Download Sympathetic Agonists and Antagonists

CLASS: 11-12
DATE: 12-1-10
PROFESSOR: DAVID KU
I.
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AUTONOMIC PHARMACOLOGY
Scribe: CHRISTINE SIRNA
Proof: MEGAN GUTHMAN
Page 1 of 7
CHART [S32]
a. First lecture is to give the basic fundamental principle of drug actions
b. Pharmacologist have two arms of pharmacology
i. Pharmacological Kinetics: absorption distribution, metabolism elimination (ATME) PK people
ii. Pharmacological dynamics: Mechanism of drug actions
1. How the drug works
c. He went over ATME already and he talked about signal transduction mechanism actions
d. Pharmacology you need to know anatomy (cell structures) and physiology (normal cell function)
e. Disease is when cell becomes out of whack
f. Finally come to pharmacologists which bring abnormal cell function back to normal
i. Need to study how cell functions and disease state, what happens to them and the function, and how to
bring it back to normal
g. Either use a mymeric because they are not working well and we try to stimulate them
h. If overreactive we try to put in inhibitors antagonists to slow them down
ALPHA 1 ADRENOCEPTOR AGONISTS [S33]
a. Let’s talk about Alpha 1 agonist first: Phenylephrine
i. One example it’s the prototype
ii. Methoxamine is also an alpha 1 agonist
b. Don’t need to memorize this!
c. Only need to remember Phenylephrine is the prototype
d. Neo-synephrine: put in nose spray for nasal congestion,
i. if congested it’s good nasal decongestant
ii. constricts the nasal alpha receptors
e. Don’t need to know structures
i. Other than if it’s not a catecholamine
CHART [S34]
a. Alpha 1 receptors have 3 subtypes
i. Alpha 1A
ii. Alpha 1B
iii. Alpha 1D
b. Don’t need to memorize this hence the X at the top of the page
i. This is for what research is going on, they want to find a cloning receptor
c. Trouble is there is no agonists for them other than the phenylephrine basically activates all alpha 1A,B,D
d. Antagonist: we can only find some so don’t worry about this
e. Only thing to remember is Alpha 1 receptors are mainly for constriction
EXAMPLE OF THERAPEUTIC USE OF ALPHA 1 AGONISTS [S35]
a. Treat nasal congestions
i. Pseudoephedrine: very effective and long lasting 8-24 hours
ii. Phenylephrine is very short lived
b. They are banning pseudoephedrine because people are using it to convert to methamphetamines
i. Hard to get now so use combination antihistamine
c. Sudafed put in phenlyephrine
i. short half life so you need to keep taking it
d. Also used to treat hypertension
i. Hypotensive crisis: people go into shock and get alpha 1 agonists
e. Treat paroxysmal atrial tachycardia
f. Atria arrhythmia issues can cause mydriasis
g. Cause local vasoconstriction to localize the local anesthetics: for dentistry always use lidocaine and some
alpha agonist to constrict the blood vessel so the lidocaine does not diffuse into different areas.
CHART [S36]
a. Memorize alpha one and what they do and some uses
ALPHA 2 ADRENOCEPTOR AGONISTS[S37]
a. Clonidine is the prototype
b. There are others such as methyldope and alpha methylnorepinephrine also activate alpha two
c. All you have to remember is clonidine
d. Clonidine is definitely not a catecholamine
TERMINATION AND FEEDBACK MECHANISMS [S38]
a. Most alpha 2 receptors are presynaptic at nerve terminals for negative feedback mechanisms
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 2 of 7
i. Some are expressed on the post synaptic membrane
ii. Smooth muscle cells and some other cell types have alpha 2
iii. Predominantly alpha 2 on pre synaptic site
b. Primary site of action for alpha 2 agonists is CNS
i. for example highly selective alpha 2 agonist, Dexmedetomidine, is used as sedative during cardiovascular
surgery
c. Primary mechanism of action is mediated via a decrease in cAMP, K and Ca channels.
d. Don’t worry about the additional mechanism action only know Alpha 2 mainly in CNS
VIII.
