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Hemicholinium
Choline uptake inhibitor, total body effects
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Botulinum Toxin
Blocks the binding the of the vessicle (at the snaptobrevin protein). Prevents ACh release, used in blepharospam (eyelid twitch), strabismus/hyperhydrosis, dystonia, cosmetics
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AChE Inhibitors
Major mechanism of termination of postjunctional actions of ACh
only effective at innervated sites!!
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Vesamicol
blocks the vesicle full of ACh from binding
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Post-Junctional Receptor Effects (cholinergic)
N & M receptor activation (direct-acting cholinomimetics) & blocking agents
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Muscarinic Direct Agonist: ACh
Activity: M & N, +++ AChE hydrolysis, short t1/2, no clinical use
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Muscarinic Direct Agonist: Bethanicol *
- Activity: M receptor
- -AChE hydrolysis
- Rx: ileus (post op/neurogenic)
- Rx: urinary retention
- Beth Anne, call if you want your bowels & bladder to move
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Muscarinic Direct Agonist: Methacholine
- Activity: M > N receptors
- + AChE hydrolysis
- Dx: bronchial hyperreactivity (challenge test to dx asthma)
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Muscarinic Direct Agonist: Carbachol
Rx: gluacoma, pupillary contraction, release of intraocular pressure
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Muscarinic Direct Agonist: Pilocarpine
- Activity: M receptors
- - AChE hydrolysis
- Rx: glaucoma (topical eye drop), ciliary muscle contraction
- Rx: xerostomia (oral) - Sjrogens
- Piles on the sweat and tears
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Indirect - AChE Inhibitor: Edrophonium *
- Characteristics: short acting (~30s)
- Clinical use: dx of myesthenia; used to differentiate myasthenia from cholinergic crisis
- Action: increases endogenous ACh
- the drug has a 'd' in it for dx!
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Indirect - AChE Inhibitor: Physostigmine *
- Characteristics: tertiary amine, lipid soluble, enters CNS crosses BBB
- Clinical uses: glaucoma, antidote in atropine overdose
- Action: increases endogenous Ach
- phys is for eyes
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Indirect - AChE Inhibitor: Neostigmine *
- Characteristics: quaternary amines (+ve charge), no CNS entry
- Neo CNS = No CNS
- Clinical use: ileus, urinary retention, Tx (not dx) of myesthenia, reversal of depolarizating of NM block, post op reversal of neuromuscular junction
- Action: increases endogenous ACh
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Indirect- AChE Inhibitor: Pyridostigmine *
- Characteristics: quaternary amines (+ve charge) no CNS entry
- pyro- the fire stays below (out of the CNS)
- Action: increases endogenous ACh
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Indirect - AChE Inhibitor: Donepezil, Tacrine *
- Characteristics: lipid soluble (CNS entry)
- Clinical use: Alzheimer disease
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Indirect- AChE Inhibitor: Organophosphates (ie echothiophate) **
- Characteristics: lipid soluble, irreversitvle inhibitors (last a loooong time), glaucoma
- Action: increases endogenous ACh
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Insecticides: carbamates & organophosphates
(ie malathion and parathion)
- Long-acting, irreversible inhibitors
- if irreversible usually a non-competitive inhibitor
- wide use in agriculture as insecticides
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3 Fates of ACh
- 1. AChE
- 2. Autoreceptor binding
- 3. Post-synaptic receptor binding
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DUMBBELSS
- Diarrhea
- Urination
- Miosis
- Bradycardia
- Bronchoconstriction
- Lacrimation
- Salivation
- Sweating
- CNS stimulation
- WET PICTURE
- Nicotinic effects: skeletal muscle excitation followed by paralysis, CNS stimulation (which will kill you)
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Muscarinic Agonist OD management
- Atropine is the antidote
- 2-PAM/pralidoxime for regeneration of AChE
- time dependent
- 2-PAM/pralidoxime removes the phosphate from the AChE's serine hydroxyl group to allow for the AChE to function again, but if the bound AChE is around too long the complex is not reversible
