Cardiac non table drugs Flashcards
Inotropes vasopressors Summary of cardiac pharm inc. antiarryhthmics (149 cards)
1
Q
Classify the inotrope agents (5)
A
Direct sympathomimetics
Indirect sympathomimetics
Phosphodiesterase inhibitors
Clacium sensitisers
Cardiac glycosides
2
Q
Describe the 2 subclasses of direct sympathomimeitcs and indirect sympathomimeitcs providing MOA
A
3
Q
What non sympathomimetic inotropes are there? Describe their mechanisms
A
4
Q
Give the properties of an ideal inotrope
- Pharmaceutics 3
Pharmacokinetics 5
Pharmacodynamics 5
Safety
2
A
5
Q
Dobutamine vs milronone
- CLass
- Chemistry
- Route of adminsitration
- Solubility and pKa
A
6
Q
Dobutamine vs milronone pharmacokinetics
A
7
Q
MOA and effect dobutamine vs milronone
A
8
Q
What are the 4 reasons arrhythmias occur? Describe the mechanism? What drugs might therefore work
A
- Abnormal automaticity
◦ where some normal tissue becomes overexcited and decides to become a pacemaker, or existing pacemakers make pace in some disorganised or abnormal manner.
◦ To treat
‣ Of normal pacemakers –> Anything that reduces the slope of phase4 of those cells e.g. calcium and beta blockers
‣ Non pacemaker tissue –> beta blockade by reducing resting potential voltage of the membrane - Early afterdepolarisations
◦ triggered depolarisations which occur during Phase 3, and which are promoted by anything which prolongs the repolarisation - Late afterdepolarisations
◦ triggered depolarisations which occur during Phase 4, and which are promoted by anything that might increase the intracellular calcium
◦ Catecholamines or calcium are the tissue –> therefore beta blockers and calcium channel blockers address this - Reentry
◦ where acton potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period
◦ Abnormally short refractory period –> Prolong by class 1a and class 3 agents
◦ As for abnormal conducting pathways - slowing conduction using class 1c agents
9
Q
How does abnormal automaticity occur? (2) What can be done to prevent each
A
- Abnormal automaticity
◦ where some normal tissue becomes overexcited and decides to become a pacemaker, or existing pacemakers make pace in some disorganised or abnormal manner.
◦ To treat
‣ Of normal pacemakers –> Anything that reduces the slope of phase4 of those cells e.g. calcium and beta blockers
‣ Non pacemaker tissue –> beta blockade by reducing resting potential voltage of the membrane
10
Q
Earyl afterdepolarisations occur because of?
A
- Early afterdepolarisations
◦ triggered depolarisations which occur during Phase 3, and which are promoted by anything which prolongs the repolarisation
11
Q
Late afterdepolarisation occur because of? How to prevent it 2
A
- Late afterdepolarisations
◦ triggered depolarisations which occur during Phase 4, and which are promoted by anything that might increase the intracellular calcium
◦ Catecholamines or calcium are the tissue –> therefore beta blockers and calcium channel blockers address this
12
Q
What is a re-entry circuit? How might you abort each
A
- Reentry
◦ where acton potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period
◦ Abnormally short refractory period –> Prolong by class 1a and class 3 agents
◦ As for abnormal conducting pathways - slowing conduction using class 1c agents
13
Q
Classify Vaughan Williams anti-arrhtyhmics?