ALPHA 2 ADRENORECEPTOR AGONISTS [S39]
a. Clonidine: usefulness is to treat hypertension
b. Hypertension can be caused by many things so it’s not easy to treat, ediology is so complex
c. Most patients are excitable type patients that have central actions because they release a lot of
catecholamines from the brain and are highly active
i. In those patients, Clonidine is effective in treating central mechanism of hypertension
d. highly lipid soluble, crosses BBB readily, activates a2 receptors in hypothalamus & medulla and results in a
decrease in NE release, thus, decreases sympatheticoutflow to the heart
i. that is the Primary mechanism action for clonidine for treating hypertension
a. Does not interfere with baroreceptor function but it does sensitize the brain stem pressor response
b. Does not produce postural hypotension
i. Postural hypertension: When you have alpha blockers you block the alpha receptors in periphery, as soon
as you stand up you will get postural hypotension
1. Clonidine will not have this problem
c. Not very severe side effects
d. Caution there are partial alpha 1 agonist also
i. Even though they are selective for alpha 2 they have a partial alpha agonist activites
ii. Will constrict blood vessel if too much clonidine and cause hypotension
II. ALPHA 2 ADRENOCEPTOR SUBTYPES AND POSSIBLE FUNCTIONS [S40]
a. Have alpha 2A,B,D
b. Different subtypes involving different things
c. Don’t worry about this
III. CHART [S41]
a. B receptors
IV. BETA 1 ADRENOCEPTOR AGONISTS [S42]
a. Dobutamine:
i. Structure is catechole
1. Big substitution at amino terminal for B 1
b. For B2: Substitution not as dramatic
c. Selective for B2 for people who have asthma, the pump are alpha 2 agonist
d. Q: Are B2 agonists catecholamines as well since they have 2 OH groups? No
i. Catechole is distinct between C3 and C4
ii. Once you substitute this it will no longer be OH group (top picture)
V. EXAMPLES OF THERAPEUTIC USE OF BETA 1 AGONISTS [S43]
a. Dobutamines are for short term treatment of cardiac decompensation (heart failure)
i. long term no good because receptor will down regulate
b. The receptor is a dynamic process in the cell membrane
c. An agonist holds onto it, if too many agonists autoexposure to receptor it will internalize
d. Most drugs we use are antagonists very few agonists do we use because mimerics always make receptor
down-regulate
e. Not recommended for chronic use because of the down-regulation
f. Undesirable side effects: tachycardia (heart goes too fast or stimulate B1), hypertension, and arrhythmias
i. Characteristic for Dobutamine so that is why we only use them short term
VI. EXAMPLES OF THERAPEUTIC USE OF BEAT 2 AGONISTS [S44]
a. B2 agonists: Dobutamine and Albuterol
i. treat asthma, bronchospasm and emphysema
b. Undesirable side effects: Nervousness, headache, tachycardia (heart is pumping), palpitations, sweating,
muscle cramps.
c. Spray for asthma will have problems because they are relative
d. Only relatively selective for B2 over B1
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 3 of 7
e. You will get tachycardia if you keep spraying by stimulating B1 even though bronchial smooth muscle is B2
primarily which is why we want to dilate them
VII. CHART [S45]
a. Don’t worry about B3 because there are no FDA approved drugs
VIII. BETA 3 RECEPTORS [S46]
a. There are B4 receptors
b. We don’t have good drugs for B3 or B4
c. B4 talk about long term memory issues because cloning receptor people are finding out but don’t worry about
this right now
d. B3 gets attention because of metabolic syndromes
i. People are obesity, diabetics
ii. Seem to have an issue with B3 receptors
1. Localized in fat cells and mediate metabolic effects
2. B3 may be involved in these populations
e. Hopefully we will get drugs to treat obesity
IX. ADRENERGIC RECEPTOR ANTAGONISTS [S47]
a. Antagonists: most drugs are this
b. Antagonists are competitive
i. Need to understand there are competitions between agonist and antagonist
c. Receptors are governed by the Law of mass action
i. depends on concentration and number of receptors
ii. More agonist more agonist activities
iii. More antagonist more antagonist activities
d. Draw graph on board
i. Y axis is response
ii. X axis is [D], drug concentration
1. Normally you see sigmoidal curve
iii. More drug you put in more response you get until you reach a maximum
1. When you put antagonist in it competes for same site, depends on how potent it is, and it will shift
curve to the right
2. Right graph is alpha antagonist
iv. By looking at the response curve you can say the drug is very potent
v. If cure shifts farther right it is more potent
vi. Depends on number of receptors and how they compete
e. Most receptors are hydrophobic, hydrogen bond are always reversible
i. called reversible or competitive or equilibrium
ii. they reach the maximum, they are competing for same site
f. If you increase agonist concentration you get same maximal response
g. Exception is those with a covalent bond, any alkylating agents, any compound with Cl or Br or F substitution
i. Most cancer drugs have Cl or F, form alkylating agents
1. Binds and doesn’t come off, they are irreversible
h. Irreversible is noncompetitive, take the receptors away
i. When you put irreversible antagonists?
