Pharmacology Flashcards
G-Protein α-Subunit Gs β-adrenoceptors; Histamine H2 receptors; Serotonin 5-HT4 receptors; Glucagon
↑adenylyl cyclase activity leading to ↑ levels of cyclic AMP
Gi1, Gi2,Gi3 α2-adrenoceptors; Muscarinic cholinergic M2 and M4; Serotonin 5-HT1; Opioids, cannbinoid
↓ adenylyl cyclase activity leading to ↓ levels of cyclic AMP; Open potassium channels
Gq Muscarinic cholinergic M1, M3 and M5; Serotonin 5-HT2; α1-adrenoceptors;
↑ phospholipase C activity leading to ↑ levels of IP3 and diacylglycerol that increase intracellular Ca2+
Target for GPCRs
Adenylyl cyclase, the enz responsible for Camp phospholipase C, the enzyme responsible for inositol phosphate and diacylglycerol (DAG) formation ion channels, particularly calcium and potassium channels
Therapeutic Uses of Direct-Acting Cholinergic Receptor Agonists Bethanechol
Postoperative ileus
Congenital megacolon
Urinary retention
Therapeutic Uses of Direct-Acting Cholinergic Receptor Agonists
Pilocarpine, Carbachol
Glaucoma
Edrophonium (Tensilon®)
, Tacrine (Cognex®),
Donepezil (Aricept®)
Galantamine (Reminyl®)
Indirect Acting Cholinomimetic Drugs:
Inhibitors of Acetylcholinesterase
Competitive Inhibitors
Reversible
Compete for ACh binding at the anionic site
Contains no ester linkage so that it is not hydrolyzed
Inhibition is rapidly reversible (increase Ach conc. will reverse their effect) DOA is not very long Tacrine discontinued due liver damage
Physostigmine,Rivastigmine (cross BBB)
Pyridostigmine, Neostigmine, (NOT CORSS BBB)
and Carbaryl, Propoxur and Aldicarb
Carbamate Inhibitors (garden products)
Reversible
They interact with 2 sites of the enzyme, the anionic site and they actually add carbamyl group to it.
Carbamyl ester linkage hydrolyzed to carbamylate enzyme Carbamyl moiety is slowly released - leads to long-lasting but reversible inhibition
Physostigmine and Rivastigmine are CNS permeable and used in treating Alzheimer’s disease
DFP (Isoflurophate); Echothiophate, (The only one therapeutically useful) Parathion, Tabun (GA), Sarin (GB), Soman (GF), VX (10x more potent than G-series)
Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
Parathion,
Indirect Acting Cholinomimetic Drugs: Inhibitors of Acetylcholinesterase Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
Tabun (GA)
Indirect Acting Cholinomimetic Drugs: Inhibitors of Acetylcholinesterase Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
Sarin (GB),
Indirect Acting Cholinomimetic Drugs: Inhibitors of Acetylcholinesterase Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
Soman (GF)
Indirect Acting Cholinomimetic Drugs: Inhibitors of Acetylcholinesterase Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
VX (10x more potent than G-series)
Indirect Acting Cholinomimetic Drugs: Inhibitors of Acetylcholinesterase Irreversible Inhibitors Used as insecticides and nerve gases Good CNS penetration (highly lipid soluble) Covalently phosphorylate the esteratic site of the enzyme (They phosphrylate that ser and the phosphrylation takes long time, good fortune) Phosphorylation is generally irreversible and enzyme must either be resynthesized or chemically reactivated by pralidoxime (2-PAM
Carbaryl
Carbamate Inhibitors (garden products) Reversible They interact with 2 sites of the enzyme, the anionic site and they actually add carbamyl group to it. Carbamyl ester linkage hydrolyzed to carbamylate enzyme Carbamyl moiety is slowly released - leads to long-lasting but reversible inhibition Physostigmine and Rivastigmine are CNS permeable and used in treating Alzheimer’s disease
Propoxur
Carbamate Inhibitors (garden products) Reversible They interact with 2 sites of the enzyme, the anionic site and they actually add carbamyl group to it. Carbamyl ester linkage hydrolyzed to carbamylate enzyme Carbamyl moiety is slowly released - leads to long-lasting but reversible inhibition Physostigmine and Rivastigmine are CNS permeable and used in treating Alzheimer’s disease
Aldicarb
