Concept: some drugs only cause effects dependent on the disease state of the patient

Example:

• effect of ChE inhibition on neuromuscular function in nl and myasthenic pts
• effects of ganglionic blockade (reflects loss of the predominant resting tone)
  

Action:

1. transformed into a "false transmitter" (α-methyl norepinephrine) by AADC and DBH. It acts in the brain to decrease SNS activity → vasodilation.
2. competitive inhibition of AADC decreases overall DA/NE synthesis → decreased SNS activity → vasodilation.

Clinical use: HTN

Problems: sympatholytic effects on CNS

Proprietary names: Aldomet

Action: selective β-2 agonist
Clinical use: bronchodilator (rescue therapy in asthma)

Other uses for selective β-2 agonists: relax uterus in premature labor, cardiac stimulation (incr contractility)

Proprietary names: Proventil, Ventolin, etc

• hypotension
• increased HR (baroreflex)
• nasal congestion
• decreased ability to ejaculate
• sedation/depression

• vasoconstriction (innervated)
• pupillary dilation
• ejaculation
• micturition inhibition
• GI inhibition

• vasoconstriction (UNinnervated)
• prejunctional inhibition of NE release (negative feedback mechanism)

Action: selective antagonist of beta-1 adrenergic receptors (cardioselective; second generation beta blocker)
Clinical use: HTN, angina, arrhythmia, ischemic heart dz, CHF

Advantages: renal excretion = longer t_1/2 (6-9 hrs) = better pt compliance

Proprietary names: Tenormin

Action: muscarinic receptor antagonist; non-selective

Effects:

• Exocrine glands: decreased secretions
• Eyes: mydriasis, cycloplegia
• CV: increased heart rate (no effect on BP)
• Resp: block of vagal bronchoconstriction
• Urinary bladder: decreased tone and constricted sphincter
• GI smooth muscle: decreased motility and tone (variable)
• CNS: block of all muscarinic receptors

Clinical use: cardiac arrest, other analogs used for effects above

Problems: many, based on actions

Concept: The brain receives information about the level of BP from peripheral baroreceptors (stretch receptors) located at the carotid sinus and aortic arch. The brain then adjusts the activity of the vagus (parasympathetic, NT=ACh) nerve innervating the heart and the sympathetic nerves (NT=NE) innervating the heart and blood vessels accordingly.

Example: if BP suddenly falls, the decreased firing from the baroreceptors results in increased firing of sympathetic nerves to the heart (incr CO) and vascular smooth muscle (incr TPR), and decreased firing of vagus n (to assist incr CO). Vice versa. Thus, HR changes opposite to a sudden change in BP.

• angina (prevention)
• cardiac arrhythmia
• hypertension
• post-MI
• CHF
• also: glaucoma (decr secretion of IOF), pheochromocytoma, migraine, performance anxiety, alcohol or opiate withdrawal, hyperthyroidism

• cardiac stimulation (innervated)
• secretion of renin

• cardiac stimulation (UNinnervated, minor)
• bronchodilation
• uterine relaxation
• vasodilation (UNinnervated)
• GI inhibition
• glycogenolysis (liver)

Action: ACh analog; pure muscarinic receptor agonist, insensitive to ChE
Clinical use: GI stimulation or treatment of urinary retention

Problems:

Contraindications: asthma, peptic ulcer, coronary insufficiency; never give IM or IV = ARDS, cardiac arrest/CV collapse

Proprietary names: Urecholine

Action: enters cholinergic nerve terminals and destroys various synaptic proteins involved in exocytotic release of ACh
Clinical use: dystonias, cerebral palsy, spasm of ocular muscles, anal fissure, hyperhydrosis, BOTOX used for cosmetic reasons

Problems: highly toxic upon systemic exposure; therefore must be used locally only

Contraindications:

Proprietary names: BOTOX

Concept: when there are conflicting actions on the heart, the vagal effect dominates the overall response.