i. Instead of 100% receptor you take the receptor away and now you only get 50% of max Y
ii. Put in irreversible noncompetitive antagonist so the maximum response has now dropped
iii. Takes receptor number away because they are no longer at equilibrium, they are now alkylating receptor
so we call it irreversible no equilibrium
iv. By studying these graphs we can tell you the potency and what kind of competition
X. PICTURE [S48]
a. This is a picture illustrating receptors (top picture normal)
b. An agonist for B receptor binds to a specific site on these receptors between 6 and 7 transmembrane domain
i. all you need to know is there is specific site agonist will bind to
1. then you will elicit some kind of conformational change
2. There is a conformation change in receptor complex and this in turn activates G protein, signal
transduction process
c. Antagonist binds to the same site as agonist
i. But does not elicit a conformational change
ii. Do not have activation of single transduction
d. Inhibitors is anything that can inhibit the actions. Different from antagonist
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 4 of 7
i. Antagonist is specific we are talking about they are competing for the receptor site
ii. Inhibitors we can find a drug that will break down this agonist and can inhibit anywhere downstream
e. Agonist and antagonist are specific on the receptor site, they are competing for the same binding site
f. Agonist elicits a response and antagonists do not elicit a response
XI. PICTURE [S49]
a. Another concept I wanted to explain is, when you talk about agonist and you activate receptors and get
conformation change and in turn active G protein and in turn activate adenyly cyclase which converts ATP to
cAMP
i. All of this process that is happening is called transducing the signals
b. When some antagonists bind to this site, they’re not supposed to elicit a conformation change but some
antagonists elicit partial agonist activities
i. Once they bind to receptor they change some conformation and partially activate this
c. We try to modulate them because we want a pure compound and sometimes we get side effects
XII. ALPHA 1 ADRENOCEPTOR ANTAGONISTS [S50]
a. Alkylating agents like for example phenoxybenzamine has a Cl so it’s alkylating
b. These are all alpha antagonists
i. You have haloalkylamine, imidazoline, and quinazoline
c. Phentolamine and tolazoline are non selective alpha blockers and are irreversible
i. They are long lasting
ii. Use mostly phentolamine for non selective
d. Quinazoline derivatives: Prazosin and Tamsulosin
i. Prazosin and tamsulosin are selective for alpha 1
XIII. PHENOXYBENZAMINE AND PHENTOLAMINE [S51]
a. Irreversible v. reversible
i. Want to decrease the number of receptor sites if non competitive and shift D-R curves if competitive
b. Other actions they block other effects, they are not pure
i. Most drugs it’s hard to find pure selective drugs
c. Adverse Reactions: Postural hypotension (very characteristic of alpha blockers antagonists), tachycardia,
miosis, nasal stuffiness, failure of ejaculation
d. Therapeutic uses are for peripheral vascular disease especially people with excessive catecholamine release
e. People with pheochromoctoma release a lot of epinephrine from adrenal glands, release a lot of
catecholamines
i. Those patients you give alpha blockers, so they will not have hypertension problems
f. These are some key things to remember about alpha blockers
XIV.
THERAPEUTIC/ANTAGONISTIC EFFECTS OF THESE ANTAGONISTS DEPEND ON [S52]
a. Depends on the cardiovascular status of the patient at the time of drug administration and the relative
selectivity of the agents used
b. Depends on the alpha receptors
i. If you block something, you are lying down and the alpha receptor is not activated
ii. If you put agonist in, you don’t see much of an effect
1. Because the receptor is not working, it is the minimal effect
2. As soon as you stand up alpha is activated
iii. If you give alpha now while you are all sitting down, pressure will drop
iv. It depends on the status of the patient at the time of drug administration
c. Sympathetic nervous system is down while we are sitting here and parasympathetic is very high
i. If he gave us an alpha or beta blocker would not see much of an effect because sympathetic is very low
ii. If you are running and given B blocker you will see an effect, heart rate will drop
d. Thing to remember: When you block something you have to remember what is going on in the basal
levels
XV. PICTURE [S53]
a. Why do we want selective alpha 1 and 2?
i. When you give phentolaine (nonselective) you block off alpha 1 and 2
b. So what happens when you block alpha 2? Alpha 2 is a negative feedback
i. When you loose negative feedback it continues to release norepinephrine
ii. NE: Alpha one will not constrict the blood vessel but will activate the heart, heart rate will go up and you get
get tachycardia
c. Even though you won’t block the smooth muscle because the NE is continually releasing you will activate
alpha 1 and heart rate increases
d. Because of all this you usually have a selective one
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 5 of 7
XVI.
