Lectures 8, 9, 10, and 11 Flashcards
1
Q
What is the permeability of peripheral blood capillaries?
A
Relatively free exchange of substances between/across cells
2
Q
What is the permeability of brain blood capillaries?
A
Strictly limit transport of substances into brain
3
Q
What is the function of astrocytes?
A
Form a sheath around capillary
4
Q
What acts as a barrier for drugs into the BBB?
A
Tight junctions and astrocytes
5
Q
When would the BBB be ineffective and when would this be advantagous?
A
- Brain infections that increase permeability
- Allows water soluble antibiotics to cross that normally wouldn’t cross
6
Q
Which mechanisms allow drugs to cross the BBB?
A
- Same mechanisms as crossing biological membranes
- Passive diffusion through aqueous channels (not common)
- Passive diffusion through lipid (most important)
- Taken up by endocytosis
- Facilitated transport via transporters
7
Q
When is passive diffusion through the BBB most optimal?
A
- Drug is mostly unionized at pH 7.4 (except quaternary amines; don’t normally cross BBB)
- Drug has MW < 400
- Drug has logP between 1-4
8
Q
Succinylcholine is a ______ NM blocking agent
A
Depolarizing
9
Q
What are used to reverse the effects of non-depolarizing NM blocking agents?
A
Acetylcholinesterase inhibitors
10
Q
Are acetylcholinesterase inhibitors used w/ succinylcholine?
A
No, succinylcholine already has a short duration of action
11
Q
What type of antagonist is a non-depolarizing NM blocker and what does this mean?
A
- Is a competitive antagonist
- Excess agonist (ACh) can overcome its effect
12
Q
What is edrophonium used for?
A
Diagnostic test for myasthenia gravis
13
Q
What is the most common anticholinesterase used in anaethesia?
A
Neostigmine
14
Q
What does neostigmine do to AChE?
A
Reversibly alkylates it, making it inactive for about 30 mins
15
Q
What is pyridostigmine used to treat?
A
Myasthenia gravis
16
Q
Which anticholinesterase crosses the BBB?
A
Physostigmine
17
Q
What occurs in myasthenia gravis?
A
Autoimmune disease characterized by production of antibodies to ACh receptors => decrease in receptor density at NMJ (no morphological changes at NMJ) => less ACh will bind
18
Q
What can be used to treat myasthenia gravis?
A
- Anticholinesterases to increase ACh at NMJ to restore muscle contraction upon stimulus
- Can use pyridostigmine or other anticholinesterases that are orally absorbed, longer acting, and do not cross BBB
19
Q
What is cholinergic crisis?
A
When the effect of anticholinesterases decreases with increasing dose b/c of depolarizing NM block
20
Q
What are side effects to anticholinesterases?
A
- Salivation
- Sweating
- Decreased heart rate
- Increased GI motility
- Bronchospasm
21
Q
What can be used to treat Alzheimer’s?
A
Anticholinesterase w/o a quaternary amine b/c need to cross BBB
22
Q
What must happen to the tertiary amine of an anticholinesterase after it crosses the BBB?
A
Must ionize so it can bind to anionic site of AChE
23
Q
What is important about the AChE active site?
A
Asp-His-Ser form a catalytic triad to make the alcohol of serine a better nucleophile
24
Q
Is AChE a fast enzyme?
A
Yes, very fast
25
Which 2 anticholinesterases work via the same mechanism?
Pyridostigmine and physostigmine
26
Why are organophosphates nerve toxins?
Have the ability to increase ACh at NMJ and synapse, which eventually leads to persistent activation of ACh receptor, depolarizing the NM block and death by asphyxia
27
What are symptoms of organophosphate poisoning?
- Pinpoint pupils
- Bronchospasm
- Decreased heart rate
- Frothy salivation, profuse sweating
- Increased GI motility
28
What is the only treatment for organophosphate poisoning and what does it do?
2-PAM binds to anionic site to position itself for reaction and removes the initial phosphorylated enzyme which would otherwise cause permanent AChE inactivation
29
What AChE inhibitors do not covalently bind to enzyme , do not alkylate AChE and are completely reversible?
- Donepezil
- Edrophonium
- Galantamine
30
Which AChE inhibitors covalently bind to enzyme but do not permanently inactivate it?
- Neostigmine
- Pyridostigmine
- Physostigmine
- Rivastigmine
31
Which AChE inhibitors covalently bind to enzyme and permanently inactivate it?
- Organophosphates
| - Anticholinesterases
32
Where do R1 and R2 of an antimuscarinic bind in the binding site?
