Final Flashcards
How do depolarizing neuromuscular blockers work?
Initially work normally, initiating muscle contraction from Na channels. But continued stimulus increases the resting membrane potential, making the channels refractory and unable to open.
Succinylcholine, nicotine
How doe non-depolarizing neuromuscular blockers work?
Simply stops Na channels from opening. Nicotinic competitive antagonist
Pancuronium
What are neuromuscular blockers used for?
Muscle relaxation during surgery
What is needed for a muscarinic agonist?
Charged N with 3 methyl groups
5 atoms long
CH3 aliphatic substitution by double bonded O to resist acetylcholinesterase (orally activity)
CH3 or NH2 on end by double bonded O
Which muscarinic agonists aren’t orally active?
Acetylcholine and Carbachol
What is methocholine? What is it used for?
Muscarinic agonist, test for asthma
What is bethanechol? What is it used for?
Muscarinic agonist used to increase urinary output after surgery or in prostatic hypertrophy that doesn’t respond to tamsulosin
What is pilocarpine? What is it used for?
Muscarinic agonist used as eye drops for glaucoma. Trans isomer
What are the characteristics of a drug necessary for optimal BBB crossing?
Mostly unionized at pH 7.4 (quaternary amides will not cross)
Molecular weight
What is edrophonium? What is it used for?
An anticholinesterase used as a test for myasthenia gravis
Competitive reversible, doesn’t covalently bind
What is neostigmine? What is it used for?
An anticholinesterase used in anesthesia. Reversibly alkylates AChE (~30 minutes)
Covalently binds but doesn’t permanently inactivate
What is pyridostigmine? What is it used for?
An anticholinesterase that reversibly alkylates AChE used to treat myasthenia gravis
Covalently binds but doesn’t permanently inactivate
What is myasthenia gravis?
A neuromuscular disorder with production of antibodies to ACh receptors that leads to a decrease in receptor density at the NMJ, less infolding and bigger gap between nerve fibre and receptor causing less muscle contraction
How can Alzheimer’s be treated?
Anticholinesterases (Rivastigmine, Galantamine, Donepezil)
Donepezil and galantimine don’t covalently bind, rivastigmine do but don’t permanently inactivate
What are some examples of organophostphate anticholinesterases? What are they used for?
Sarin as a toxic nerve gas
Parathion and Malathion as an insecticide
Hydrophobic, covalently bind and permanently inactivate
What is cyclopentolate? What is it used for?
Antimuscarinic used as eye drops prior to eye surgery to cause pupil dilation
What are antimuscarinics used for urinary incontinence?
Tolterodine and Oxybutynin
What is given in organophosphate anticholinesterase toxicity?
2-PAM
What is benztropine? What is it used for?
An atropine like antimuscarinic used to counteract “Parkinsons-like symptoms” from the treatment of schizophrenia
What is scopalamine? What is it used for?
An atropine like antimuscarinic used for motion sickness
What is hyoscine? What is it used for?
An atropine like antimuscarinic used to stop GI spasms that produce abdominal pain
What atropine like antimuscarinics are used to treat COPD?
Ipratropium and Tiotropium
What characteristics make ipratropium and tiotropium good as an inhaler?
Positively charged N decreases systemic absorption from the lungs and prevents crosses of the BBB
What are the 3 ways that the signal or noradrenaline is eliminated from the synapse?
Reuptake at the synapse
COMT (Phase II metabolism enzyme, adds methyl group in meta position to reduce activity) why not orally available
MOA (Phase I metabolism enzyme, removes N to eliminate activity, replaces with double bonded O)
How is adrenaline synthesized?
Tyrosine to DOPA to Dopamine to noradrenaline to adrenaline
How do amphetamine and amphetamine like drugs work?
Cause the release of NA and dopamine from the synapse by binding to and inhibiting MAO which increases [MA], blocks VMAT2 which takes MA up into vesicles, competitively blocks the reuptake of NA, DA and serotonin by being uptaken by the same transporter, leaving high concentrations of the neurotransmitters in the synapse, so high that the reuptake pump begins to work in the opposite direction, pumping MA and all the neurotransmitters out into the synapse
How does cocaine work?
Stops the reuptake of NA, DA and serotonin by transporters.
What foods are contraindicated while taking irreversible MAO inhibitors? Why?
Red wine, cheese and fermented foods because they contain tyramine because they have amphetamine activity
What is important for the R group of alpha agonists?
As the size of R increases the intrinsic activity decreases and affinity increases
What makes an alpha 1 selective agonist?
Imidazole group
Para and meta substitutions
What makes an alpha 2 selective agonist?
Guanidine group
Central NH
2 ortho substitutions
N substitution smaller than isopropyl (CH3)
Methyl in 2 position (reduces MAO metabolism)
What are some examples of alpha 2 agonists? What are they used for?