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Muscarinic Antagonists: Atropine
- Characteristics: tertiary amine, enters CNS, other M blockers differ based on PK properties
- Effects:
- eye: pupil dilation, cycloplegia, decreases secretions, decreases acid secretion, decreases motility, decreases urgency in cystitis, increases body temp: rapid pulse, dry-mouth, dry flushed skin, constipation, disorientation
- sympathomimetic effects
- DRY PICTURE
- hot as a hare, dry as a bone, red as a beet, blind as a bad, mad as a hatter
- Clinical uses: antispasmotic, antisecretory, management of AChE inhibitor OD, antidiarrheal, ophthalmology (long action ~2 wks)
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Other Classes of drugs with antimuscarinic pharmacology:
- Antihistamines
- TCA
- Antipsychotics
- Quindine
- Amantadine
- Meperidine (the only opiod that doesn't cause PPP - pin point pupils)
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Muscarinic Antagonists: Tropicamide, Homatropine
opthalmologic topical agent: produces mydriasis and cycloplegia
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Muscarinic Antagonist: Iprotropium
- Characteristics: no CNS entry, no chg in mucous viscosity
- Clinical use: Asthma and COPD treatment
- I pray I can breathe soon
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Muscarinic Antagonist: Scopolamine
- Clinical use: motion sickness, sedation & short term memory block
- scopol the boat
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Muscarinic Antagonist: Benztropine, Trihexylphenidyl
- Characteristics: CNS entry (lipid soluble)
- Clinical use: Parkinsonism & acute extrapyramidal symptoms (restlessness, rapid movts and uncontrollable speech) induced by antipsychotic
- PARKinson's disease - PARK my BENZ
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Muscarinic Antagonist: Tolterodine, Oxybutynin, glycopyrrolate
- Characteristics: central actions
- Clinical use: urinary retention, reduce urgency in mild cystitis and reduce bladder spasms
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Muscarinic Antagonist: Methoscopolamine, Pirenzepine, Propantheline
Clinical use: peptic ulcer tx
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Nicotinic Receptor Antagonists: Ganglion Blocking Agents: Hexamethonium & Mecamylamine
- Clinical Use: reduces the predominant autonomic tone (whatever was winning doesn't win anymore)prevents barorecpetor reflex changes in HR
- Toxicity: severe orthostatic hypertention, blurred vision, constipation, sexual dysfunction
- put a HEX on smokers (nicotine) to help them quit smoking
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Predominant innervation
ARTERIOLES
SNS
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Predominant Innervation
VEINS
SNS
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Predominant Innervation
SWEAT GLANDS
SNS
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Predominant Innervation
HEART
PNS
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Predominant Innervation
IRIS
PNS
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Predominant Innervation
CILIARY MUSCLE
PNS
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Predominant Innervation
GI TRACT
PNS
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Predominant Innervation
BLADDER
PNS
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Predominant Innervation
SALIVARY GLANDS
PNS
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Adrenergic Presynaptic: Methyl-p-Tyrosine (met-tyrosine)
Action: blocks tyrosine hydroxylase (rate limiting step (tyrosine/Na symporter blocked)
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Adrenergic Presynaptic: Phenylzine (MAOI)
Action: blocks MAO (so that you don't degrade NEp) = increasing the mobile pool
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Adrenergic Presynaptic: Release Enhancement
- amphetamines
- enhance release of NEp from the vesicles
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Adrenergic Presynaptic: Reuptake Blockers
Cocaine, TCA, amphetamines
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Adrenergic Presynaptic: Alpha2 agonists / antagonists
Clonidine, methyl dopa
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Adrenergic Presynaptic: Reserpine
Action: blocks VMAT (prevents DA from entering the vessicle, thus preventing NEp from being formed)
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Adrenergic Presynaptic: Guanethidine/Bretylium
- Action: prevents exocytosis
- analogous to botox