A
- Class I: fast sodium channel blockers i.e. interfere directly with depolarisation
◦ Class Ia: prolong the action potential (eg. quinidine)
◦ Class Ib: shortens the action potential (eg. lignocaine)
◦ Class Ic: no effect on the action potential (eg. flecainide) - Class II: Beta-blockers (eg. metoprolol) - antisympathetic
- Class III: Potassium channel blockers (eg. sotalol and amiodarone) - prolong the duration of the action potential
- Class IV: calcium channel blockers (eg. verapamil and diltiazem)
14
Q
What effect do the subclasses of Vaughan Williams 1 antiarrhtyhmics have on the action potential
A
- Class I: fast sodium channel blockers i.e. interfere directly with depolarisation
◦ Class Ia: prolong the action potential (eg. quinidine)
◦ Class Ib: shortens the action potential (eg. lignocaine)
◦ Class Ic: no effect on the action potential (eg. flecainide)
15
Q
How do you reduce pacemaker automaticity
A
- Reduction of pacemaker automaticity: agents which decrease the calcium currents in pacemaker cells, i.e. Class II and Class IV agents
16
Q
How do you reduce abnormal automaticity
A
- Reduction of abnormal automaticity: agents which decrease the membrane resting potential in ventricular myocytes, i.e. mainly Class II agents
17
Q
How do you stop or reduce early afterdepolarisations 2
A
agents which reduce the action potential and repolarisation duration, i.e. Class II and Ib agents
◦ Some agents actually increase early afterdepolarizations by delaying repolarisation
◦ These are the same agents that prolong the QT interval (i.e. Class Ia and Class III agents)
18
Q
How do you reduce delayed afterdepolrisations 3
A
◦ Agents which decrease the availability of intracellular calcium (i.e. Class II and IV agents)
◦ Agents which decrease the availability of intracellular sodium (i.e. Class I agents)
19
Q
What agents slow AVN conduction 4
A
◦ Agents which slow AV nodal conduction (i.e. adenosine, digoxin, Class II and Class IV agents)
20
Q
What afents slow velocity of conduction
A
◦ Agents which slow the velocity of conduction (i.e. Class Ia and Ic agents)
21
Q
What afgents increase the refractory period
A
◦ Agents which increase the refractory period (i.e Class III, Ia and Ic agents)
22
Q
Class 1 agents bind to what? When do they bind to this
A
Class 1 agents
* All have local anaesthetic effects
* All bind to a site in the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel
* All prefer to bind to open or inactivated sodium channels (though slowly dissociating class 1c drugs remain bound even when the channels return to their resting state)
* Effects are more pronounced in ischaemic tissue
23
Q
How does a class 1 agent affect each of the aetiologies of arrhthmias
A
- Automaticity of normal pacemakers
◦ Will remain normal on class 1 agent - phase 4 of normal pacemaker cells does in fact depend on sodium currents (funny current targeted by ivabradine) but distinct from the voltage gated fast ones.
‣ Class 1 agents may somehow affect phase 4 but this is debated - flecainide appears to assist with rhythm control for AF by mechanisms unknown. - Automaticity of non pacemaker tissue
◦ should also remain unchanged but decreases but by uncertain mechanisms as these drugs are used for VT and VF - Early afterdepolarisations - can increase with class 1 gents particularly 1a which prolong repolaristion therefore risk of polymorphic VT
- Late afterdepolarisations - should decrease with sodium channel blockade as decreased intracellular sodium for sodium/calcium exchanger so less intracellular calcium available (and this is what is responsible for this phenomenon). However these agents to do not appear to help with this
- Re-entry - most effective - by decreasing velocity of conduction AP propogation is slowed along abnormal conducting pathways preventing re-entrant tachycardias (class 1c ideal)
24
Q
Draw an action potential for each class 1 agent
A
25
Describe the 3 states of a sodium channel
26
What i the refractory period of cardiac conduction tissue
250-350msec
27
How is the refractory period in cardiac conduction tissue caused
Inactivation of sodium channels
28
What effect do class 1 antiarrhtyhmics have on cardiac conducting tissuerefractory period
* Class 1a agents increase the effective refractory period - action potential is longer
* Class 1c agents have no effect on the effective refractory period of anything except AV node and atrial muscle where it is prolonged.
* Class 1b agents shorten the effective refractory period by shortening the duration of the overall action potential
29
How do class 1 drgus affect the ECG
Class Ia drugs prolong both the QRS and QT
Class Ib drugs have no effect on the QRS, and slightly shorten the QT.