Carbamate Inhibitors (garden products) Reversible They interact with 2 sites of the enzyme, the anionic site and they actually add carbamyl group to it. Carbamyl ester linkage hydrolyzed to carbamylate enzyme Carbamyl moiety is slowly released - leads to long-lasting but reversible inhibition Physostigmine and Rivastigmine are CNS permeable and used in treating Alzheimer’s disease
Organ System Effects of Cholinesterase Inhibition Cardiovascular
Bradycardia Decreased Cardiac Output (CO) Hypotension (modest except in toxic doses
Organ System Effects of Cholinesterase Inhibition Respiratory System
Bronchoconstriction Increased secretion (copious) Paralysis of diaphragm
Organ System Effects of Cholinesterase Inhibition GI Tract
Increased tone Increased motility Increased secretions
Organ System Effects of Cholinesterase Inhibition Skin
Increased sweating
Organ System Effects of Cholinesterase Inhibition Eye
Miosis Near accommodation
Organ System Effects of Cholinesterase Inhibition Central Nervous System
Tremor Anxiety Confusion Convulsions Coma
Therapeutic Uses of Cholinesterase Inhibitors
Glaucoma Postoperative ileus, congenital megacolon, urinary retention Diagnosis and Treatment of Myasthenia Gravis Surmounting effects of competitive neuromuscular blocking agents Treatment of Alzheimer’s disease (increasing adverse cardiovascular events!!!) Treatment of Atropine poisoning (and al types of anticholinergic poisoning)
Diagnosis and Treatment of Myasthenia Gravis
Therapeutic Uses of Cholinesterase Inhibitors
Postoperative ileus, congenital megacolon, urinary retention
Therapeutic Uses of Cholinesterase Inhibitors
Glaucoma
Therapeutic Uses of Cholinesterase Inhibitors
Surmounting effects of competitive neuromuscular blocking agents
Therapeutic Uses of Cholinesterase Inhibitors
Treatment of Alzheimer’s disease (increasing adverse cardiovascular events!!!)
Therapeutic Uses of Cholinesterase Inhibitors
Treatment of Atropine poisoning (and al types of anticholinergic poisoning)
Therapeutic Uses of Cholinesterase Inhibitors
Treatment of Cholinesterase Inhibitor Poisoning
Contains: 1) Atropine to block M R effect 2) 2PAM becasue of the organophophate exposure, so 2PAM reactiviate the enzyme. Pralidoxime (2-PAM) for reactivation of enzyme (oxime group has high affinity for phosphorus) and is effective at the neuromuscular junction It does not take care for the N side so the paralysis of diaphragm and the CNS effects are problematic and need supportive therapy
Methacholine
Therapeutic use if Direct-Acting cholinergic receptor agonist Bronchial Reactivity
Hexamethonium
Nondepolarizing Ganglionic Blocking Agent Noncompetitive antagonist of the NN receptor (allosteric antagonism) Not used therapeutically but experimentally. Blocks the open state of the ion channel
Trimethaphan
Nondepolarizing Ganglionic Blocking Agent Competitive Antagonist of the Nn receptor Used therapeutically
Mecamylamine
Nondepolarizing Ganglionic Blocking Agent Competitive Antagonist of the Nn receptor Used therapeutically
Nicotine
Depolarizing Ganglionic Blocking Agents Agonist at NN receptors (low concentrations) Stimulates release of catecholamines from the adrenal medulla Stimulates baroreceptors leading to vasoconstriction and tachycardia Higher concentrations lead to ganglionic blockade that proceeds through two distinct phases
Characteristics of Neuromuscular Blocking Drugs
Agents do not produce analgesia or anesthesia Most are poorly absorbed (quaternary ammonium compounds) and do not cross BBB Usually administered intravenously
d-Tubocurare; pancuronium, vecuronium, rapacuronium, rocuronium; and cisatracurium, atracurium, and mivacurium
Non-depolarizing Neuromuscular Blocking Drugs Competitive inhibition of ACh binding at the nAChR (NM) receptor (Stabilizing blockade) Rapidly developing muscle weakness followed by flaccid paralysis Curare is least selective among the agents as it also produces some ganglionic blockade and induces histamine release but no longer available in US (historical significance See notes
Succinylcholine
Nicotine?