Large hydrophobic binding pockets
33
Where does R3 of an antimuscarinic bind in the binding site?
Secondary H-bonding site
34
Where does X of an antimuscarinic bind in the binding site?
Primary H-bonding site
35
Where does N of an antimuscarinic bind in the binding site?
Anionic binding site (must be positively charged amine)
36
What are common uses of antimuscarinic drugs?
- Dilation of pupil
- Frequent urination or abdominal pain caused by GI spasms
- Bronchodilation (asthma or COPD)
37
What is atropine used for?
- Painful urethral spasm or intestinal cramping
- Given w/ 2-PAM for organophosphate anticholinesterase toxicity and sometimes w/ neostigmine after surgery when recovering from NM block
38
What is benztropine?
Dopamine blocker
39
What is scopolamine used for?
To prevent motion sickness
40
What is hyoscine used for and what is important about its structure?
- Used to stop spasms in GI tract that produce abdominal pain
- Quaternary amine means it has a permanent positive charge so little of it is absorbed from GI tract
41
What is ipratropium used for and what is important about its structure?
- Reduce bronchospasms from COPD
| - Quaternary amine decreases systemic absorption from lungs and prevents crossing BBB, so no CNS side effects
42
What is important about the structure of tiotropium?
Quaternary amine decreases systemic absorption from lungs and prevents crossing BBB, so no CNS side effects
43
What is tiotropium used for and what is its advantage over ipratropium?
- Used for COPD
| - Longer half-life than ipratropium
44
What are some side effects from antimuscarinics?
- Dry mouth
- Pupil dilation, blurred vision
- Hot, flushed, dry skin
- Increased heart rate
- Urinary retention and constipation
45
Alpha 1 is G alpha __
q
46
Alpha 2 is G alpha __
i
47
Beta 1, 2, and 3 are G alpha __
s
48
What are 3 ways to eliminate signal for noradrenaline?
1) Reuptake at synapse (most important)
2) Catechol-o-methyl transferase (COMT)
3) Monoamine oxidase (MOA)
49
Where is noradrenaline very potent?
Alpha 1, alpha 2, and beta 1
50
Where is adrenaline very potent and where is it moderately potent?
- Very potent at beta 1 and 2
| - Moderately potent at alpha 1 and 2
51
What does biosynthesis of adrenaline and noradrenaline produce?
DOPA, dopamine, and tyramine
52
What is the function of amphetamine and amphetamine-like drugs?
Cause release of noradrenaline, serotonin, and dopamine from presynaptic vesicles into synaptic cleft
53
What is the mechanism of amphetamine?
- Blocks VMAT2 which decreases vesicular uptake of monoamine
- Binds to and inhibits MAO which increases non-vesicular [monoamine] causing the increase of non-vesicular [NA], [dopamine] and [serotonin]
54
What is the mechanism of cocaine?
Competitive inhibitor of MA reuptake transporter, causing increased concentration of NA, dopamine, and 5-HT in synaptic cleft
55
What causes the psychological effects of amphetamine and cocaine?
Their effects on dopamine, including euphoria, addiction, and psychotic symptoms
56
Tyramine has ____ activity
Amphetamine
57
What is contraindicated w/ foods that contain high levels of tyramine?
Irreversible MAO inhibitors, b/c inhibition of MAO while taking tyramine increases [NA], [dopamine], and [5-HT] in synapse
58
What are the 3 basic types of sympathomimetics?
1) Drugs that bind to receptors of symp NS, aka agonists or direct acting (most important for therapeutic drugs)
2) Drugs that have amphetamine-like actions, called indirect acting
3) Drugs that do both (mixed acting)
59
Which structure do all sympathomimetics have?
Phenethylamine
60
What is dexamphetamine used for?
- Treatment of ADHD and possibly narcolepsy
| - High doses cause hallucinations and psychotic symptoms that are schizophrenia-like
61
Which isomer of NA and A is preferred?
(R)
62
Can clonidine be inactivated by COMT?
No b/c it has no meta OH
63
Does clonidine cross the BBB? Why or why not?
Does cross b/c it is hydrophobic and has a low enough pKa that a portion is in the unionized form at pH 7.4
64
What is clonidine used for?
Treatment of symptoms of menopause
65
What is methyldopa used for?
Occasionally to treat hypertension in pregnancy
66
What are imidazoles used for?
Topical decongestants, which cause vasoconstriction of arterioles causing decreased appearance of red eyes and decreased swelling in nasal membranes
67
What is phenylephrine used for?
In many cough and cold preparations
68
What is a side effect of pseudoephedrine, so what does this mean for recommending products?