Class Ic drugs markedly prolong the QRS, and have minimal effect on QT.
30
What is use dependence and describe how it occurs and what aegnts it effects
* Tendancy for class 1 agents to favour ianctvie sodium channels and to dissociate slowly makes them more effective at faster HR
◦ Observe: each time the channel opens, block develops, and then gradually un-develops during diastole. Ergo, the shorter your diastole, the less block you lose between beats, and the more potent the block which affects the next beat. This is manifested as an increase in QRS duration which occurs with tachycardia.
◦ On the other hand, if the drug dissociates extremely rapidly from the sodium channels, its activity will again be unaffected by heart rate. Even with a preposterously short diastole, most of the drug will be gone from the active site long before the next systole - which means tachycardia will not do anything to change the effectiveness of the block.
◦ Extremely slowly dissociating drugs (Class Ic agents such as flecainide) should be the most affected by use dependence, and their effect should be amplified considerably by a fast heart rate.
◦ Moreover, for drugs with use-dependence, the QRS prolongation effect should increase with the duration of the tachycardia, as more and more drug molecules end up trapped at the effect site because frequent systoles prevent them from dissociating.
31
Electrochemical actions of class 1 a
* Class Ia: prolong the action potential (eg. quinidine)
◦ Prolongs the duration of the action potential (mainly by their potassium channel blocker effects); prolong the QT interval and QRS complex because of a longer Phase 0
32
Electrochemical actions of class 1b
* Class Ib: shortens the action potential (eg. lignocaine)
◦ No effect on the duration of Phase 0 (do not prolong the QRS); shorten the QT interval
33
Class 1 c electrochemical actions
* Class Ic: no effect on the action potential (eg. flecainide)
◦ Prolong Phase 0 more than other subclasses; have little effect on the duration of the action potential and therefore do not prolong the QT interval
34
Non vaughan williams anti-arrhtyhmics
Non-VW agents:
* Agents which slow AV nodal conduction (i.e. adenosine, digoxin)
* Physiological membrane stabilisers (magnesium)
35
Class 2 Vaughan willaims drugs
Class II: Beta-blockers (eg. metoprolol)
* Increase IK1 inward rectifier potassium current and reduce other currents;
* Lower resting membrane potential, reduce action potential duration, promote rapid repolarisation in Phase 3, decrease AV node conduction
36
Class 2 Vaughan willaims drugs electrochmical action
Class II: Beta-blockers (eg. metoprolol)
* Increase IK1 inward rectifier potassium current and reduce other currents;
* Lower resting membrane potential, reduce action potential duration, promote rapid repolarisation in Phase 3, decrease AV node conduction
37
38
Class 3 electrochemical actions
Class III: Potassium channel blockers (eg. sotalol and amiodarone)
* Block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential
* Increase the duration of the refractory period and of the action potential as a whole
39
Class 4 electrochemical actions
Class IV: calcium channel blockers (eg. verapamil and diltiazem)
* decrease the rate of Phase 0 rise in pacemaker cells
* shorten repolarisation by decreasing the duration of Phase 2
* decrease AV node conduction
40
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
41
Combined beta and alpha beta blocker
labetalol, carbedilol
42
Non selective beta blocker
propanolol
43
Class 2 effect on
- Depolarisation rate (phase 0)
- Conduction velocity
- AP duration
- PR duration
- QRS duration
- QTc duration
- Effective refractoyr period
- Automaticity
- Dissocation rate
44
Beta blocker vs phase 0 of action potential
* an unchanged slope of Phase 0
◦ Fast voltage gated sodium channels largely unaffected except by propanolol which does decrease the slope by 30%