PICTURE [S54]
a. If you give selective alpha 1 blockers here you will leave the alpha 2 blockers alone
b. NE goes up and alpha 1 is shut down so NE is regulated and you will not see tachycardia issues
c. That is example why we want selective one and not nonselective one
XVI.
CLINICAL PHARMACOLOGY/USES OF SELECTIVE ALPHA 1 ANTAGONISTS [S55]
a. Another example of clinical usefulness is treating primary hypertension or people with BPH in prostate
i. Will see Hytrin and Flomax agents are hyperactive in smooth muscle cell
b. Don’t worry about bottom part
c. Memorize selective alpha 1 antagonists are to treat hypertension and BPH
XVII. CHART [S56]
a. Alpha 2 antagonists
XVIII. CLINICAL PHARMACOLOGY OF SELECTIVE ALPHA 2 ANTAGONISTS [S57]
a. Why do we want a selective alpha 2 antagonist?
i. Alpha 2 is used for negative feedback
ii. Little clinical usefulness
b. Theoretically, blockade of presynaptic 2 receptors could promote neurotransmitter release and improve
autonomic function
c. Yohimbine has been used to promote male sexual functions. That was before viagra came out
a. Yohimbine is also a good antidote for clonidine toxicity
i. Clonidine is alpha 2 agonist
ii. Best way to treat toxic dose of clonidine is to give alpha 2 blocker otherwise little usefulness for alpha 2
II. STRUCTURES [S58]
a. B blockers
i. This is a catecholamine structure on top
b. One thing characteristic of B blockers is they all share similar structure
i. All have O methyl bridge
c. Alpha blockers do not have similar structure
d. Right side is selective for B1
e. Left side are non selective, will block B1 and B2
III. SALIENT FEATURES OF SOME B BLOCKERS[S59]
a. There are a lot of B blockers
i. B blockers were drug from the 70s
ii. Currently 13-14 B blockers
b. To summarize these are the salient features of B blockers
i. Propranolol: first B blocker approved in this country
1. Prototype for all B blockers, non selective
ii. Timolo: first B blocker used for opththalmic
1. used to treat glaucoma
iii. Metoprolol: first cardioselective approved B blocker
1. second generation B blocker
c. Need to know the different B blockers
d. What are feature to know:
i. Their metabolism
1. propranolol, timolol, metoprolol all B blockers are metabolized through the liver by the enzyme
a. they are lipophilic
b. For patients with liver disease, you want to stay away from those B blockers
c. Why? They could not metabolize those B blockers and you will have toxicity problems
2. You need to give drugs that excrete through the kidney
a. Atenolol is cardioselective but goes through the kidneys
b. Nadolol B blocker metabolized through kidney
c. Liver disease patient if you want cardioselective use atenolol
d. If they have kidney problems stay away from atenolol and give propranolol
e. Other things is plasma half life of B blocker is 3-6 hours
i. Most B blockers you take twice a day
ii. Ideal drug wanted half life of 6-8 hours because you only take twice a day
iii. 3-4 hours will need to take 3 or 4 times a day
1. Most patients will miss the middle dose
2. Most doctors will not want to prescribe
iv. If once a month drug companies won’t make money
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 6 of 7
v. Once a day is good but if you toxicity problem don’t want drug that lasts that long
1. Ideal drug is twice a day
f. There are once a day blockers and rapid onset (Esmolol) which is only about 9 minutes
g. Why would you want B blocker that only lasts 9 minutes? Use in ER
i. if you want to control patient because heart rate is too fast and want quick dose on and off
ii. do not want long lasting effect
h. Research is not only worried about mechanism action but economics as well
IV. CHART [S60]
a. Potency
i. Everything is compared to propranolol
ii. For patient standpoint 1mg v. 6 mg doesn’t matter
iii. For scientists it is important
iv. Need to remember cardioselectivites
1. B blockers are selective and non selective
v. Partial agonist activity: some elicit but most do not
1. Elicit conformation changes
vi. Membrane-stabalizing activity is important, be aware of that especially when we talk about cardiovascular
drugs because of membrane stabilizing abilites
V. PICTURE [S61]
a. Recap of agonist and antagonist
VI. CLINICAL USES OF B BLOCKERS [S62]
a. Anyone can use a B blocker to treat hypertension
i. Short tern no change in BP
ii. Long term: decrease renin
iii. Better drugs now such as ACE
b. Antiarrhythmic treat arrhythmia
i. Supraventricular: decrease AV transmission
c. Ventricular PVCs (Premature ventricular contraction): due to excessive catecholamines
d. Antianginal: good for treating heart attack, redistribution of blood flow and decreasing heart muscle damage
i. All CV related B blockers are very effective
e. Hyperthyroidism
f. Open angle-Glaucoma-Timolol
g. Anxiety: people sometimes are overreactive, B blockers are good to calm the nerve, better than giving valium
h. Migraine: block craniovascular B receptors and reduce vasodilation
VII. MAJOR ADVERSE SIDE EFFECTS OF B BLOCKERS [S63]
a. Bradycardia (excessive decrease of B receptors): heart will go too slow
i. Trigger congestive heart failure
b. Bronchospasm: especially for non selective
i. For patient with asthma stay away from non selective
c. Repeated use of B blocker leads to: tiredness, dizziness, shortness of breath, diarrhea, flatulence &
heartburn.
