DIRECT Muscarinic agonist

• Actions: stim muscarinic R's-->
  • Increased intestinal motility
  • Empty bladder
• Applications:
  
  • postpartum post-op bladder MT,
  • GI disorders: atony, megacolon
  • Zerostomia:  ↑ salivation
• Adverse:
  
  • Sweat, salivate, flush, ↓BP, nausea, abdominal pain, diarrhea, bronchospasm

DIRECT MUSC AND NIC AGONIST

• ACTIONS
  • musc AND nic agonist, no Ace bkdn, 1 hr action
  • Stim then depresses CV, GI (stim's adrenal)-->epi
  • meisois + contracts ciliary muscle (near vision)
• APPLICATIONS
  • rarely use: non-specific and long-acting
  • Glaucoma: meiosis and ↓intraocular pressure
• ADVERSE
  • none when used opthalmically

Pilocarpine

DIRECT MUSCARINIC AGONIST

Tertiamy amine, stable wrt. Ace, mostly muscarinic

• ACTIONS
  • rapid meiosis and corneasl musc. contraction (opposite of atropine)
  • Very Potent stim of secretions (sweat, tears,saliva):  but non-selective
• USE
  • drug of chioce in BOTH narrow adn wide angle glaucoma: opens trabecular meshwork around Schlemm
• ADVERSE
  • can enter CNS and disturb. 
  • Profuse sweat, salivation

Acetylcholine

DIRECT CHOLINERGIC AGONIST

QAC:  can't penetratemmbranes

No theraputic importance d/t

1. multipliciity of actions(both musc and nic.)

     > stim ganglia

     > secrete epinephrine from adrenal medulla

     > Stimulation of voluntary muscle

2. Rapid inactivation by Ace

Methacholine

DIRECT CHOLINERGIC AGONIST

• Predominantly Musc agonist
• USE:
  • Bronchial hyperreactivity and asthma
  • Xerostomia

Muscarine

Alkaloids

DIRECT CHOLINERGIC AGONIST

• MUSCARINE:  musc agonist
• ARECOLINE: musc AND nic agonist
• PILOCARPINE: mainly muscarinic (see card)

NICOTINE

DIRECT CHOLINERGIC AGONIST

Affects NMJ in [] only slightly > than those for ganglia

• SIMULTANEOUS SYMP AND PSYMP STIM
• Low-dose: ganglionic stimulation via depolarization
• High-dose: ganglionic and Neuromuscular blockade

• CV:  symp........↑HR, F:  d/t adrenal release of epi
• GI, urinary.......N/V, diarrhea, voiding urine
• Secretions......../stun salivary and bronchial secre.

NICOTINE

Poisoning and uses

DIRECT CHOLINERGIC AGONIST

• SX of poisoning
  
  • sweat, N/V, salivation, abdominal pain
  • mental confusion, weakness
  • ↓BP , weak pulse
  • DEATH from paralysis of resp muscles or central resp. failure
• USES
  • Nicotine patch to stop smoking

TETRAMETHYLAMONIUM (TMA)

and

DIMETHYLPHENYL PIPERAZINIUM (DMPP)

DIRECT CHOLINERGIC AGONIST

Stimulation of Ganglion

NOT followed by blockade

EXPERIMENTAL USE ONLY

VARENICLINE

• DIRECT NICOTINIC AGONIST

• Partial agonist @ neuronal NICOTINIC receptors
• Smoking cessation
• "Chantix"

ENDROPHONIUM

AchE INHIBITOR

• QAC
• USE
  • Myasthenia Gravis DIAGNOSIS: rapid, short
  • Following surgery: reverse NM block from non-depol blockers

Physostigmine

AchE INHIBITOR

• Intestinal and bladder atony
• Glaucoma
• OD of anticholinergic drugs:  DO NOT GIVE TO TCA OD: CAN AGGRAVATE CARDIAC DEPRESSION

NEOSTIGMINE

AchE INHIBITOR

• Stimulate bladder and GI
• Antidote for competitive NMJ blockers
• Symptomatic Tx of MYASTHENIA GRAVIS