◦ HOWEVER - 2 studies found that the slope of phase 0 is affected by beta inhibition therefore it is possible for the QRS to widen
45
beta blocker vs conduction velcoity
* decreased conduction velocity through specialised conducting tissue e.g. AV node
◦ Myocyte conduction velocity is unaffected
46
beta blocker vs effective refractory period
* decreased effective refractory period
◦ The Stoerling table from which the table on the right is derived suggests this is the case however other resources suggest it is increased
47
Beta blocker vs action potential duration
ncreased action potential duration
◦ reduce calcium entry preventing earlier repolarisation - phase 2 is prolonged and phase 3 begins later
48
Beta blocker vs action potential duration
increased action potential duration
◦ reduce calcium entry preventing earlier repolarisation - phase 2 is prolonged and phase 3 begins later
49
Beta blocker vs QTc duration
* Decreased QTc duration - prolong at slow rates and shorten at faster rates, promoting L type calcium channel inactivation (reverse of beta agonists which delay L type calcium channel inactivation prolonging QTc)
50
beta blocker vs automaticity
* decreased automaticity
◦ of normal pacemakers as catecholamines are one the main stimulants of this phenomenon - they do this by lowering the resting membrane potential during phase 4
◦ Reduce appearance of VEB by lowering resting membrane potential preventing automaticity in non pacemaker tissues
51
Beta blocker vs early and late afterdepolarisations
* Decreased early afterdoparisations because repolarisation time is reduced counteracting pro-arrhtyhmic effects of class 3 agents
* Late afterdopalarisations are realted to intracellular calciume xcess and improve due to the anti-catecholamine actions of beta blockers
52
Re-entry vs beta blockers
* Re-entry is unaffected as myocyte conduction velocity is largely unchanged except for AV nodal re-entry
53
Draw and describe the effect of a beta blocker on an ECG
Corresponding ECG thereofre
* Longer PR interval
* Shorter QT interval
54
What does a class 3 antiarrhthmics do
◦ Prolongs repolarisation by interfering with inward rectifier and outward delayed rectifier potassium currents increasing refractory period and action potential as a whole
◦ In short, these drugs mainly block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential. Class III drugs are not unique in the effect, as there are many other drugs which interfere with this current (notably, macrolide antibiotics and antipsychotic drugs).
55
What occurs with rapid infusion of amiodarone
‣ Hypotension due to decreased contractility (polysorbate 80)
56
Acute use amiodarone effects
Class 2 and 4 effects - delayed AVN conduction
57
Chornic use of amiodarone causes what class of effects
- How does it affect repolarisation
- QTc duraiton
- AP
- re0entry
- Earyl afterdpolarisation
- QRS
◦ With chronic use, Class Ia and Class III effects
‣ Prolonged repolarisation and QTC duration
‣ Prolonged action potential duration
‣ Decreased reentry, as the result of this
‣ Increased risk of early afterdepolarisations
‣ Minimal effect on QRS
58
Draw a AP for someone on amiodarone
59
Effect of class 3 agents on autoamticity
◦ Automaticity of normal pacemakers unchanged with pure potassium blockade but as beta blocker effects seen in sotalol and amiodarone rate slowing occurs
◦ Abnormal autoamaticity of non pacemaker tissue - increased early afterdopalarisations due to prolonged repolarisation but counteracted by beta blockade in sotalol/amiodarone
60
Effect of class 3 agents on early afterdpolarisations
◦ Automaticity of normal pacemakers unchanged with pure potassium blockade but as beta blocker effects seen in sotalol and amiodarone rate slowing occurs
◦ Abnormal autoamaticity of non pacemaker tissue - increased early afterdopalarisations due to prolonged repolarisation but counteracted by beta blockade in sotalol/amiodarone
61
Effect of class 3 agents on late afterdepoalrisations
