Med chem midterm

ACHi uses (4)

ACHi uses (4)

reverses induced muscle relaxation after surgery

myasthenia gravis

alzheimer's disease

glaucoma

acyl-enzyme intermediate compared to carbamoyl intermediate

acyl enzyme intermediate is rapidly hydrolized to remake the enzyme while the carbamoyl is much more stable to hydrolysis and is much slower than ACh

carbamoyl groups on a drug will have what effect on AchE inhibition

non competitive inhibition (transient) due to covalent bond with enzyme

a ester group on ACh or edrophonium will have what effect on AchE inhibion

competitive inhibition due to no covalent bonds being formed between enzyme

Edrophonium

-Anticholinesterse - increases ACh

-Historically used to diagnose myasthenia gravis

-short duration

Neostigmine

cholinesterase inhibitor

-carbamylated and is non competitive inhibition (transient)

-used to reverse anesthesia

Pyridostigmine

-Anticholinesterse - increases ACh

-carbamylated and is non-competitive inhibition (transient)

-Used in myasthenia gravis (long acting)

-Does not penetrate CNS

Physostigmine

-Anticholinesterse - increases ACh

-carbamylated and is non-competitive inhibition (transient)

-Crosses the blood-brain barrier (CNS)

-treats glaucoma

myasthenia gravis

a chronic autoimmune disease that affects the neuromuscular junction and leads to a decrease in receptor density

AChEi cannot have what to be able to cross the BBB?

cannot have a 4 amine

Rivastigmine

-Anticholinesterse - increases ACh

-treeats Alzheimer disease

-non-competitive(transient)

Galantamine

-Anticholinesterse - increases ACh

-treats Alzheimer disease

-competitive inhibitor

Donepezil (Aricept)

acetylcholinesterase inhibitor treats Alzheimer's

-competitive inhibition

Sarin gas

irreversible AChE inhibitor aka Nerve gas

-permanently inhibits

organophosphates

Found in pesticides, can cause cholinergic overstimulation by inhibiting cholinesterase,

Parathion, Malathion

AChE inhibitors; organophosophate; insecticides

Symptoms of organophosphate poisoning

DUMBBELSS

Diarrhea

Urination

Miosis

Bradycardia(los BP)

Bronchospasm

Excitation of skeletal m./Emesis

Lacrimation(tears)

Salivation

Sweating

(organophosphates irreversibly inhibit AChE; jimson weed is muscarinic antagonist--> opposite effects)

Aged enzyme

permanently inactivated enzyme

2-PAM

allows acetylcholinesterase to function again. Used as an antidote in cholinesterase inhibitor poisoning to free up the blocked enzyme(ONLY ON THE NON AGED ENZYME)

how to recongnize a muscarinic antagonist by their SAR structure

usually two rings attached to a center C

charged tertiary or quaternary amine with at least 2 substituents (methyls, ethyls, propyls, isopropyl, butyls)

Atropine-like (Anticholinergic) SARs are reconizable by their

8 carbon ring with a N attached

Antimuscarinic side effects

"cant see, can't pee, can't poo, can't spit"

blurred vision

urinary retention

constipation

dry mouth

hot,dry skin

dilated pupils

increased HR

unintended antimuscarinics can be recongnized by what normally?

tricyclic fused ring system attaches to X

COMT

enzyme that breaks down excess dopamine into inactive chemicals that cannot stimulate the dopamine receptors

MAO

monoamine oxidase found in the mitochondria

Sympathomimetic drugs and the three types

A class of drugs whose effects mimic those resulting from the stimulation of the sympathetic nervous system.

1.direct acting

2.indirect acting (amphetamine)

3. mixed (direct and indirect acting)

Amphetamine mechanism of action

blocks VMAT an MAO, increases norepinephrine, dopamine at the synapse

2 drugs with amphetamine activity

dexamphetamine and methamphetamine

Mixed acting sympathomimetic drugs structure

have an OH on the beta position and a CH3 on the alpha position

examples are pseudoephedrine and phenylpropanolamine

amphetamine sympathomimetic drugs structure and how it differs from direct acting

amphet. contains no OHs and only has a CH3 on the alpha position

unlike direct acting, they contain OH groups on the meta and beta positions

what to add to make a molecule more affinity for a2 over a1 agonist

-guanidine groups

-ortho substituents on the ring

-methyl is the alpha position

-NH on beta position

Methyldopa

alpha 2 agonist that is a prodrug

A2 agonist are used for (3)

hypertension

symptoms of menopause(clonidine)

-methyldopa is used to treat hypertension during pregnancy

imidazolines are selective at?

alpha 1 adrenergic receptors

what kind of substituents on the ring favours a1 over a2

meta and para

A1 agonists are used for:

decongestants(cause vasoconstriction)

- in the eyes(reduces red eyes)

-in the nose(reduces swelling)

what substituent favors alpha1 over alpha 2 in the beta position

Ch2 (instead of NH which favours a2)

decongestants should not be used if you have which condition

hypertension

what postion on the SAR is the main position of alteration to distinguish between a B agonist and an a agonist?

the R position

isopropyl on the R of a Beta SAR will be selective for...

selective fro B1 and B2 over a

t-butyl on the R of a Beta SAR will be selective for...