PYRIDOSTIGMINE

AchE INHIBITOR

• Myasthenia gravis
• MOST COMMONLY USED AchE inhibitor for MG

ECHOTHIOPHATE

AchE INHIBITOR

• ORGANOPHOSPHATE
• Used for glaucoma

MALATHION

PARATHION

AchE INHIBITOR

INSECTISIDES

TACRINE

DONEPEZIL

RIVASTIGMINE

GALANTAMINE

AchE INHIBITOR

• Alzheimer's

PRALIDOXIME

• AchE INHIBITOR
• Splits the phosphorus-enzyme bond if not aged

TABUN

SARIN

SOMAN

AchE INHIBITOR

War gasses

potent synthetic agens

Tx with atroping (competitive) + pralidoxime

ATROPINE

MUSCARINIC RECEPTOR ANTAGONIST

Prototype M receptor antagonist

Belladona (with Scopolamine)

• Binds completely to muscarinic receptors
• Tertiary amine: lipophillic--> PNS and CNS
  • Eye: mydriasis, cycloplegia
  • GI ↓ motility
  • Urinary: ↓ hypermotility of bladder
  • CV: low dose: brady d/t Ach receptors that limit Ach release IN SINUS NODE
  • CV: hi dose: block M2: tachy
  • Secretions: sweat,drool blocked may --> HT

ATROPINE

MUSCARINIC ANTAGONIST

• USES
  • mydriasis, cycloplegia
  • Antispasmodic for GI and bladder
  • Antidote for cholinergic agonists
  • Antidote for muscarine poison
  • Block resp. secretions prior to surge
• ADVERSE
  • dry mouth, eyes, tachy, constipation, blurr vision
  • CNS: restless, confusion, halluc., delerium, depression, collapse of circulatory and resp syst.
  • death

SCOPOLAMINE

MUSCARINIC ANTAGONIST

Belladonna alkaloid

• Prevention of motion sickness
• Block short-term memory during surge

IPRATROPIUM

TIOTROPIUM

MUSCARINIC ANTAGONIST

synthetic

• Asthma and COPD
• Tiotropium only for COPD

HOMATROPINE

CCLOPENTOLATE

TROPICAMIDE

MUSCARINIC ANTAGONISTS

Tertiary Amine, synthetic

• m;ydriasis
• Pref. to atropine because of SHORT DURATION (2-3h)
• Tropicamide most popular

BENZOTROPINE

TRIHEXYPHENLDYL

MUSCARINIC ANTAGONISTS

synthetic tertiary amines

• Parkinsonism
• extrapyramidal efects of antipsychotic drugs

GLYCOPYRROLATE

ANTIMUSCARINIC

• ORALLY to inhibit GI motility
• Paraenterally to prevent badycardia dg. surgery

TOLTERODINE

ANTIMUSCARINIC

• overactive bladder

Name 2 contraindications of

ANTIMUSCARINIC AGENTS

1. ANGLE CLOSURE GLAUCOMA
2. PROSTATIC HYPERTORPHY (relaxes SMC to may block urine path)
3. ELDERLY (hallucinations)

Hexamethonium

NICOTINIC BLOCKER - GANGLION

• Not used clinically
• Ganglion blocker
• Used for test questions on which system/effect dominates
• Lecture notes page 21 lecture 12/13

MECYLAMINE

ANTINICOTINIC - GANGLION BLOCKER

• Only ganglion blocker used in teh US
• Management of moderate-severe hypertension or malignant HT

TUBOCURARINE

COMPETITIVE (NON-DEPOL) Ach NM BLOCKER

• Competitive
• Used during surge to relax skeletal muscle

Succinylcholine

AGONIST (depolarizing) NM BLOCKER

• binds ot Nic receptor and DEPOLARIZES the receptor-->receptor DESENSITIZES-->flaccid paralysis
  • Intubation
  • ECT

Adverse efects

of

DEPOLARIZING AGENTS

(Ach-receptors)