Unaffected
62
R
63
Re-entry vs class 3 agents
Decreased due to prolonged effective refractory period
64
Amiodarone side effects
- 4 major system
- 4 minor system
- Pharmacokinetic
- Toxicity
* Cardiac:
◦ Bradycardia (5%)
◦ Torsades de pointes (<1%)
◦ Hypotension with rapid IV administration (due to polysorbate 80)
* Pulmonary
◦ Pulmonary fibrosis (1.6%)
* Dermatological
◦ Photosensitivity (25-75%)
◦ Blue skin discolouration (<10%)
* Ophthalmic
◦ Corneal deposits and cataracts (100%)
◦ Optic neuritis (<1%)
* Thyroid
◦ Wolff-Chaikoff effect: iodine-induced hypothyroidism (1-23%)
◦ Hyperthyroidism can also occur (1-32%)
* Hepatic
◦ LFT derangement (15%)
◦ Hepatitis and cirrhosis (<3%)
* Neurological
◦ Ataxia, tremor, peripheral neuropathy
◦ Sleep and memory disturbances
* Urogenital
◦ Epididymitis
* Pharmacokinetic
◦ By binding to albumin and other protein, amiodarone can displace other highly protein-bound drugs, and increase their free fraction (increasing their effect)
◦ INhibitor of P glycoprotein an efflux pump for eliminiatino of digoxin - leading to digoxin levels being raised
◦ Inhibitor of CYP3A4 impairing clearance of
‣ Warfarin
‣ Atorvastatin and simvastatin
‣ Flecainide
‣ Phenytoin
‣ Cyclosporin
* Obstetric
◦ Penetrates the placenta, causing iodine overload and hypothyroidism of the foetus, causing neurodevelopmental abnormalities
◦ Excreted into breast milk
65
What effect do class 4 agents have on
- Conduction velocity
- Effective refractory period
- QT interval
- AP
◦ No effect on conduction velocity of normal tissues, but AV nodal slowing occurs
◦ No effect on effective refractory period
◦ No effect on QT interval
◦ Decreased action potential duration according to CICM source - but others vary and it is uncertain
66
How does a class 4 agent affect the 4 types of arrhythmias
◦ Decreased autoamaticity of normal pacemakers as decreased rate of rise of phase 0 of pacemaker cells (L type calcium channels)
◦ Abnormal automaticity of non pacemaker tissue unchanged as less reliant on calcium channels
◦ Early afterdepolarisations - reduced as this is mainly related to prolonged repolarisation and calcium channel blockers shorten duration of phase 2
◦ Later after depolarisations are reduced
◦ Re-entry unaffected except for AV nodal
67
Digoxin effects (2)
* Digoxin and the other cardiac glycosides mainly exert their antiarrhythmic effects by a vagomimetic action on the AV node, where they slow the conduction of action potentials.
By increasing the availability of intracellular calcium, digoxin may lead to an increased risk of late afterdepolarisations. Other than that, it has no real positive effect on the arrhythmogenesis of ventricular myocardium
◦ By inhibiting conducting tissue NaK-ATPase, digoxin alters the action potential by, (according to a CICM text that is probably wrong)
68
How does digoxin affect the cardiac action potential
Perhaps more correctly
* The whole action potential duration decreases (Ruch et al 2003)
* Phase 0 can be either shortened or lengthened (Hordof et al, 1978); most textbooks seem to think it is lengthened.
* Phase 1 is shortened (Woodbury & Hecht, 1952).
* Phase 2 is shortened the most (Woodbury & Hecht, 1952).
* Phase 3 is lengthened (Woodbury & Hecht, 1952).
* Phase 4 slope is increased in pacemaker tissues (Hordof et al, 1978) and in Purkinje fibres (Rosen et al, 1975), increasing their automaticity.
69
When is magnesium useful for arrhtymias? How does it work?
* Magnesium has antiarrhythmic properties which are most pronounced in those arrhythmias where the mechanism involves early or delayed afterdepolarisations. It can be classified along with Class III and Class IV agents, as its effects are mainly involved in decreasing the duration of repolarisation by acting as an antagonist of potassium and calcium currents (Fazekas et al, 1993). By the same effect, it counteracts the depolarisation of pacemaker tissues, like a calcium channel blocker.
