physio-cholinergic and adrenergic drugs

• anaerobic bacillus clostridium tetani--> invades into interneuron by retrograde 
• enters the PNS by cut or wound and passes to CNS by retrograde

• causes inhibition of Glycine trasmitter by breaking down synaptobrevin (so vesicle release) 
• yielding to hyperreflexia,hypertonia in both flexor and extensor muscles (antagonist and agonist muscles)

• plant alkoid strychnine blocks some glycine receptors in the CNS
• similar effect as tetanus toxin

• inhibit exocytosis of Ach vesciles at presyaptic cleft.
• -degrades SNAREs (synaptobrevin) necessary for exocytosis-causes muscle weakness, decrease in sweat (hyperhidrosis), cardiac arrhythmia (irregular heart beat)
• -double vision, difficulty in swallowing, dry mouth, and difficulty in speaking
• -could be related to eaton-lambert syndrome
• -Treatment: AchE inhibitors (physostigmine)

-could be used for reduction of saliva production in parkinson's disease, spasticity hemifacial spasm, neirological conditions

• -Ache Inhibitors -short acting (2-10 min) 
• -inhibit by binding to the enzyme's active site
• -rapid onset 
• -useful for diagnosis of muscle weakness (Myathsthenia Gravis and Eaton-Lambert syndrome)
• hydroxyl group

• -AcheE inhibitor 
• chronic treatment of Myasthenia Gravis 
• longer acting 
• direct cholineric agonist affect on Nm receptors
• reversible 
• carbamic

• AchE inhibitor 
• long lasting 
• non-polar moleculem so able to cross BBB --> could for CNS anticholinergic toxicity 
• used as treatment for Eaton-lambert syndrome

• autoimmune disease
• antibody binds to Ca2+ channels, thus cannot release Ach vesicles 
• treat by increasing half life of Ach by inhibiting AchE. ie. physostigmine

• -autoimmune disease 
• antibodies blocking ach receptors. (Nm at NMJ)
• treat with AchE inhibitors ie. neostigmine

• AchE inhibitor 
• irreversible-hydrolyze and make stable complex
• toxic 
• used in pesticides 
• only new receptors can facilitate AchR activity but could take weeks

• nicotinic agonist 
• blocker depolarizer 
• keeps binding to Nm junction Ach receptors.
• desensitize over time 
• works as agonist, but gives antagonist effect 
• causes respiratory depression, Bradyarryhthmia, prolonged paralysis
• could be used as muscle relaxation during anesthesia and surgery

• Nicotinic receptor antagnoist 
• reversible 
• paralyze skeletal muscles during surgery
• more selective towards Nm receptor than Nn.
• Long acting 
• side effect: hypertension, apnea, bronchospasm,

• muscuranic receptor agonist
• weak base (alkoid),
• used for treatment of drymouth (xerostomia) in sjogren's syndrome
• treatment for glaucoma

muscuranic agonist 

• 3X more resistant to AchE 
• selective for cardiovascular muscranic receptors. (M3)

• -treatment for post-operative, post-partum
• -increase GI contractility 
• -urinary tract motility and retention 
• completely selective for muscuranic receptors

• muscuranic antagonist
• used for eye exam to dilate pupil
• side effect: tachycardia, decrease secretion of salivary, bronchial, GIT 
• competitive antagonist

• prevents choline reuptake at presynaptic
• (choline-Na cotransport : rate limiting step)

prevents storage of Ach (inhibit Ach-H+ antiport)

• -alpha 1 agonist 
• -increase vasoconstriction
• -nasodecnogenstion, opthalmic hyperemia *visine), treatment of shock 
• SE: hypertension

• interferes with exocytosis to promote massive release and depltion of Ach.
• promotes fusion of synaptotagmin and neurexin --> massive release fast  
• initial surge of Ach release and irreversible failure of release Ach.
• contraction then followed by paralysis
• Black widow spider venom
• at NMJ

• act as an agonist 
• binds to NMJ
• are insenstitive to AchE, thus undergo prolonged binding and could lead to desensitizing the Ach receptors
• along with nicotine and succinylcholine, cannot get degraded by AchE

• cholinergic inhibitor
• irreversibly binds to calcium channel 
• inhibit release of Ach vesicles at the nerve terminal (NMJ)
• leads to flaccid paralysis 
• snail toxin

• binds to Ach recetor (competitive reversible) 
• blocks impulse conduction and could lead to flaccid paralysis.
• at NMJ
• curare can be used as muscle relaxation during anesthesia and surgery

• effective Ach antagonist --> synapse in sympathetic ganglia 
• used as treatment for high blood pressure by ganglionic blocking drugs

binds irreversibly ot actin and possibly other cytoskeletal components in cholinergic nerve endings and block Ach release

• -inhibit K+channel and prolongs duration of impulses invading the nerve terminal.  
• Prolonging depolarization of synaptic coutons enhances entry of Ca ions and thus release of Ach
• used as treatment for lambert-Eaton syndrome
• causes increase in Ach release

• inhibit Ca channel at presynaptic cleft
• no Ach exocytosis
• can also block AchR at postsynaptic cleft
• reversible; thus able to outcompete by increasing Ca concentration 
• used as Aminoglycoside antibiotics

• anti-anxiety drug
• binds to gamma 2 subunits and alpa subunits on GABA(a) receptor (ionotropic) 
• This causes allosteric change in binding sites, which enhances the binding of GABA too the receptors. 
• The action will increase inhibition in the amygdala, where the development of fear and anxiety takes place.