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Adrenergic: Post Synaptic: Agonists/Blockers of alpha1, beta1 receptors
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4 Fates of NEp:
- 1. Binding of receptor
- 2. Binding the autoreceptor (alpha1)
- 3. Breakdown by COMT
- 4. Uptake of NEp to be degraded by MAO
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Direct Acting Sympathomimetics: General: Alpha 1 agonists
- Action: increases mean blood pressure via VC
- increase BP that may have a reflexive tachycardia
- CO may decreaseed but also off set by increased venous return
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Direct Acting Sympathomimetics: Alpha-1 Agonists: Phenylepherine
- Mechanism: alpha1 > alpha2
- Clinical use: nasal decongestant, ophthalmologic use (mydriasis w/o cycloplegia), VC
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Direct Acting Sympathomimetics: Alpha-1 Agonist: Methoxamine
Clinical use: paroxysmal atrial tachycardia thru vagal reflex
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Direct Acting Sympathomimetics: Alpha-1 Agonist: Midodrine
Clinical use: atrial/venous contraction, tx of postural hypotension
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Direct Acting Sympathomimetics: Alpha-2 Agonist: Clonidine, Methyldopa
- Mechanism: stimulate the prejunctional receptors in the CNS to decrease sympathetic outlfow
- Clinical use: mild-moderate htn, used in pregnancy htn
- See CV section
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Direct Acting Sympathomimetics: Beta Agonists: Isoproterenol
- Receptor affinity: B1 = B2 (ISOlated to B)
- Side effects: flushing, angina, arrhythmias
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Direct Acting Sympathomimetics: Beta Agonist: Dobutamine
- Receptor affinity: B1>B2, inotropic but not chronotropic
- Clinical use: shock, heart failure, cardiac stress testing
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Direct Acting Sympathomimetics: Beta2 Selective: Metaproterenol, Albuterol, Salmeterol, Terbutaline
- Receptor affinity: B2>B1
- Clinical use: MAST
- Salmeterol: LT asthma tx
- Terbutaline: reduce premature uterine cxn
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Direct Acting Sympathomimetics: Beta2: Ritodrine
Clinical use: reduces premature uterine contractions
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Direct Acting Sympathomimetics: Epinephrine
- Receptor Affinity: alpha1, alpha2 (not much effect on heart rate tracings though), beta1, beta2 (low doses are selective for B1 - BLOW)
- Dosing: low dose acts like isoproterenol, high dose acts like NEp
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Direct Acting Sympathomimetics: Norepinephrine
- Receptor Affinity: alpha1, alpha2 >B1
- Clinical Use: hypotension (but decreases renal perfusion)
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Epinephrine Reversal
- if you give an Alpha1 blocker it unmasks Beta1 activity
- differentiation btw Ep and NEp:
- Alpha blocker w/ Ep --> hypotension (unmasked Beta2)
- Alpha blocker w/ Nep --> normotension after (bc there is no Beta2 activity)
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Indirect Sympathomimetics: Tyramine
- Characteristics: displaces NEp from mobile pool, red wine and cheese, bioavailability limited by MAO-A metabolism in gut/liver
- Side effects: MAO-A inhibition increases bioavailability and hypertensive crisis
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Indirect Sympathomimetics: Amphetamines
- Mechanism: releases stored catecholamines, psychostimulant due to central release of Da, NEp, 5HT
- Clinical uses: Narcolepsy, obesity, ADD (particularly methyl phenidate)
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Indirect Symphatomimetics: Ephedrine
- Mechanism: releases stored catecholamines
- Clinical uses: nasal decongestant, urinary incontinence, hypotension
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Indirect Sympathomimetics: Cocaine
- Mechanism: uptake inhibitor
- Clinical uses: VC, local anesthesia
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Non Selective Alpha Receptor Antagonists:
Phentolamine (competitive inhibitor) Phenoxybenzamine (noncompetitive)
- Characteristics: decrease TPR, decrease MAP, may cause reflexive tachy, Na and water retention
- Clinical uses: htn, pheochromocytoma (nonselective alpha blocker)
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Selective Alpha1 Receptor Antagonists: Prazosin, doxazosin, terazosin, tamsulosin