70
What is an inotrope
Increases myocardiac contractility by increased velcoity and force of myocardial fibre shortening
71
What is a vasopressor
vasoconstriction leading to increased systemic or pulmonary vascular resistance (increased BP) e.g. noradrenaline, vasopressin, metaraminol, methylene blue (i.e. mimic sympathetic nervous system)
* All produce an increase in IC calcium in vascular smooth muscle which is mediated through:
◦ Alpha receptor stimulation
◦ Raise IC calcium concentration by a non-alpha receptor mechanism
◦ Raising extracellular calcium concentration
72
Sympathomimetic is
exert effects via adrenoreceptors or dopamine receptors either directly (via receptors) or indirectly (stimulate NA release)
73
SNS comes off where in the spine
T1 - L2
74
Describe the pre and post ganglionic nervous structure of the NSS
◦ preganglionic nerve cells
‣ arise from lateral horns T1-L2--> primary anterior rami --> rami communicates --> sympathetic chain
‣ release ACh to stimulate post ganglionic cells (nicotinic receptor) - in the sympathetic chain at the same level, a different level of leaving through splanchnic nerves to a prevertebral ganglion
◦ post ganglionic cells can be
‣ unmyelinated pass into adjacent spinal nerve via grey rami communicates
‣ Adrenergic --> release norepinephrine
* Special circumstance --> adrenal medulla which has preganglionic nerves directly synapsing with chramoffin cells which secrete adrenaline (80%) into the blood stream in response to ACh stimulation
‣ Cholinergic --> sweat glands, vasodilator blood vessels in skeletal muscle
75
Describe the pre and post-ganglionic nervous structure of the SNS
- Where they arise form
- Myelintion
- Transmitters used
- Receptors
◦ preganglionic nerve cells
‣ arise from lateral horns T1-L2--> primary anterior rami --> rami communicates --> sympathetic chain
‣ release ACh to stimulate post ganglionic cells (nicotinic receptor) - in the sympathetic chain at the same level, a different level of leaving through splanchnic nerves to a prevertebral ganglion
◦ post ganglionic cells can be
‣ unmyelinated pass into adjacent spinal nerve via grey rami communicates
‣ Adrenergic --> release norepinephrine
* Special circumstance --> adrenal medulla which has preganglionic nerves directly synapsing with chramoffin cells which secrete adrenaline (80%) into the blood stream in response to ACh stimulation
‣ Cholinergic --> sweat glands, vasodilator blood vessels in skeletal muscle
76
Alpha receptors
- Found ?
- Stimulation leads to?
Post synaptic
Stimulation
Vasoconstriction
77
MOA of alpha receptors
‣ MOA --> Gprotein (Gq) --> Pjospholipase C --> IP3 + DAG --> Ca2+ release from sarcoplasmic reticulum and increased calcium sensitivity
78
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
79
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
80
Myocardiac beta receptor proportions
85% Beta 1
15% beta 2
81
Where else other than the myocardium do you find beta 1 receptors
platelets
82
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
83
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
83
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
84
85
86
Beta 1 activation leads to?
‣ Activation increased cAMP which alters cellular function --> phosphorylation of voltage sensitive calcium channels inmyocrdium (increase calcium influx across the sarcolemma) --> increased isotropy
87
What is cAMP broken down to?
5AMP
88
Beta 2 receptors found where 4
Cause
‣ Bronchi, vascular smooth muscle, uterus and heart --> relaxation of smooth muscle (GPCR --> increased cAMP --> increased Na/K activity and hyper polarisation)
89
Dopamine receptors respond to?
Catecholamine
Dopamine
90
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
90
What is cAMP broken down to?