• substance P is released from DRG neurons (nociceptors) 
• substance P = tachykinin 
• mediates damage and pain sensation 
• capsaicin -->1) suppress pain by desensitizing vanilloid receptors or 2) suppress "death" primary afferent neurons from spinal cord to decrease release of substance P

• beta-endorphins
• Enkephalins 
• Dynorphins 
• they dont cross BBB 
• mechanism: enkephalin exerts presynaptic inhibition at the synpases of nociceptors on projection neuron (DRG neurons)

• block hallucinations (including L-dopa-induced hallucinations) and delusion 
• good for treatment of schizophrenia, parkinsno's disease, and huntington's chorea
• ie. neuroleptics

• dopamine receptor agonist 
• effective in alleviating the signs of parkinson's disease

• -blocks Na voltage gated channel at extracellular site;  presynaptic axons of  NMJ
• -causes flaccid paralysis
• found in pufferfish since they digest bacteria that synthesize TTX storing poison in tissue. 

-for saxitoxin, found in shellfish

• alpha 1 and alpha 2 agonist 
• treat nasal congestion, opthalmic hypermia 
• alpha 1 is partial and alpha 2 is full agonist 
• SE: hypertension

• alpha 2 antagonist 
• treat male impotence,
• SE: increase in sympathetic outflow, hypertension

• Alpha 2 agonist 
• treat hypertension and opioid withdrawal, cancer pain 
• SE: brachycardia, hypotension

• Alpha 1 antagonist
• treatment for hyperplasia
• genitourinary smooth m. type
• SE:  less postual orthostatic due to low BP

• alpha 1 & alpha 2 antagonist 
• non-selective and irreversible 
• treat pheochromocytomoa 
• increase in VMA, NE and Epi, 
• Hypertension and sweating

• AchE inhibitor 
• can cross BBB 
• used as treatment for Alzheimer's disease, dementia, cognitive disease
• reversible

• Tyramine, which displaces NE in stored vesicle, are found in wine and cheese 
• when a patient who is on MAO inhibitor drug consumes cheese or wine, you will have increase NE concentration at the synpase 
• causes high BP and HR, throbbing headache, nausea

• inhibit MAO --> reduced NE degradation, increase NE at synapse
• used as depression treatment 
• MAO degrades seratonine, dopamine, NE, epi
• irreversible and nonselective

• inhibit NET --> no reuptake of NE
• used as treatment for depression 
• increases NE at synaptic cleft

• mu-enkephaline 
• analgesic effects 
• binds to c-fibers from nociceptive (pain) at substatia geltinosa 
• (descending tract) 

• 1. nociceptors -->decrease excitability of peripheral sensory neurons 
• 2. spinal cord --> binds to mu receptor on presynaptic of secondary neuron (inhibit release of glutamate) and post synaptic of primary afferent neuron (hyperpolarize).
• 3.  supraspinal : activates GABA at periaquaductal gray --> descend down to raphe nucleus in pons, activate to release NE or seratonin (5-HT) 
• 4. euphoric effect on limbic lobe

• inhibit reuptake of NE by blocking NET 
• increases NE at synaptic cleft,
• blocks not only NE but also uptake of Dopamine, seratonine (5-HT)  
• also blocks Sodium channel from inside

• inhibits storage of catecholamine
• increase in NE activity at B and Alpha receptors
• banned in the U.S. 
• uses up NE more so less storage 
• catecholamines are stored via VMAT in vesicles

• -non selective B and alpha 1 antagonist
• -B1 blockade: decrease in HR
• -alpha1 blockade: vasodilation 
• -decrease BP by lowering renin level and vasodilation

• non selective B antagosnit 
• treatment for hypertension and angioa 
• SE: worse sedation and dyspnea

• B2 antagonist 
• experiemental, no clinical use

• selective B1 antagosnit 
• treats hypertension, angia (severe pain in chest) 
• decrease BP by lowering renin level 
• SE: sadation, dyspnea

• partial B1 agonist = weak antagonist 
• treat bradycardia, low cardiac output
• helps to treat hypertension 
• used for hypertension with patients with bradycardia or low cardiac output
• smaller effects in increasing BP and HR or leads to smaller decrease in BP and HR

• B2 agonist 
• longer duration (12-24 hrs) of asthma reliever due to lipophilic feature 
• used to prevent bronchoconstriction

• asthma reliever 
• rapid action (15min), short duration (4-6 hrs)
• B2 agonist 
• avoid cardiac and skeletal side effect

• selective B1 agonist 
• increase contractility, cardiac output, but NOT heart rate 
• short half life due to COMT metabolism
• used for acute management of heart failure

• non selective beta agonist 
• increase in contractility (b1) 
• relaxation, bronchodilation (b2) 
• emergency arrythmias, bronchospasm

• non selective alpha antagonist 
• prevents vasoconstriction and decrease blood pressure 
• reversible 
• treat pheochromocytoma

• Catechol amine inhibitor 
• 1) blocks NET
• 2) weak inhibitor of MAO
• 3) displaces stored endogenous Ca from vesicles

• alpha 1 antagonist
• treat hypertension and benign prostatic hyperplasia 
• SE: postural orthostatic, hypotension via 1st dose phenomena