B2 vs B1

dobutamine is used for

Beta 1 agonist used in acute HF, shock, septic shock and after-surgery

t1/2 of dobutamine

very short--> is metabolized by COMT therefor needs to be given by continuous IV

what are 4 ways of reducing metabolization of beta agonist by MAO

1. add methyl or ethyl grp to the alpha position to act as a steric shield

2. t-butyl grp on N will ELIMINATE MAO while also conferring more B2 selectivity

3. isopropyl on N will reduce MAO but not eliminate

4. more giant than 7 atom branches after N, will reduce MAO

what substituent can you add to a beta agonist to eliminate MAO activity as well as confer more B2 selectivity over B1

add an ethyl grp to the alpha position

which position of the OH is the preferred site of COMT METHYLATION?

THE META

what three substituents can you add to the meta

OH on a beta agonist to reduce metabolism of COMT?

1. hydroxyethyl

2.N-formyl

3.sulfonamide(can cause allergies)

4. resorcinol

resorcinol grps confer what as opposed to selectivity and COMT metabolism

confers B2 over B1 and resists COMT methylation due to its improper geometry

Salbutamol(Ventolin)

short acting Beta2 agonist

Terbutaline (Bricanyl)

second most common B2 agonist

-dry powder

orciprenaline

slightly less selective B2 agonist,due to its isopropyl grp

Side effects of B2 agonists

Muscle Tremors

increased heart rate

desensitization of B2 receptors from overuse

drug tolerance

the purpose of two B2 receptor binding sites

to make longer acting B2 agonists

the two B2 receptor binding sites are....

t-butyl binding site and the extended hydrophobic binding region(hydrophobic chain is attached to the t-butyl)

Salmeterol is considered...

LABA

LABA can be identified by their structure because they normally have what attached to the NH?

extended heavy atom hydrophobic chain with an aromatic grp and sometimes an ether O

BP= ___ x ___

CO x TPR

CO=_____ x______

HR x SV

two ways of controlling blood pressure

decrease TPR and Decrease CO(decrease HR and SV)

what three receptors are involved in decreased TPR?

a1 receptors

angiotensin 1 blockers

Ca2+ channel blockers

what two receptors are involved in decreased CO

B1 receptors and Ca2+ channel blockers

two types of alpha antagonists are?

non selective and selective

selective a1 antagonists examples (3)

prazosin,terazosin, doxazosin

The quinazolines (prazosin, terazosin, doxazosin) have an amine (NH2) attached to the quinazoline ring. What is the purpose of this group to the drugs' function?

enhances a1 receptor affinity

Phenoxybenzamine

-Nonselective α-blocker

-Irreversible

-Used to treat adrenal gland tumor

-Toxicity: orthostatic hypotension, reflex tachycardia

phentolamine

-Nonselective α-blocker

-has antimuscarinic properties

-treats cocaine induced hypertensive crisis

Quinazoline uses

decrease BP without increasing HR

-treats hypertension

-treats BPH

a furan ring will do what to hepatic metabolism

increases hepatic metabolism

Terazosin (Hytrin)

alpha 1 blocker

-more powerful that prazosin for BPH

-longer half life

Prazosin (Minipress)

alpha 1 blocker

-low bioavailability and short half life

Doxazosin (Cardura)

alpha 1 blocker

-treats BPH and more useful than terazosin

quinazoline side effects

orthostatic hypotension

syncope(fainting)

Tamsulosin (Flomax) selectivity

alpha 1A and Alpha 1D over Alpha 1B

what alpha receptors are on the prostate?

a1A

unintended a antagonists are similar to....

muscarinic antagonists

general a antagonist side effects

-orthostatic hypotension

-syncope(fainting)

-nasal congestion

-dizziness

-headache

-reflex tachycardia

none of these are caused by tamsulosin

Beta blockers should only be taken when?

if you previously had a heart attack, stroke, MI

if you haven't had any previous heart conditions (heart attak,MI,stroke) what is best drug to reduce hypertension?

ACE inhibitors, Ca2+ channel blockers ,ARBs

Ca2+ channel blockers examples

Verapamil

Diltiazem

Two classes of beta blockers

aryl ethanolamine and aryloxypropanolamine

beta blockers with PA activity are normally which class of beta blocker(aryl-)

aryl ethanolamine

effects of B-blockers

-reduces HR

decrease renin release in kidneys

-membrane stabilizing activity(local anesthetic effect)

-bronchospasms

-decreases IOP and production of aqueous humor(glaucoma)

Propanolol

non-selective beta blocker with low bioavailability and is super lipophilic

Nadolol

non-selective beta blocker more hydrophilic than propranolol and has a longer half life

Timolol is used for

glaucoma

Levobunolol

beta blocker that treats glaucoma

sotalol

beta blocker, antiarrhythmic

which two beta blockers are the most useful arylethanolamines?

sotalol an labetolol

pindolol

non-selective beta blocker that has PA activity

Carteolol

non-selective beta antagonist that has PA activity

what additional substituents can be added to a beta blocker to confer partial agonist activity? (2)

meta NH(sp2)

directly attached OH subst to the ring

what additional substituents can be added to a beta blocker to confer B1 specific selectivity

a single straight chain para substituents on the ring

Metoprolol

selective beta blocker

-has some MSA (antiarrhythmic)

-can reduce mortality in HF

Atenolol

selective beta blocker

-does not cross bbb

Acebutolol

selective beta blocker

-has some MSA

-has PA activity

Betaxolol

selective beta blocker

-treats glaucoma

Esmolol

selective beta-blocker

-very short half-life, must be administered in IV

Bisoprolol

selective beta blocker

-can reduce mortality in HF

labetolol is a

B1B2a1 antagonist

Carvedilol

B1B2a1 antagonist

-has PA activity

-treats hypertension and HF(significantly reduces Mortality in HF and MI)