5AMP
90
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
90
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
91
Where do you find dopamine receptors
CNS, renal, splanchnic, coronary
92
Dopamine 1 receptor causes
post synaptic on sympathetic nerve --> stimulation leads to vasodilation of renal, mesenteric, coronary and cerebral vessels + sodium excretion
93
Dopamine 2 receptor leads to
◦ DA2 --> pre-synaptic --> activation inhibits release of noradrenaline (like alpha 2) + produces nausea and vomiting + reduced pituitary hormone release
94
Pure alpha 1 action causes 3
◦ Vasoconstriction - arterioles of heart, brain, kidneys, lungs, skeletal muscle, skin
◦ Mydriasis
◦ Inhibition of insulin release
95
Pure beta 1 action causes
◦ Heart - increased contractility, tachycardia (SA node rate), increased AV conduction velocity, reduced refractor period
◦ Increased glycogenlysis and adipose tissue lipolysis
96
pure beta 2 action causes
asodilation - skeletal muscle
◦ Bronchial relaxation
◦ Uterine relaxation (if pregnant)
◦ Hypokalaemia - sodium/potassium pump potentiation
97
Structural elements of a catecholamine
Catechold ring - benzene ring with 2 hydroxyl groups
Ethylamine tail
98
How many hydroxyl groups on a catecholamine ring
2 conventionally at 3,4 position of a benzene ring
99
What effect does dropping a hydroxyl group off the benzene ring of a catecholamine have?
Increased lipid soliubility
Increased potency 10 fold
Prevents COMT metabolism prolonging duration
100
What effect does dropping both hydroxyl groups off a catecholamine ring have?
◦ Losing both hydroxyl groups decreases the potency 100-fold - maximum potency occurs when separation of the hydroxy groups and ethyl amine groups is maximal.
‣ Changing the hydroxyl groups to the 3 and 5 position increases beta-2 selectivity when there is also a large substitution present on the amine group
‣ Losing both hydroxyl groups however reduces COMT metabolism nd increased oral bioavailability (the same applies to a lesser extent with one hydroxyl group loss) although become indirectly acting agents (no direct action)
101
Why is the benzene ring important to catecholamine action
Improves central actions without decreasing beta or alpha ctions
102
What does the ethylamine tail of a catecholamine contain
Beta carbon - first carbon
Alpha carbon - 2nd carbon
Amine group
103
What effect do the alpha and beta carbons have on catecholamines
‣ Beta carbon - The first carbon.
* Adding a hydroxyl group decreases lipid solubility and CNS penetration
* Adding any group increases both alpha and beta selectivity
‣ Alpha carbon - The second carbon.
* Adding a group prevents metabolism by MAO, prolonging duration of action --> ephedrine or amphetamines
* Methylation increases indirect activity
104
What function does the terminal amine group have on catecholamines?
mine group - The terminal nitrogen.
* Addition of a methyl group generally increases beta selectivity
As the chain length increases, so does the beta selectivity; conversely the same applies when it gets shorter to increasing alpha activity
105
What are the catecholamines
adrenaline
* noradrenaline
* dopamine
* dobutamine
* isoprenaline
* dopexamine
106
What is cAMP broken down to?
5AMP
106
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
106
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
107
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
108
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
108
What is cAMP broken down to?
5AMP
108
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
108
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
109
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
109
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
109
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
109
What is cAMP broken down to?
5AMP
110
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
110
Alpha 1 vs alpha 2
- Duration of action
- onset time
- Sensitivity to pH and temperature
- Relationship with AT2
- Central role
Alpha 2
* The effects of activation of these differ from alpha 1
◦ Slower in onset
◦ Longer lastic
◦ More sensitive to pH and temperature change
◦ Can also be affected by AT2
◦ Central affects lower sympathetic outflow (postulated mechanism for clonidine)
‣ Also causes sedation and analgesia
110
What is cAMP broken down to?
5AMP
110
Alpha 2 receptors
- Where are they found?
- What is their effect in each loaction?
both presynaptic and post synaptic
‣ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
‣ Inhibit adenylate cyclase production --> reduce cAMP concentration
111
Atropine derived from where? Chemical structure?
Alkaloid from Atropa Belladona - a tertiary amine
112
Atropine chemically prepared as?