Depolarizing Neuromuscular Blocking Drugs
Inhibition of activation of the NM receptor similar to the blockade of NN receptor (Desensitization)
Muscle fasciculations (initial depolarization followed by increasing weakness leading to flaccid paralysis)
Desensitization occurs when end-plate is repolarized but not able to be activated by agonists
Blockade of initial part of phase II desensitization will not be reversed by cholinesterase inhibitors
Therapeutic Uses of Neuromuscular Blocking Agents
Relax skeletal muscle during surgery Permit reduction in
anesthetic dose Assist with orthopedic procedures
Facilitate procedures involving skeletal muscle (e.g. intubation, laryngoscopy, endoscopy, ECT)
Comparison of Characteristics of Long Acting Isoquinolines with other NM Blocking Agents
**Drug cuases Prolonged apnea **
•Adverse Effects Associated with Neuromuscular Blocking Agents
Succinylcholine
Adverse Effects Associated with Neuromuscular Blocking Agents
- Prolonged apnea (Succinylcholine)
- Increased intraocular pressure, increased intragastric pressure, hyperkalemia (can produce cardiac arrest)
- Muscle pain
- Malignant Hyperthermia (combination of inhalational anesthetic/depolarizing agent)
Effects of Cholinergic Receptor Stimulation:
Muscarinic Receptors
Wet and Wild (Mostly GI)
- Nausea, belching, vomiting, cramps and defecation
- Urination
- Salivation, increased sweating
- Bronchoconstriction, increased mucociliary secretion
- Increased lacrimation, rhinorrhea
Effects of Cholinergic Receptor Stimulation:
Muscarinic Receptors
Cardiovascular System (M2, M3)
•Decreased heart rate and rate of conduction
Effects of Cholinergic Receptor Stimulation:
Muscarinic Receptors
Eye (M3)
- Contraction of iris sphincter (miosis)
- Contraction of ciliary muscle (accommodation)
Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
Central Nervous System (mainly scopolamine)
•Low Dose
–Drowsiness
–Amnesia
•Dreamless sleep
•High Dose (Jimson weed, Devil’s breath, burundanga, Borrachero tree):
–Excitement
–Confusion/disorientation
–Hallucinations
–Coma
–Loss of intention
Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
Eye
–Pupillary dilation (mydriasis)
–Paralysis of accommodation (cycloplegia)
–Increased intraocular pressure
Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
•Cardiovascular System
–Tachycardia
–Antagonizes vasodilation and hypotension produced by choline esters
Comparison of Muscarinic Receptor Blockade versus Occupancy
The effect with increase dose of Atropine. The effect does mimick the R occupancy except for early stages. The best guess is its interacting with presynaptic M2 R
Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
•Respiratory System
–Bronchodilation
–Inhibits secretion and reduces mucociliary clearance
–Complete blockade of salivary secretion
•Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
•GI and Urinary Tract
–Inhibition of GI tone and peristalsis
–Inhibition of gastric acid secretion
–Urinary retention
- Organ System Effects of Muscarinic Cholinergic Receptor Antagonism
- Skin
–Inhibits sweating
Relative Sensitivity to Muscarinic Cholinergic Receptor Blockade
Atropine, the protypuical antimuscranic agent.
Increase in Atropine’s dose measures 4 outcomes:
decrease in salivation
decrease in micturition
decrease in accomodation
increase in H.R
To which activity does Atropine has the greater potency?
Dry mouth is the hallmark side effect for Atropine.