- Decreased sleep
| - Recommend tablets that work for 6 hours and make sure last dose is 3-4 hours before bed
69
What are side effects for phenylephrine and pseudoephedrine?
- Peripheral vasoconstriction and increased heart rate
| - Only a problem in people w/ existing hypertension
70
What is sinusitis?
Inflammation or swelling of the tissue lining the sinus
71
Are oral or nasal decongestants preferred and why?
Oral b/c don't cause rebound congestion
72
When should oral decongestants not be used?
Those w/ high BP
73
What are beta 1 agonists used for?
Acute heart failure or decreased cardiac output that can occur after heart surgery
74
What are beta 2 agonists used for?
Treatment of asthma and COPD
75
Most therapeutically used beta agonists are _____
Secondary amines
76
The majority of beta agonists are _____
Phenylethylamines
77
Since the SAR for alpha agonists and beta agonists are the same, what method is used for selectivity at beta receptors and why?
- Large R substituents on N
- Increase affinity at both alpha and beta receptors
- Decrease intrinsic activity at alpha receptors but increase or keep intrinsic activity the same at beta receptors
78
What does the structure of potent beta 2 agonists suggest about binding sites?
- Suggests there are 2 binding sites beyond the Asp-COO- on TM3 to which the N ion pairs
- Nearest site to N accommodates a t-butyl group and distal to this is a hydrophobic binding pocket that seems to require a phenolic OH or a longer hydrophobic chain for optimal binding
79
What is isoproterenol used for?
- Sometimes used to treat heart block or shock
- Decreases vascular resistance by causing vasodilation in muscular blood vessels and also increases CO and force of contraction
80
What is dobutamine used for?
- In acute heart failure, cardiogenic shock, septic shock, and for cardiac insufficiency after heart surgery
- Modestly increases heart rate but increases contractile force more
81
Which beta agonists have a short half life and are rapidly metabolized by MAO and COMT?
Dobutamine and isoproterenol
82
Why is isoproterenol not appropriate as a bronchdilator?
Targets beta 2 and beta 1 receptors, so it has effects on the heart
83
How can the short half life of dobutamine be worked around?
By given by continuous infusion
84
What is important to remember when making substitutions to block COMT metabolism?
Some part of the substitution should be capable of forming H-bonds or affinity will decrease
85
Why are resorcinol derivatives good for resisting COMT methylation?
Do not form the right geometry for Mg2+ coordination complex
86
What are short-acting beta 2 agonists used for?
Fast bronchodilation in the event of an acute asthmatic attack
87
Asthma treatment should include a short-acting beta 2 agonists and a ______
Inhaled glucocorticoid to decrease frequency and severity of asthmatic attacks
88
When are long-acting beta 2 agonists used?
- When asthma is not controlled w/ short-acting beta 2 agonists and inhaled glucocorticoids
- Used in COPD
89
What is the most common short-acting beta 2 agonist?
Salbutamol
90
Why is orciprenaline used less often than salbutamol?
Has an isopropyl group, which makes it less beta 2 selective
91
What are some side effects of beta 2 agonists?
- Muscle tremors
| - Increased or irregular heart rate
92
What is a sign that shows a patient is using their rescue inhaler too often and what should be done when you notice this symptom?
- Muscle tremors
| - Add a long-acting beta 2 agonist or increase dose of glucocorticoid
93
LABA's are highly _____
Lipophilic
94
What does an increased logP for a LABA generally mean and what is the exception to this?
- Longer duration and slower onset
| - Exception is indacaterol which has the same logP as salmeterol, but has a longer duration and a faster onset
95
Can salmeterol or formoterol be used for asthmatic attacks?
No b/c onset is too slow
96
What is indacaterol used for?
COPD, but could be used for asthma
97
Why does indacaterol have a short onset and a long duration?
Charged at 2 sites, but exists as a zwitterion at physiological pH, which gives it the properties of lower and higher logP beta 2 agonists (it can partition through membranes and bind to receptors)
98
What is systolic blood pressure?
Maximum pressure in the arteries after the ventricles contract
99
What is diastolic blood pressure?
Minimum pressure between ventricular contractions
100
BP must be more stringently controlled in _____
Diabetics
101
What effect does age have on systolic blood pressure?
Increased age means increased systolic blood pressure, so a person w/ a high systolic pressure does not have high blood pressure
102
What is hypertensive crisis?
Systolic > 180 or diastolic > 110
103
What are the 2 formulas for blood pressure?
- BP = CO * SVR
| - BP = HR * SV * SVR
104
What effect do transient increases in blood volume have on blood pressure?