Tertiary amine as the ester of tropic acid and tropine - comes as a racemic mixture of D and I hyoscyamine (I form active)
113
MOA of atropine
An anticholinergic acting by competitive antagonism of acetylcholine at muscurinic receptors
Minimal action at nicotinic receptors except at high doses
114
Atropine presentation
Clear colourless solution for injectino containing 0.5 or 0.6mg/mlatropine sulfate
Also as a tablet 0.6mg
115
Routes of adminsitration fo atropine
IM, IV
Oral
116
Dose of atropine in adults
0.015-0.02mg/kg in adults
3mg needed for complete vagal block in adults
117
Atropine effects
Cardiovascular - low doses produces an initial bradycardia followed by tachycardia, little effect on BP. Decreases AV condution time and may produce arrhtyhmias.
Respiration - bronchodilation and increases dead space, reduces secretions, RR increased, reduced laryngospasm
CNS - either excitation or depression - if centrala nticholinergic syndrome somnolence, confusion, amnesia, hallucinations, ataxis, dysarthria
Antiemetic
Antiparkinsonian
Reduces salivations, gastric secetions and perisalsis. Antispasmodic. Reduces lower oesophageal tone
Cucloplegia, mydriasis and increased IOP
BMR increased and sweating inhibited
Suppresses ADH secretion
118
Toxicity of atropine
Dry mouth
Anticholinergic syndrome
urnary retention
Gluacoma if ocular adminitration (not in IV or IM)
119
Absorption of atropine
rapidly absorbed from gut, bioavailability 20%
120
Distribution of atropine
50% protein bound
2-4L/kg Vd
Cross placenta and BBB
121
Metabolism fo atorpine
Hydrlysed in liver and tissue to tropine and tropic acid
122
Excretion fo atropine
94% in urine within 24 hours uncahnged, clearance 70L/hr and half life 2.5 hours
123
Atropine derived from where? Chemical structure?
Alkaloid from Atropa Belladona - a tertiary amine
124
Atropine chemically prepared as?
Tertiary amine as the ester of tropic acid and tropine - comes as a racemic mixture of D and I hyoscyamine (I form active)
125
MOA of atropine
An anticholinergic acting by competitive antagonism of acetylcholine at muscurinic receptors
Minimal action at nicotinic receptors except at high doses
126
Atropine presentation
Clear colourless solution for injectino containing 0.5 or 0.6mg/mlatropine sulfate
Also as a tablet 0.6mg
127
Routes of adminsitration fo atropine
IM, IV
Oral
128
Dose of atropine in adults
0.015-0.02mg/kg in adults
3mg needed for complete vagal block in adults
129
Atropine effects
Cardiovascular - low doses produces an initial bradycardia followed by tachycardia, little effect on BP. Decreases AV condution time and may produce arrhtyhmias.
Respiration - bronchodilation and increases dead space, reduces secretions, RR increased, reduced laryngospasm
CNS - either excitation or depression - if centrala nticholinergic syndrome somnolence, confusion, amnesia, hallucinations, ataxis, dysarthria
Antiemetic
Antiparkinsonian
Reduces salivations, gastric secetions and perisalsis. Antispasmodic. Reduces lower oesophageal tone
Cucloplegia, mydriasis and increased IOP
BMR increased and sweating inhibited
Suppresses ADH secretion
130
Toxicity of atropine
Dry mouth
Anticholinergic syndrome
urnary retention
Gluacoma if ocular adminitration (not in IV or IM)
131
Absorption of atropine
rapidly absorbed from gut, bioavailability 20%
132
Distribution of atropine
50% protein bound
2-4L/kg Vd
Cross placenta and BBB
133
Metabolism fo atorpine
Hydrlysed in liver and tissue to tropine and tropic acid
134
Excretion fo atropine
94% in urine within 24 hours uncahnged, clearance 70L/hr and half life 2.5 hours