Concept: selective antagonism at beta-1 adrenergic receptors (and not beta-2 receptors) to produce effects selective for treating cardiac symptoms

Examples: metoprolol, atenolol, esmolol

Action: beta blocker, reduces toxic effect to myocardium of long term catecholamine exposure after CHF

(short term catecholamine exposure enhances contractility; long term exposure accelerates CHF)
Clinical use: reduces motality and morbidity in CHF

*always start with low dose and increase gradually

Problems:

Contraindications:

Proprietary names: Coreg

Synthesis: tyrosine → dopa → dopamine → norepinephrine → epinephrine

Rate limiting step: tyrosine hydroxylase (tyrosine → dopa)

Significance: adrenergic pharmacology

Action: (imidazoline type) α-2 receptor agonist; acts in the CNS (brainstem) to decrease sympathetic nervous system activity to the heart and blood vessels
Clinical use: tx HTN, other CNS related tx

*Structural analogs used in tx of glaucoma: decrease secretion of intraocular fluid resulting in reduced intraocular pressure

Problems: sedation, dry mouth, withdrawal sx after prolonged use (HTN, tachycardia, angina, or MI)

Contraindications:

Proprietary names: Catapres, Duraclon

Action: specific inhibitor of catecholamine reuptake

1) peripheral: increased BP and HR

2) central: euphoria, increased alertness, arousal

Clinical use: topical local anesthetic in surgery involving nasal mucosa or lacrimal ducts (vasoconstriction of blood vessels minimizes bleeding)

Problems: stroke, cardiac arrhythmias, myocardial infarction, sudden death

Concept: Nicotinic receptors are specifically adapted to the transient nature of ACh as a neurotransmitter. When agonists are bound to the nicotinic receptors (or there is too much Ach via ChE inhibition), the resulting persistent depolarization (because the agonist does not degrade as fast as ACh, or inhibited ChE fails to degrade ACh) prevents "resetting" of fast Na+ channels → receptor blockade → failure of signal transmission.

Example: sarin, VX, parathion (organophosphate ChE inhibitors) cause buildup of ACh →  chronic activation of nicotinic receptors → muscle weakness → respiratory failure → death

Action:

• stimulation of dopamine (D1) receptors → dilation of renal blood vessels
• direct alpha and beta receptor agonist properties and indirect sympathomimetic activity
  

Clinical use: tx of shock; also some pts with CHF

Problems: must be given by IV infusion

Contraindications:

Proprietary names: Intropin

Action: irreversible substrate inhibitor of ChE; serves as substrate and forms stable (irreversible) enzyme-substrate complex (via phosphorylation)
Clinical use: 

1. paralytic ileus or bladder atony (usually Neostigmine)

2. glaucoma (esp. Echothiophate)

3. Alzheimer's disease

4. Myasthenia gravis (esp. Neostigmine)

Problems:

Contraindications:

Proprietary names:  Phospholine

Action: competitive inhibitor of ChE; occludes active site
Clinical use: Tensilon test for Myasthenia Gravis

Problems:

Contraindications:

Proprietary names: Tensilon

Action: α and β adrenergic receptor agonist; resistant to MAO/COMT (orally active); indirect sympathomimetic activity

Clinical use: decongestant, OTC dietary supplements for weight loss and strength training

Problems:

1) indirect CNS effects (NE displacement → NE release → NE effects)

2) adverse effects similar to amphetamines (increased BP & stroke, cardiac arrhythmia & MI, CNS stimulation & seizures)

Contraindications: MAO-I (causes very high BP)

Proprietary names: Sudafed, etc

Concept: Epi has the ability to both vasoconstrict and vasodilate because it can stimulate different adrenergic receptors that have opposite effects on vascular smooth muscle. When PHENTOLAMINE is used to block alpha receptors, only the beta effects of epi are seen.

Control condition: Epi raises BP.

Phentolamine: Epi decreases BP.

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Action: a catecholamine; stimulates all α and β adrenergic receptors
Clinical use: tx of acute anaphylaxis or cardiac arrest; adjunct with local anesthetics; OTC bronchodilator (Primatene mist)

Problems: pharmacokinetics; also the "action" above (very low selectivity)

Proprietary names: Epipen, Primatene

Action: ultra-short acting beta blocker (cardioselective)
Clinical use: susceptible to enzymatic hydrolysis in blood; given by infusion to limit catecholamine-mediated cardiac stimulation, especially in surgery

Problems:

Contraindications:

Proprietary names: Brevibloc

Concept: a false transmitter is any substance capable of being stored and released in place of the substance normally serving as the transmitter in a given neuron. Enzymes in the catecholamine biosynthesis pathway (AAADC, DBH) are promiscuous, which facilitates formation & accumulation of false transmitters in sympathetic vesicles.

