Neuropharm 2 - Dr. Dravid PDF

Preview

Summary

Dr. Dravid...

Description

Direct-acting muscarinic agonists: clinical uses

Parasym pathetic A c h ind ire ct

●

symp athet ic in dir ec tA cdire hct

therapy ACHE inhibitors used to treat Alzheimer’s disease ● Tacrine ● Donepezil ● Rivastigmine ● Phenserine ● Galantamine ● There is indication that facilitating the function of the CNS n and m receptors can help with cognition ○ But not dramatic changes in cognition

mu scl NE Bethanechol - stable to hydrolysis by AChE e Adrener ○ Used to treat postoperative ileus, gi retention congenital megacolon and urinary M3 > M2 recepto ■ Postoperative ileus is GI tract r immobility → After surgery, can reverse this with bethanechol Effective in treatment of ineffective esophageal motility Pilocarpine - partial agonist ○ Used to constrict pupil in ophthalmology and to manage glaucoma ○ Also used to treat xerostomia associated with head and neck radiation treatments ■ Xerostomia - salivary glands don’t produce enough mucus ○ M3 ~ M1 > M2 ○ Sweat test ■ If you apply pilocarpine to your skin, you’ll start to sweat there ■ Activates symp, but does not release NE ■ Comes from thoracolumbar division ■ Produce Ach instead ■ Sweat test used to detect changes in ion concentration Methacholine - challenge test for asthma ○ Would be para agonist → constricts the lungs (bc you don’t need as much air) ○ In a normal person, it won’t produce a dramatic effect ○ If you have asthma, your respiratory symptoms will show ○ *To treat asthma, you would never use any of these agonists, would use a blocker for these receptors Carbachol - glaucoma ○ Carbachol makes it more resistant to … Cevimeline - dry mouth associated with radiation ○

●

●

● ●

● ●

For Alz meds, need to pass the BBB Neostigmine ○ Bc its charged, it’s hard to pass BBB ● Physostigmine - can pass BBB ● Muscarine receptor is direct? ● Betel nut - chew it after you eat food ○ Facilitates salivary/GI tract functions ○ Stimulates parasymp ● Don’t have to remember these drugs, just 1-2 prototypes Cholinoceptor-blocking drugs Antimuscarinic drugs

○

● atropine/scopolamine only differ in their oxygen Effects of muscarinic antagonists ● Inhibition of secretions; anti-M1 pirenzepine reduces gastric acid ● Blockade of vagally mediated bradycardia ● Mydriasis ● Inhibition of GI motility ● Relaxation of smooth muscle: bronchial, biliary and urinary tract ● CNS effects: scopolamine - antiemetic, motion sickness medication ● These would inhibit all the secretions ● Side effect - lose near vision ○ Ciliary muscles → cannot contract ○ Lens shifts → cannot accommodate for near vision Examples of muscarinic antagonists ● Surgery: before and during ○ Prototype: Atropine - preanesthetic ○ Glycopyrrolate: reduces respiratory and GI secretions ■ Doesn’t cross blood-brain barrier ● Motion sickness ○ Scopolamine: central action ● Respiratory ○ Ipratropium and tiotropium used as inhalation drug for asthma and COPD ○ But this is not the first line of action ○ Bocking these receptors provide extra benefits for the patients ● GI ○ Treatment of diarrhea, irritable bowel syndrome and rarely to treat peptic ulcer (Pirenzepine, glycopyrrolate) ○ These reduce acidity in stomach Clinical pharmacology of antimuscarinics ● CNS ○ Adjunctive use in Parkinson’s disease:

■ Diphenhydramine ■ Benztropine ■ Procyclidine In Parkinson’s there is neurodegeneration of dopaminergic neurons ■ Usually there’s a balance between movement and inhibition of movement ■ Parkinson’s shifts the balance to inhibition of movement ■

■

■ ●

D2-MSN → decrease dopamine Parkinson’ s messes with this Ac Block muscarinichreceptors →

can stop the inhibition to treat it? Before you start L-dopa, you start these these other drugs first

Ophthalmologic ○ Examination of the retina facilitated by mydriasis, and cycloplegia permits accurate measurement of refractive index (contraindicated in patients with glaucoma): ■ Tropicamide ● Cardiovascular ○ Attenuate response of reflex vagal discharge accompanying pain of myocardial infarction ■ Can inhibit vagal discharge ● Urinary ○ Treatment of urinary urgency and incontinence ■ Tolterodine, and others ● Cholinergic poisoning - insecticides ○ Atropine or other tertiary amine Side effects of muscarinic antagonists ● Dry mouth ● Tachycardia ● Increased intraocular pressure ● Difficulty in micturition ● Constipation due to GI atony ● High dose toxicity: “hot, red, dry, and mad” ● But you will not sweat bc you’re blocking the muscarinic receptors from the sweat glands

receptor binding sites Causes ion channel to open within the receptor protein ■ Opens a Na+ channel ○ Cause muscle contraction Always excitatory (EPSPS) ○

●

nAChR Subunit composition

● ●

Summary of side effects Bottom right shows atropine’s effect on blocking muscarinic receptors ○ Can produce anti-parkinson’s ● Bronchoconstriction ● Skin and sweat glands → dry ● Increased heart rate → tachycardia ○ This is because at rest, the parasympathetic determines heart rate ● Increased pupil size ● Problems with near vision ● Can facilitate this to drain the aqueous humor impaired ● Don’t have to remember the drug names, just the jist of it ■ Know atropine ■ Know direct and indirect ■ Stigmines ■ … ■ What conditions these will be used for Responses to nicotinic cholinergic stimulation ● Nicotinic receptors (ligand-gated): ○ Ionotropic, pentameric ○ Nicotinic receptors in ■ Neuromuscular junction ■ CNS ○ ACh binds to 2 nicotinic receptor binding sites ■ These are permeable to positively charged … ○ Causes ion channel to open within the