1. Malignant hyperthermia
   1.  d/t excessive release of Ca++ from SR
   2. mostly d/t combination of succinylcholine and halogenated aneshetic
2. Tx with Dantrolene (blocks release of Ca++ from SR, mechanism unknown)

HEMICHOLINIUM-3

INHIBITOR OF Ach SYNTHESIS-presynaptic

• Blocks the CHT so choline not brought into pre-synapse
• Reasearch tool only

VESAMICOL

Blocks the Ach-H+ antiporter in the pre-synapse so Ach not transported into the vesicles for storage and release

Research tool

BOTULINUM TOXIN

INHIBITS Ach RELEASE

• Prevents vesicle docking with end terminal
• Use locally IM to treat muscle spasms
• Cosmetic use (eeeeeek, scary looking people!)

Name 4 direct adrenergic agonists

Act directly on alpha and beta receptors

1. Epi
2. Norepi
3. Isoproterenol
4. Phenyleprine

1. Amphetamine
2. Tyramine

• Taken into presynaptic neuron
• Cause release of norepi

Name two MIXED-action adrenergic agonists

1. Ephedrine
2. Metaraminol

• Activate adrenoreceptors AND release norepi (work BOTH sides of the street!)

EPINEPHRINE

ENDOGENOUS ADRENERGIC AGONIST

• Released by adrenal medulla
  
• Acts on BOTH alpha and Beta receptors
  
• Low-dose, B2 effects (wasodilation)
• Hi dose, alpha efects (vasoconstriction) AND B1 (↑HR, , ↑contractility) efects
  

Effects of a LARGE dose of

EPINEPHRINE

IV

• INCREASE IN BP
  • Increase in ventricular contraction (b1)
  • Increase HR (B1)
  • Vasoconstriction (alpha1)

what happens when a LOW

dose of

EPINEPHRINE

is given IV?

• Increase in SYSTOLIC pressure ↑ contractility
• DECREASE in DIASTOLIC B2 receptors more sensitive than alpha1 so peripheral resistance falls!
• BP may ↓ (see above)
• no increase in map, so baroreceptor reflex doesn't kick in !  (just wider sys-diast. pressure range)

Whate are the efects on METABOLISM of EPINEPHRINE?

• ↑ glycogenolysis in liver (B2)
• ↑ Lipolysis in adipose (B3)

• ANAPHYLACTIC SHOCK drug of choice
• ACUTE ASTHMATIC ATTACKS
• LOCAL ANESTHETIC: prolongs duration via vasoconstriction at the injection site
  
• GLAUCOMA (NOT currently used):

NOREPI

actions

• Endogenous catecholamine 
  • Potent on alpha1 and B1 and B3
  • Little action on B2
• VASOCONSTRICT  (alpha1)
• ↑ HR, contractility, renin release, lipolysis 
• Increase in BP --> baroreceptor--> brady (M2)  contractility increases, but not HR !!

ENDOGENOUS CATECHOLAMINE

• Activates BOTH alpha and B1,2,3 receptors
• Used to treat SHOCK
• Raises vascular resistance and CO -->↑ BP
• BUT doesn't ↓ blood flow to kidney(D1) as does norepi

ISOPROTERENOL

BETA ADRENERGIC AGONIST

• Stim B1 (↑HR, contractility)
• Stim B2 (vasodilates skeletal muscle arterioles->↓PVR)
• Little action on alpha

• PVR↓-->systol P ↓(B1), diastol↓ (B2), HR↑ (B1)
• BRONCHODILATION (B2)
• USED TO STIMULATE HEART IN EMERGENCIES

DOBUTAMINE

• - ISOMER: alpha1 agonist, weak B1 agonist
• +ISOMER: alpha1 ANTagonist, Potent B1 agonist

Clinical result 

SELECTIVE B1 AGONIST

(The alpha 1 action cancels out!!!)