Significance: transmission will be altered if the effect of the false transmitter on post-junctional receptors differs significantly from that of the normal NT.

Examples:

• NE (a vasoconstrictor) can be replaced by a-methyl-NE (a vasodilator) if methyl-dopa is processed by AAADC & DBH.
• Tyramine is converted by DBH into octopamine, which is inactive at adrenergic receptors but displaces NE in presynaptic vesicles.

Action: uncoupler of stimulus/secretion in SNS. Pumped into pre-synaptic nerve terminals and displaces NE in vesicles. NE release initially, followed by drug release upon nerve stimulation. No CNS effects.
Clinical use: HTN, obsolete.

Problems: Peripheral sympatholytic effects.

Proprietary names: Guanadrel

Action: antagonist of ACh at ganglionic nicotinic receptors → paralysis of entire ANS! No longer available for use; mecamylamine still available.
Clinical use: (limited) treatment of HTN, dissecting aortic aneurysm, and autonomic hyperreflexia, and to control hemorrhage in surgery. Effects of ganglionic blockade on a given tissue/organ/function will reflect the loss of the predominant tone.

Problems:

Contraindications:

Proprietary names:

Concept:
1. Drug gains access to nerve terminal via Uptake I
2. Drug enters storage vesicles and displaces NE into cytoplasm
3. Some of NE released into cytoplasm is inactivated by MAO
4. NE uses Uptake I backwards to leave nerve ending and acts on receptors to cause sympathetic effects

Examples: ephedrine, pseudoephedrine, amphetamines, methamphetamines, dopamine

Concept: drug provides a low resting stimulation of beta receptors

Example: pindolol (partial agonist of beta adrenergic receptors)

Action: antimuscarinic with receptor activity similar to atropine, but with quaternary nitrogen (fixed + charge) that prevents crossing of biomembranes
Clinical use: treatment of asthma and COPD; poor absorption ensures local effects in airways. Often combined with albuterol.

Problems: few bc of poor absorption; toxic doses may cause hypotension (ganglionic blockade), and muscle weakness (neuromuscular blockade)

Contraindications:

Proprietary names: Atrovent

Action: stimulates β1 and β2 adrenergic receptors (cardiac stimulation, renin secretion, bronchodilation, uterine relaxation, GI inhibition, vasodilation)
Clinical use: a profound cardiac stimulant (incr HR, decr BP, decr peripheral resistance)

Problems: rapid inactivation by COMT and MAO

Proprietary names: Isuprel

Action: organophosphate cholinesterase inhibitor; converted into toxic form by host
Clinical use: insecticide (not toxic to humans)

Action: antagonist of ACh at ganglionic nicotinic receptors → paralysis of entire ANS! Similar to hexamethonium and still available for use.
Clinical use: (limited) treatment of HTN, dissecting aortic aneurysm, and autonomic hyperreflexia, and to control hemorrhage in surgery. Effects of ganglionic blockade on a given tissue/organ/function will reflect the loss of the predominant tone.

Problems:

Contraindications:

Proprietary names: Inversine

Action: ACh analog; pure muscarinic receptor agonist
Clinical use: provocative test for hyperreactive airways

Problems: some susceptibility to ChE

Contraindications: asthma, peptic ulcer, coronary insufficiency; never give IM or IV = ARDS, cardiac arrest/CV collapse

Proprietary names: Provocholine

Action: selective antagonist of beta-1 adrenergic receptors (cardioselective; second generation beta blocker)
Clinical use: HTN, angina, arrhythmia, ischemic heart dz, CHF

Problems: pharmacokinetic (t_1/2 = 3-4 hrs in most individuals)

Contraindications: not for pts who are "slow hydroxylators," due to 2xF and 1/2xCl (4x steady state concentration!)

Proprietary names: Lopressor, Toprol

Action: Competitive inhibitor of tyrosine hydroxylase; depletes catecholamines everywhere
Clinical use: pheochromocytoma

Problems: sedation/depression, crystalluria, GI upset

Proprietary names: Demser

Action: looks like ACh, stimulates muscarinic cholinergic receptors
Clinical use: 

Problems: parasympathetic overstimulation causes bradycardia, nausea/cramps/vomiting/diarrhea, bronchoconstriction, salivation, sweating, visual disturbances, hypotension (uninnervated blood vessel receptors that cause vasodilation)

Contraindications:

Proprietary names:

G protein-linked receptors of which 5 subtypes are known. Not much clinical significance to subtypes.