d. CNS-related: hallucinations, depressions
i. Chronic use of B blockers give us suicidal tendency depress the CNS
ii. Be very careful with those that can cross the blood brain barrier
e. Potential hypoglycemia, especially in patients with insulin-dependent diabetes
i. B receptor triggers glycogenolysis, conversion of glucose
ii. If you block that they will not release glucose, this will make it hard for them to recover
VIII. PICTURE [S64]
a. If you are a diabetic patient taking insulin you will decrease glucose levels and it will take a long time to
recover from glucose
IX. CONTRAINDICATIONS FOR THE B BLOCKERS [S65]
a. People use B blockers for all kinds of cardiovascular disease but they need to be careful because if you have
those kind of problems you contraindicate
b. Another problem is withdrawal problems
X. PICTURE [S66]
a. Overexposure to receptor agonists, receptor will down regulate
b. If you give B blocker for long time the receptor becomes super sensitive, up regulate
c. When patient is scheduled to do cardiovascular surgery the surgery says stop all medications
CLASS: 11-12
Scribe: CHRISTINE SIRNA
DATE: 12-1-10
Proof: MEGAN GUTHMAN
PROFESSOR: DAVID KU
AUTONOMIC PHARMACOLOGY
Page 7 of 7
i. If you stop overnight when patient comes to surgery the B receptor is super sensitive and they have
problems with arrhythmias
d. When you have to withdraw the B blocker you don’t stop it overnight do it over like 7 days
e. Let receptor reestablish itself otherwise it will be supersensitive
XI. CHART [S67]
a. Don’t worry about B3 no drug for this yet
XII. 1ST GENERATION OF B BLOCKERS [S68]
a. This is to summarize B blocker generations over the years
b. First generation: classic non selective
c. Second generation: B selective
d. If you had to develop a blocker antagonist would want to have selective alpha 1 or 2? Alpha 1
e. B receptors do you want B 1 or 2? Beta 1
i. So you don’t have lung problems
f. During late 70s his charge was to develop a combined drug alpha1 blocker with B1 blocker
i. Point is to really treat hypertension
ii. If you have selective B1 and alpha1 you can really do it
g. 3rd generation: non selective B blocker and alpha blocker also have vasodilations
h. Soon there will be fourth generation
XIII. STRUCTURES [S69]
a. Example of this
i. Labetralol: alpha 1 and B1 and B2 antagonist
ii. Combined alpha and beta blocker
iii. Intent is to treat hypertension
b. Carvedilol alpha 1 B1 and B2
c. Structure is same O methyl bridge just like other B blockers, just with large substitution
XIV.
EFFECTS OF 3 SELECTIVE B BLOCKERS ON MORTALITY IN CHF [S70]
a. Take home message
b. When we developed drugs originally we just wanted to eliminate symptoms
i. Now we want to improve survival because we don’t want to die
c. So prognosis always given with drugs
d. Now it’s not about whether the drug works or not because we know the drug produces the effect
i. No longer end point effects we want survival
ii. Now you will see drugs with survival index
e. Far left is decrease mortality
f. Middle in increased survival
g. B blockers: metoprolol, bisoprolol and carvedilol are three drugs for treating for congestive heart failure
h. Improve quality of life and Increase survival
i. These are the third generation B blockers
[End 44:19 mins]