●

●

●

At least two alpha-subunits per pentameter (ACh binding sites) ○ Alpha1: muscle only ○ Alpha2 - alpha 9: neuronal Variable stoichiometry for remaining subunits ○ Brain: usually ααβββ ○ Muscle: ααβγδ Channel conductance ○ Subunit compositio n

Channel conductan ce

EC50 (potency)

α3β2

15 pS

350 μM

α4β2

20 pS

0.7μM

α7

45 pS

110 μM

○ ○

● ●

Channel conductance shows the level that the channel is permeable to ions This is required for the channel to open → Na passes through → depolarization Nicotine is most potent in α3β2

CNS cholinergic synapse

Mechanism of action of natural and drug rewards on mesolimbic dopaminergic neurons ●

Choline acetyltransferase can be a marker for cholinergic receptors ○ Catalyzes the reaction to make Ach from acetyl CoA and choline Nicotinic receptor subunit knockout mice ● Β2 subunit knockout mice display profound decrease in brain [3H]nicotine binding sites (receptors) ● α4 subunit knockout mice display profound decrease in analgesic and rewarding actions of nicotine ● There’s an experiment where rat is injected with nicotine and with saline at different times and put in two rooms separated by a closed door ● Later, open the door between the two rooms ○ The drugs that are rewarding → rat will spend more time there ● Nicotine has high affinity for α4 ○ α4 responsible for rewarding

Increase in dopamine when you get natural rewards and drugs of abuse ● Natural rewards ○ Food ○ Water ○ Sex ○ Nurturing Mesolimbic dopamine system: reward center

●

Can do stuff like block reuptake receptors to increase the amount of dopamine in the synapse Nicotinic receptor modulation of reward circuitry

●

Varenicline: a nicotinic receptor partial agonist

● ●

Used to stop addiction to nicotine Var shows small effect → that’s why it’s a partial agonist ○ Not as much of an effect as Ach ● Can do a concentration/response curve for var ○ Y axis is % response as opposed to Ach ○ Var is only 15% ● Bottom chart is a competition against ○ Use 20 micromolar of Ach (standard concentration) ○ Then you start doing the concentration for low [var] and increase dosage ○ Full response at -8 log M [var] ○ There is competition between var and Ach ○ Final response at high [val] -> lower concentration of Ach ● Can measure amount of domanine by sticking in an electrode and injecting a rewardings drug → see spike in dopamine in nucleus accumbens ○ Look at the big chart ○ If you bring down the dopamine level, you reduce the rewarding effect → don’t do bad habit as much Ganglionic blocking drugs ● Block nicotinic cholinergic receptors in autonomic ganglia either by competitive antagonism or blockade of ion channel

● ● ●

●

Spend most of CNS These are more more selective for nicotinic receptors ? Effect of this drug on the heart ○ Whatever system is active at that time it’s the opposite effect Most organs receive dual sympathetic and parasympathetic…

Autonomic tone ● In most organ systems, both divisions exert a tonic action, holding the effectors in a state of intermediate activity ● Three possibilities ○ Opposing effects ■ “Balanced antagonism” most common ■ Eg respiratory smooth muscle, heart ○ Complimentary effects ■ Eg skeletal muscle, vasculature ○ No interaction ■ Pupillary control in eye ■ Two separate muscles ● One controlled by parasympathetic (sphincter) ● One controlled by sympathetic (radial) Predominant tone - very useful in understanding the effects of ganglionic antagonists ●

GI

PS

Cardiac

PS

Vasculature

S

Upper respiratory

S

Iris muscles

PS

● ●

Vasculature → antagonists can reduce blood pressure by vasodilation Ganglionic blockers: nicotinic cholinergic receptor antagonists ● Effects on organs with predominately sympathetic tone ○ 1- arterioles and veins ■ Cause vasodilation ○ 2- sweat glands ■ Decrease sweating ● Effects on organs with predominately parasympathetic tone ○ 1- heart ■ Tachycardia ○ 2- eye ■ Cycloplegia and pupillary dilation ○ 3- salivary glands ■ Dry mouth ○ 4- GI ■ Relaxation of intestinal muscle ■ Constipation ○ 5- bladder ■ Difficulty in emptying ● These have effects depending on what system has the dominant tone Skeletal muscle relaxants ● Block these to get skeletal muscle relaxation ● Use these for surgical purposes ● Tubocurarine is one prototype ● Depolarizing agents vs. competitive agents are different classes ● Half of succ. Is basically Ach → acts as agonist for nicotinic muscarinic receptors ○ If you activate succ. You’ll get fasciculations at first, and then eventually paralysis ○ Receptors will get desensitized ○ This overacts the receptors and makes them desensitized

Comparison of competitive relaxants ● Pharmacological blockade may be accomplished by two general mechanisms ○ Competitive nondepolarizing block (eg dtubocurarine) ○ Depolarizing block (eg succinylcholine)

● ●

●

Initial effect is transient fasciculations If you want to block the effect of these drugs, ○ Increase Ach concentration by blocking acetylcholinesterases Bc d-TC ad succinylcholine have opposite effects, … ○ If the doctor injets one of these in the patient and the patient passes out, how can you figure out which one was given? ○ Important to know which one bc one blocks the effect of the other ○ Important that when you start with one, you stick to it...