends to be permanent
Nephrotoxicity tends to be reversible
307
What type of AKI occurs with aminoglycosides?
Acute tubular necrosis
308
Why do aminoglycosides increase the potency of non-depolarising muscle relaxants?
Decrease pre-junctional release of ACh and reduce post-junctional sensitiviy to ACh
309
Are quinolones inhibitors or inducers of cytochrome P450?
Inhibitors
310
What are the only good oral agents against pseudomonas?
Oral quinolones
311
Why do quinolones increase risk of convulsions?
GABA antagonism