• ↑CO in CHF with little change in HR !   (don't know why)
• so doesn't significantly ↑ O2 demands of heart
  

TERBUTALINE

ALBUTEROL (SUBALBUTAMOL)

FORMOTEROL

SELECTIVE B2 AGONIST

• Treat ASTHMA
• Long-acting: 12hrs
• Slow onset (not good for breakthrough attacks:  use EPINEPHRINE for those ! )

PHENLEPHRINE

SELECTIVE ALPHA1 AGONIST

• Vasoconstrictor
  • Nasal decongestant
  • Mydriatic
  • Induces brady when given IV
  • Used to ↑BP and TERMINATE SUPRAVENTRICULAR ARRYTHMIA

CLONIDINE

METHYLDOPA

SELECTIVE ALPHA2 AGONIST

• CLONIDINE- PARTIAL ALPHA2 AGONIST
  
  • antihypertensive (CNS)
  • Acts CENTRALLY to limit sympathetic vasomotor
• METHYLDOPA
  • CENTRAL alpha2 receptors--> ↓ adrenergic outflow--> ↓BP
  • Drug of choice for HT during PREGNANCY

AMPHETAMINE

INDIRECT ADRENERGIC AGONIST

• Release of norepi from presynaptic terminals
• (no action on postsynaptic terminal)

METHYLPHENIDATE

AMPHETAMINE ANALOG:

INDIRECT ADRENERGIC AGONIST

• ADHD

TYRAMINE

INDIRECT ADRENERGIC AGONIST

• Fermented foods, ripe cheese, Chianti wine
• Normally oxidized by MAO
• IF PATIENT TAKING MAO INHIBITORS, CAN CAUSE SERIOUS VASOPRESSOR EPISODES

ACTIONS OF MIXED ACTION ADRENERGIC AGONISTS

Induce release of norepi

Activate adrenergi receptors

(Work both sides of the street!)

EPHEDRINE

MIXED action adrenergic agonist

• Stimulates alpha AND B receptors AND releases NE
• NOT A CATECHOLAMINE !!!!  (no COMT/MAO metabolism--> long acting)
  
• EXCELLENT ORAL ABSORPTION 
• PENETRATES TO CNS
  

EPHEDRINE

actions

MIXED ACTION ADRENERGIC AGONIST

• ↑systolic, diastolic bp
• Bronchodilation (prophylactic in chronic asthma)
• Mild stim of CNS: ↑Alertness ↓fatigue, prevents sleep
• improves athletic performance
  
  • nasal decongestant, asthma, increase bp
    

PSEUDOEPHEDRINE

One of 4 EPHEDRINE ENANTIOMERS

USED AS OTC NASAL DECONGESTANT

PHENOXYBENZAMINE

NON-SELECTIVE ALPHA BLOCKER

• Irreversible
• No Good for Hypertension 
• Used in Pheochromocytoma before tumor removal
• for chronic management of inoperable tumors

REVERSIBLY blocks alpha 1 AND alpha2's

• PHEOCHROMOCYTOMA : short-term HT control
• Dx of Pheochromocytoma by PHENTOLAMINE BLOCKING TEST
• also used for HT crisis d/t sudden withdrawal of sympathiolytic antihypertensive drugs (e.g. clonidine)

EPINEPHRINE REVERSAL

EXAM QUESTION !!!!

• all alpha blockers reverse alpha agonist fx of epi
• the vasoconstrictive alpha1 rxn is blocked, but the B2 receptor vasodilation action is not !!

Therefore the systemic blood pressure DECREASES in response to epi given in the presence of pheoxybenzamine (an alpha antagonist)

PRAZOSIN

ALPHA 1 SELECTIVE ADRENERGIC BLOCKER

• Useful in tx of HYPERTENSION
• Prazosin is the PROTOTYPE
• relax BOTH arterial AND venous smooth muscle
• First dose produces exxagerated hypotensive response:  must be 1/3 or 1/4 normal dose 
• hypertension:  not drug of choice
• BPH: alpha1 antagonist improves urinary flow:  DRUG OF CHOICE

TERAZOSIN

DOXAZOSIN

ALPHA 1 SELECTIVE BLOCKER

• Prazosin analogs with longer half-life
• Used for Hypertension and BPH

SELECTIVE ALPHA 1 BLOCKER

• Approved for BPH
• Little effect on BP
• Good for patients with orthostatic HypOtension d/t alpha1 block