Clonidine for menopause
Methyldopa for hypertension in pregnancy
What suggest no amphetamine like activity in an alpha agonist?
meta OH, beta OH
What suggests amphetamine like activity in an alpha agonist?
No ring substitutions
What are alpha 1 agonists used as? What are some examples?
Decongestants (vasoconstriction)
Xylometazoline, oxymetazoline, tetrahydrozoline (topical)
Phenylephrine, psuedophedrine (oral)
What is needed for beta agonists?
As size of R increases, so does affinity for beta receptors and intrinsic activity
2 aromatic ring substituents capable of H bonds
What makes a selective beta 1 agonist?
R is isopropyl
No beta OH
What makes a selective beta 2 agonist?
R is t-butyl, ethylphenol (increased affinity and intrinsic activity)
Ethyl (CH2CH3) in alpha position
2 meta OH
Long hydrophobic chains at R increase affinity and activity while prolonging duration
What is isoproterenol? What is it used for?
A mixed non-selective beta agonist. To treat hear block or shock.
What is dobutamine? What is it used for?
A beta 1 agonist that is used for acute heart failure, shock, cardiac insufficiency after surgery.
How can we reduce metabolism by MAO?
Alpha position: Methyl reduces activity, ethyl eliminates it
Beta position: Methyl reduces activity, t-butyl reduces or eliminates activity (steric block)
How can we block metabolism by COMT?
Put H, CH2OH, N-formyl or sulfonamide (allergy risk) in the meta position
What are some examples of short acting beta 2 agonists? What are they used for?
Salbutamol, Terbutaline, Orcipenaline, Fenoterol
Used when there is difficulty breathing or asthma attack and COPD
What should everyone with asthma be taking?
A short acting beta 2 agonist and a glucocorticoid (regular use)
What is ritodrine? What is it used for?
A beta 2 agonist used to arrest premature labour (might not actually help)
What is needed to make a beta 2 agonist long acting?
At least 7 atom hydrophobic chain
2 rings sometimes with an ether
What are some examples of long acting beta 2 agonists?
Salmeterol, Formetrol, Indacterol (zwitterion)
In what groups does the definition of high blood pressure change?
More highly controlled in diabetics (>140/>89-99)
Systolic will rise as you get older than 65
Shorter people tend to have lower blood pressure
What is considered a hypertensive crisis?
> 180/>110
What are alpha antagonists used for?
Hypertension, Benign prostatic hyperplasia (BPH)
Raynaud’s disease
What is the general rule for the N substituents (R groups) for alpha antagonists?
Must be CH3 or larger than t-butyl to have affinity for the alpha receptors
What are some examples of non-selective alpha antagonists?
Phenoxybenzamine (irreversible) for adrenal gland tumor and Phentolamine (reversible)
What are some examples of alpha 1 antagonists (quinazoline)?
Prazosin, Terazosin, Doxazosin, Tamsulosin
What does the charged tertiary nitrogen of the alpha antagonist do?
Forms ion pair interaction with an Asp residue in the alpha adrenergic receptors
What is the starting dose for quinazolines?
1 mg at night and then titrate to BP
What are some examples of non-selective beta antagonists?
Propranolol, nadolol, timolol (eye drops for glaucoma), bunolol (eye drops), sotalol (also K channel blocker), pindolol (hypertension and depression treatment)
What are some examples of beta 1 antagonists?
Metoprolol, atenolol, acebutolol, betaxolol, esmolol, bisoprolol
What gives a beta antagonist partial agonist activity? Which ones exhibit this?
sp2 hybridized NH in the meta position
Pindolol, acebutolol, cartelol
What is labetalol?
A beta 1 and 2 antagonist and alpha 1 antagonist
Beta because of CH3, meta N-formyl
Alpha because of extended hydrophobic N substituent
What is carvedilol?
beta 1 and 2 and alpha 1 antagonist
What are beta blockers used for?
Hypertension, arrythmias, heart failure, angina, MI, glaucoma, migraines, tremors
What are some side effects of beta blockes?
Fatigue, bronchospasm (non-selective in asthma), cold exremities, left ventricular insufficieny, NVD
What are the contraindications for beta blockers?
Asthma (non-selective), bradycardia, diabetes
What is aliskiren?
A reversible competitive antagonist that mimics angiotensinogen (OH bond cannot be cleaved), stops entire RAS system.
Would a peptide like drug have high oral bioavailability?
No, cleaved by enzymes in the stomach
What are ACE inhibitors used for?
Heart failure, hypertension and acute and post MI, diabetes, renal failure
What makes phosphonate ACE inhibitors different from dicarboxylate ACE inhibitors?
Longer chain, tetrahedral transition state