(decrease in salivation)
Ipratropium (Atrovent®)
Synthetic Muscarinic Antagonists
Interesting drug. It is a solution that you inhaled
Tiotropium (Spiriva®)
Synthetic Muscarinic Antagonists
4° amines
It is inhaled powder. Why? Because these agents are 4° amines that are not soluble in water. So they use a solvent contains soya lecithin.
contraindicated in patients hypersensitive to soya lecithin or other food products (soy bean or peanuts) and used with caution in patients with prostatic hypertrophy
•Tolteridine
•Oxybutynin
•Trospium
Darifenacin
Prototypical Synthetic Muscarinic Antagonists
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
Tolteridine (Detrol®) and Fesoterodine (Toviaz®), Oxybutynin (Ditropan®, Oxytrol®, Gelnique®), Trospium (Spasmex®), Flavoxate (Urispas®), Darifenacin (Enablex®) and Solifenacin (VESIcare®)
•Synthetic Muscarinic Antagonists
Used to treat overactive bladder
•Solifenacin
Synthetic Muscarinic Antagonists
Used to treat overactive bladder
being most selective for M3 R
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
Solifenacin, Darifenacin and Oxybutynin are somewhat selective for M3 receptors with Darifenacin being most selective
Synthetic Muscarinic Antagonists
are somewhat selective for M3 receptors with Darifenacin being most selective (selective but not specific)
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Tolteridine
•Synthetic Muscarinic Antagonists
Used to treat overactive bladder
Appear lest selective for M3R
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
extended durations of action (daily dosing)
•Fesoterodine
Synthetic Muscarinic Antagonists
Used to treat overactive bladder
appear less selective M3
extended durations of action (daily dosing)
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Oxybutynin
•Synthetic Muscarinic Antagonists
•Used to treat overactive bladder
somewhat selective for M3 receptors
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Trospium
•Synthetic Muscarinic Antagonists
Used to treat overactive bladder
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Darifenacin
•Synthetic Muscarinic Antagonists
•Used to treat overactive bladder
•Darifenacin being most selective
for M3 receptors
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Flavoxate
•Synthetic Muscarinic Antagonists
Used to treat overactive bladder
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
•Solifenacin
- Synthetic Muscarinic Antagonists
- somewhat selective for M3 receptors
Caution for most of the agents when used concomitantly with CYP3A4 inhibitors
Homatropine
Synthetic Muscarinic Antagonists
–Short acting analogue of atropine
–Used to produce brief mydriasis and cycloplegia
–Combined with hydrocodone as Hycodan® for use as an antitussive
Duration 1-3 days
•Cyclopentolate (Cyclogyl®)
•Synthetic Muscarinic Antagonists
–Ultra short acting agents for ophthalmological examination
–Short-lived mydriasis and cycloplegia
Duration 1 day
Tropicamide (Mydriacyl Ophthalmic®)
•Synthetic Muscarinic Antagonists
–Ultra short acting agents for ophthalmological examination
–Short-lived mydriasis and cycloplegia
Duration 0.25 days
•Therapeutic Uses of Muscarinic Cholinergic Receptor Antagonists
Prevent motion sickness (Scopolamine) – transdermal patches
Produce sedation, amnesia and tranquilization (hallucinogenic properties exploited as well)
Produce mydriasis and cycloplegia
Inhibit salivation and respiratory tract secretions (e.g. hyperhidrosis or prior to and during surgery)
Treatment of asthma and COPD
Treatment of cholinomimetic poisoning (especially bradycardia and hypotension)
Why anitmascarnic agents are C/I with patients with narrow angle glaucoma?
Because these agents dilate the pupil, so they move the iris away from the angle of the eye. So in patient who has narrow angle glaucoma, that angle is already compressed. Now if dilate the iris with these agents, you will block the out flow facility of the eye preventing fluid from passing.
How to overcome the anitmascarnic blocking effects?
With Anitacytlcholinesterase inhibitor to increase the level of Ach in the synaptic cleft