YOHIMBINE

ALPHA 2 SELECTIVE BLOCKER

• Blocade of alpha2-->↑ release of norepi
• --> stimulation of cardiac B1 receptors and vascular alpha1 receptors
• Used in past for ED
• Viagra replaced it

NON-SELECTIVE BETA BLOCKER

THE PROTOTYPE

• Slow HR, ↓contractility
• ↓ glycogenolysis, glucagon secretion (opposite of epi)
• Lowers BP by ↓CO
• Effective in diminishing intraocular pressure in GLAUCOMA
• Effective in reducing MIGRANE
• HYPERTHYROIDISM: blunt Sympathetic stimulation
• ANGINA: ↓O2 requirement of heart muscle
• Useful in CHRONIC angina, not acute
• Protect myocardium in MI

Adverse effects of

NON-SELECTIVE BETA BLOCKERS

NON-SELECTIVE BETA BLOCKERS

ADVERSE EFFECTS

• BRONCHOCONSTRICTION :pot. lethal in asthmatics
  
• UP-REGULATION OF RECEPTORS Tx w/ B blockers leads to UP REGULATION of B receptors.  When therapy suspended, the increased receptors can worsen HT or angina ! 
• CNS Efects: sedation, sleep, sleep disturb, depres'n  (Propranolol very lipophillic: used for performance anxiety)

TIMOLOL 

and

NADOLOL

NON-SELECTIVE BETA BLOCKER

(LIKE PROPANOLOL)

• NADOLOL: long duration of action
• TIMOLOL: used as oclar hypotensive

ATENLOL

METOPROLOL

ESMOLOL

B1 SELECTIVE ANTAGONIST

• Useful in HT patients w/ IMPAIRED PULMONARY fn

• Useful in diabetic hypertensives who are receiving INSULIN or oral HYPOGLYCEMIC AGENTS (B2 block would block glycogen breakown and glucose release)
• ESMOLOL: ultra-short acting 

LABETALOL

ALPHA1 AND BETA BLOCKER

• HT, pheochromocytoma and hypertensive emergencies
• Used to tx HT accompanied by tachy d/t STIMULANT DRUG OD (cocaine or amphetamines)

CARVEDILOL

ALPHA1 AND BETA BLOCKER

• Used in hypertension and congestive heart failure

PINDOLOL

PARTIAL BETA AGONIST

• produces SMALLER REDUCTIONS IN HR AND BP
• preferred as anti-HT in folks with diminished cardiac reserve or PROPENSITY TO BRADYCARDIA

ALPHA METHYLTYROSINE

(METYROSINE)

INHIBITOR OF NOREPI SYNTHESIS

• PRESYNAPTIC
• Competitive inhibitor of tyrosine hyroxylase (inhibits conversion of tyr-->DOPA)
• MALIGNANT PHEOCHROMOCYTOMA
• PRE-OP PREP OF PATIENTS FOR RESECTION OF PHEOCHROMOCYTOMA TUMOR

RESERPINE

INHIBITOR OF NOREPI SYNTHESIS

• Dmages VMAT irriversibly. 
• Vesicles can't store norepi or doamine
• MAO degrades norepi in cytoplasm
• GRADUAL DECREASE IN BP AND SLOWING HR
• used in past to tx HT

GUANETHIDINE

PRESYNAPTIC INHIBOTOR OF NOREPI SYNTHESIS

• displaces norepi from vesicles
• leads to depletion of norepi
• inhibits release 

• ANTIHYPERTENSIVE:  gradual ↓BP, HR
• major use in 1970's for HT

MAO INHIBITORS

• Prevents deamination of catecholamines
• More cathecolamine accumulates in vesicels for release during each action potential.
• Used to tx DEPRESSION AND PARKINSON'S

COCAINE

BLOCKS MONOAMINE REUPTAKE

They accumulate in synaptic space

potentiates and prolongs CNS and PNS actions