Clinical use: hypertension, urinary retention BPH, nephrolithiasis management, dizziness, headache
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Selective Alpha2 Receptor Antagonists: Mitrazapine
- Clinical uses: antidepressant
- Toxicity: sedation, increase serum cholsterol, increased appetite
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Beta-Blockers:
Selectivity
- A--> M (B1 blocker)
- N--> Z (non selective B blocker)
- Nonselective alpha/beta blockers: carvedilol, labetalol
- Partial B-Agonists: Pindolol, Acebutolol
- Beta1 Cardioselectivity: less effect on vasculature, bronchioles, uterus, metabolism, safer in asthma, DM, PVD
- Intrinsic sympathomimetic activity: partial agonists, less bradycardia (B1), slight VD or bronchodilation (B2), minimal chg in plasma lipids (B2)
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Beta Blockers: Clinical Use
- General uses: angina, htn, post MI (all B-blockers)
- Antiarrhythmics: class II: propranolol, acebutolol, esmolol)
- Htn
- Angina pectoris
- MI: decreases mortality
- SVT (propranolol, esmolol): decreases AV conduction velocity
- CHF: slows progression
- Glaucoma: decreases aqueous humour production
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Beta Blockers: Toxicity
- Impotence
- exacerbation of asthma
- CV adverse effects ( bradycardia, AV block, CHF)
- CNS adverse effects (sedation, sleep alterations)
- May mask hypoglycemic sxs if used in diabetics
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Antiarrhythmic Beta Blockers
Class II: propranolol, acebutolol, esmolol
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Closed Angle Glaucoma Tx: Beta Blocker: Timolol
- Clinical use: glaucoma
- Mechanism: blocks actions of NE at the ciliary epithielium and decreases aqueous humour formation
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Beta Blockers with combined alpha1 and Beta effects
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Beta Blockers with K channel blockade
- Sotalol
- Clinical use: antiarrhythmic (class III)
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Closed Angle Glaucoma Tx: Pilocarpine, Echothiophate
- Drug class: cholinomimetic
- Mechanism of action: Activation of M receptors caues contraction of ciliary muscle that increases flow thru the canal of Schlemm, also an AChE inhibitor
- Note: echothiophate is an organophosphate
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Closed Angle Glaucoma Tx: Acetazolamide
- Drug class: Carbonic Anhydrase Inhibitor
- Mechanism of action: decrease aqueous humour production
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Closed Angle Glaucoma Tx: Mannitol
- Drug class: Osmotic forces
- Mechanism of action: increases outflow of aqueous humour
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"Do not fear, for I am with you; do not anxiously look about you, for I am your God. I will strengthen you, surely I will help you, surely I will uphold you with My righteous right hand." Isaiah 41:10
:)
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Glaucoma Drugs: Alpha Agonists: EP
- Mechanism: decreases aqueous humour synthesis due to VC
- Side effects: mydriasis, stinging, do not use in closed angle glaucoma
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Glaucoma Drugs: Alpha Agonist: Brimonidine
- Mechanism: decreases aqueous humour synthesis
- Side effects: no pupillary or vision changes
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Glaucoma Drugs: Beta-Blocker: Timolol, Betaxolol, carteolol
- Mechanism: decreases aqueous humour production
- Side effects: no pupillary or vision changes
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Glaucoma Drugs: Diuretics: Acetazolamide
- Mechanism: decreases aqueous humour secretion due to less bicarb (via inhibition of CA)
- Side effects: no pupillary or vision changes
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Glaucoma Drugs: Cholinomimetics: Direct (pilocarpine, carbachol), Indirect (phosphostigmine, echothiophate)
- Mechanism: increases outflow of aqueous humour, conract ciliary muscle and opens trabecular meshwork; use pilopcarpin in emergencies; very effective at opening the meshwork into the canal of Schlemm
- Side effects: miosis, cyclospasm (contraction of ciliary muscle during accomodation)
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Glaucoma Drugs: Prostaglandins: Latanoprost (PGF2alpha)
- Mechanism: increases outflow of aqueous humour
- Side effects: darkens colour of iris (browning)
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