Will increase BP b/c increase stroke volume
105
What do noradrenaline and adrenaline on alpha 1 receptors do to blood pressure?
Increase SVR (systemic vascular resistance), so increase BP
106
What do noradrenaline and adrenaline on beta 1 receptors do to blood pressure?
Increase cardiac output, so increase BP
107
What does adrenaline on beta 2 receptors do to blood pressure?
Decreases SVR, so decreases BP
108
What are the 2 main ways to control BP?
1) Decrease SVR w/ vasodilation (block alpha 1 receptors to prevent noradrenaline and adrenaline-induced vasoconstriction)
2) Decrease cardiac output
109
What are other ways to decrease SVR besides blocking alpha 1 receptors?
- Block AT1 receptor w/ AT1 antagonists
- Production of NO, hydrochlorothiazide, or hydralazine
- Calcium channel blockers
110
How can you decrease cardiac output?
- Decrease heart rate
| - Decrease stroke volume or contractile force
111
How do you decrease stroke volume or contractile force?
- Block beta 1 receptors to prevent noradrenaline and adrenaline-induced increase in heart rate and contractile force
- Calcium channel blocker
112
What are alpha antagonists used for?
- Controlling blood pressure
| - Controlling benign prostatic hypertrophy
113
Drugs tend to have unwanted ______ or ______ activity
Antimuscarinic or alpha antagonist
114
Do all drugs w/ the minimum SAR for alpha antagonists actually have alpha antagonist activity?
No b/c sufficient affinity may not be there to have a significant alpha blocker effect, put the potential will exist
115
What are the 2 examples of non-selective alpha antagonists and are they reversible or irreversible?
- Phenoxybenzamine (irreversible)
| - Phentolamine (reversible)
116
What are 2 examples of selective alpha antagonists?
1) Alpha 1 selective (most important) -- quinazolines
| 2) Tamsulosin for BPH
117
What does phenoxybenzamine do once it is bound to the alpha receptor?
Can dissociate as a reversible competitive antagonist or can react w/ a nucleophile in the receptor (typically Cys or Ser residue)
118
What happens when phenoxybenzamine is covalently bound to the receptor?
Is an irreversible non-competitive inhibitor
119
Why does phenoxybenzamine have long-term antagonist activity?
Irreversibly alkylates receptors
120
What is phenoxybenzamine used to treat and why?
Pheochromocytoma (adrenal gland tumour) b/c increases noradrenaline and adrenaline
121
What are side effects for non-selective alpha antagonists?
- Reflex tachycardia b/c of decrease in BP
- Decreased effectiveness of baroreceptor reflex b/c of inhibition of alpha 1 receptors
- Also has antimuscarinic activity and increased release of histamine
122
What is phentolamine used to treat?
Cocaine and amphetamine induced hypertensive crisis
123
What are quinazolines used for?
- Decrease BP w/o increased HR or CO
| - Used to treat hypertension and BPH
124
Do quinazolines have antimuscarinic activity?
No and don't release histamine
125
Quinazolines are alpha ___ selective
1
126
Why does prazosin have low bioavailability?
Highly metabolized by liver b/c of planarity
127
What are terazosin and doxazosin used for?
Induces apoptosis of prostate smooth muscle cells, not dependent on alpha 1 blockade
128
Is terazosin or perazosin more useful for BPH?
Terazosin
129
What is the starting dose for all quinazolines?
1 mg at bedtime to decrease incidence of postural hypotension (dose is titrated to BP)
130
What is the metabolism of quinazolines?
O-dealkylation produces active metabolite or N-dealkylation, then phase 2 reactions produce conjugation and/or elimination
131
What is a serious side effect of quinazolines?
Orthostatic hypotension; most risk at few hours-days after initiating or changing dose or adding another antihypertensive drug
- No effect on BP
132
What is syncope?
Passing out/fainting b/c of orthostatic hypotension
133
Which receptor does tamsulosin have selectivity for?
Alpha 1 A
134
What is tamsulosin used to treat?
BPH
135
What is the most common side effect of tamsulosin?
- Decreased urination
| - At normal doses, does not cause any of the general side effects of alpha antagonists
136
What causes the efficacy of alpha 1 antagonists in BPH?
Relaxation of smooth muscle via alpha 1 receptor antagonism in bladder and prostate
137
What are some general alpha antagonist side effects?
- Orthostatic hypotension and syncope
- Hypotension b/c of decreased TPR
- Dizziness, lightheadedness
- Nasal congestion
- Headache
- Reflex tachycardia (especially w/ non-selective alpha blockers)
138
Which patients are most at risk for syncope?
Those taking quinazolines for high BP (rather than for BPH)
