Test 2 part IV Flashcards
Which category of Alpha Antagonists can be overcome by increasing the concentration of the agonist?
Reversible
Most beta antagonists are ______ antagonists, but some are _____ agonists, and there is potential for ______ agonism.
Pure (reversible); partial; inverse
Some Beta Antagonists are _____ agonists, meaning they inhibit the action of the receptor in the presence of high catecholamine concentrations, but moderately activate the receptors in the absence of endogenous agonists. It is not yet clear to what extent this is or is not clinically valuable.
Partial Agonists
Which Beta Antagonists have the potential to act as inverse agonists?
- Metoprolol
- Betaxolol
Despite some drugs being Beta 1 Specific (MAE), in very high doses, selectivity is _________.
Abolished (Selectivity is dose related and diminishes at higher doses)
Most Beta Antagonists resemble which drug at a chemical level to some degree?
Isoproterenol
Beta Antagonists are generally ________ absorbed, but do undergo _____ first-pass metabolism
Well; Extensive
Beta Antagonists are _______ distributed, with _______ Vd, with half-lives averaging ________.
Rapidly; large; 3-10 hours
Which Beta Antagonist is the exception to the usual rule, and is short acting?
Esmolol
What metabolizes Esmolol?
It is metabolized by hydrolysis in plasma by pseudocholinesterase. Need a decent dose because it immediately is partially metabolized when it’s injected
What are the two types of Cholinomimetic Drugs?
- Direct Acting
- Indirect Acting
What is the mechanism of action for direct acting cholinomimetic drugs?
Act directly at either or both the NR or MR. Some drugs are more highly selective for either NR or MR.
Where are Nicotinic receptors located?
PNS/SNS Autonomic ganglia, skeletal muscle
Where are Muscarinic receptors located?
Sweat glands of SNS, effector organs of PNS
What are the two types of Direct Acting Cholinomimetic Drugs?
- Choline Esters
- Alkaloids
Which type of Direct Acting Cholinomimetic Drugs are either Acetylcholine or structurally similar to Acetylcholine (Exogenous)?
Choline Esters
Are the Choline Esters Quaternary or Tertiary?
All are Quaternary
What are the example drugs of Choline Esters?
- Acetylcholine
- Bethanechol
- Carbocol
- Methacholine
Choline esters are all rapidly ______, but each drug will have a varying susceptibility to that, leading to differences in effects on duration of action
Hydrolyzed
Which type of Direct Acting Cholinomimetics are Tertiary?
Alkaloids
What are the example drugs of the Alkaloids?
- Nicotine
- Muscarine
- Lobeline
- Pilocarpine
What is the mechanism of action of the Indirect Acting Cholinomimetics?
Act on Ach-E to prevent degradation of Ach (remember, Ach-E is hanging out in the postsynaptic side of the membrane). End up with increased Ach, PNS is amplified. Some may also have direct stimulating effects on the NR.
What are the subtypes of the Indirect Acting Cholinomimetics?
- Simple Alcohols
- Carbamic Acid Esters
- Organic Derivatives of Phosphoric Acid
What are the reversible types of Indirect Acting Cholinomimetics?
- Short-acting: Edrophonium
- Intermediate-acting: Neostigmine, Pyridostigmine, Physostigmine (Physostigmine is not reversible)
Which Indirect Acting Cholinomimetic is Tertiary?
Physostigmine
Which Indirect Acting Cholinomimetics are Quaternary?
All except Physostigmine and Organo-Phosphates
Which type of Indirect Acting Cholinomimetics are Irreversible?
Organo-phosphates such as Nerve Gases
What is the mechanism of action of the Organo-phosphates (Indirect Acting Cholinomimetics)?
Forms an irreversible bond with Ach-E, so have to wait for more to be synthesized. Takes a long time.
Which drug of the Organo-Phosphate category is non-toxic in ophthalmic form?
Ecothiopate is nontoxic in ophthalmic form.
Why is Ecothiopate nontoxic?
It is highly polar, so not well absorbed. Other organophosphates are toxic.
Are the Organo-phosphates well absorbed or poorly absorbed?
Well absorbed, can cross the blood-brain barrier. Exception is Ecothiopate which is highly polar.
Which Indirect Acting Cholinomimetic is given to treat central anticholinergic toxicity (Central Nervous tissue causing too little Ach)
Physostigmine
All of the organophosphate (indirect acting cholinomimetics) drugs are well aborbed through the skin, gut, lung, and conjunctiva except for:
Ecothiopate
Is Neostigmine Quaternary or Tertiary?
Quaternary
Stimulation of the Muscarinic Receptor causes PNS or SNS effects?
Parasympathomimetic effects only
Stimulation of the Nicotinic Receptor causes what effects?
Autonomic (SNS and PNS) and Somatic Effects
What parasympathetic receptor is located more in the brain, and which is located more in the spinal cord?
Muscarinic; Nicotinic
Which Indirect Acting Cholinomimetic drug forms a covalent bond (long lasting), and has the quality of Aging (AKA, the longer the bond is active, the stronger it gets)
Organo-Phosphates
What refers to breaking of one of the O2-P4 of the inhibiting agent, further strengthening the covalent bond (Varies by agent)?
Aging
What kind of bond do Simple Alcohols form?
Electrostatic reversible bonds and H+ bonds
Short (2-10 min)
What kind of bond to Carbamic Esters form?
Covalent bond
Long (30 min - 6 hrs)
What are some of the general effects of Ach on Muscarinic Receptors?
- Inc K+ flux across cardiac cell membranes (Hyperpolarization)
- Dec K+ in the ganglion and smooth muscle
- Inhibits adenylyl cyclase activity (dec cAMP = no relaxation of smooth muscle, inc GI activity)
- Modulates the increase in cAMP by hormones/catechols
Muscarinic Receptors use ______, and activate the ________, and cause an increase in _______.
- G-protein coupling
- Activates the IP3 and DAG cascade (Inc Ca+ Release)
- Increases cGMP
Nicotinic Receptor activation causes:
Depolarization of the nerve cell or motor end plate
What is the mechanism of action of Nicotinic Receptor Activation?
Presence of a NR agonist prevents electrical recovery of the post-junctional membrane = a depolarizing blockade (opens channels and prevents repolarization. Ex: Succinylcholine).
-Refractory to reversal by other agents
PNS stimulation of the M3 receptor results in ______, which can be problematic for which patient population?
Contraction of the smooth muscle of the bronchial tree and increased tracheobronchial mucosa secretion; Asthmatic Patients
Direct Stimulation of the M2 (heart) and M3 (vasodilation) receptors results in what mechanism of action?
- Increase in K+ to the SA node, AV node, Purkinje cells, atrial and ventricular muscle cells
- A decrease in the inward Ca current
- A reduction in the hyperpolarization-activated current of diastolic depolarization
Leads to decreased HR
Vasodilation requires _________ to release EDRF (Endothelium relaxing factor)
Intact Epithelium
What is the mechanism of action of EDRF?
EDRF → NO → Guanylyl cyclase → cGMP
Why does HTN/Atherosclerosis decrease the release of EDRF?
Atherosclerosis damages the endothelium and eliminates the NO/cGMP pathway
True/False: Direct slowing of the SA node and AV conduction is opposed by the reflex SNS discharge elicited from the decrease in MAP.
True