Uninnervated muscarinic receptors are located in all blood vessels and mediate vasodilation via NO. No effect on vasoconstriction.

Action: reversible substrate inhibitor of ChE; serves as substrate and forms more stable (but still reversible) enzyme-substrate complex
Clinical use: 

1. paralytic ileus or bladder atony (usually Neostigmine)

2. glaucoma

3. Alzheimer's disease

4. Myasthenia gravis (esp. Neostigmine)

Problems:

Contraindications:

Proprietary names: Prostigmin

Action: a tertiary amine that can act as an agonist at nicotinic receptors in all autonomic ganglia, NMJ, sensory nerve endings, and CNS
Clinical use: smoking cessation programs; ulcerative colitis, neurodegenerative dzs, psychiatric disorders

Problems: few side effects with gum or patch because of low dose; systemic nicotine can cause CNS stimulation, vomiting, ADH release, increased HR, increased BP, PSNS stimulation then block, NM block.

Acute nicotine toxicity: convulsions, coma, HTN, arrhythmias, neuromuscular failure.

*Effects of nicotine or ANY nicotine receptor agnoists may reflect stimulation or blockade of nicotinic receptors.*

Contraindications:

Proprietary names:

Ligand-gated ion channels that mediate rapid increases in Na+ and K+ permeability, resulting in depolarization.

2 subtypes:

• Ganglionic (neuronal) nicotinic receptors (N_g or N_n): found in all autonomic ganglia (incl adrenal medulla) and in the CNS
• Neuromuscular nicotinic receptors (Nm): found on skeletal muscle at the NMJ
  

Action: stimulates α and β1 adrenergic receptors (not β2)
Clinical use:

Other uses for alpha adrenergics: nasal decongestion, adjunct to local anesthetics, maintenance of BP (eg in spinal anesthesia, shock), eye drops, mydriatic, paroxysmal atrial tachycardia (PAT)

Problems:

Proprietary names: Levophed

Action: organophosphate cholinesterase inhibitor; converted into toxic form by host
Clinical use: insecticide (toxic to humans as well)

Treat with atropine & 2-PAM!

Concept: utilization of the pharmacokinetic properties of a drug to target specific tissues; especially useful in cholinergic pharmacology.

Examples:

• Bethanechol: an ACh analog; fixed positive charge is not readily absorbed in the gut, but when it is absorbed its pos charge causes it to be rapidly excreted by the kidneys and concentrated in the bladder → perfect for targeting gut for GI stimulation and targeting bladder for tx of urinary retention
• Scopolamine: antimuscarinic; lipid solubility allows entry into the CNS → targets motion sickness
• Ipratropium: antimuscarinic; quaternary nitrogen (fixed +) prevents crossing of biomembranes → local effects on respiratory airways for treatment of asthma and COPD
• Neostigmine: ChE inhibitor with quaternary nitrogen (fixed +); oral admin results in marked GI effects, systemic action limited by low bioavailability
  

Action: non-competitive inhibition of alpha adrenergic receptors (non-selective)
Clinical use: tx of pheochromocytoma; not useful in tx of HTN

Problems: excessive cardiac stimulation (arrhythmia, MI) due to non-selective alpha receptor blockade: loss of negative feedback mechanism of NE release in vascular smooth muscle and cardiac muscle (alpha 2 receptors)

Contraindications:

Proprietary names: Dibenzyline

Action: non selective competitive alpha blocker
Clinical use: tx of pheochromocytoma; not useful in tx of HTN

Problems: excessive cardiac stimulation (arrhythmia, MI) due to non-selective alpha receptor blockade: loss of negative feedback mechanism of NE release in vascular smooth muscle and cardiac muscle (alpha 2 receptors)

*When administered before Epi it causes  a phenomenon called Epi Reversal.*

Proprietary names:  Regitine, Oraverse

Action: α receptor agonist increases BP, which recruits the baroreceptor reflex to cause reflex bradycardia, which combats tachycardic symptoms
Clinical use: paroxysmal atrial tachycardia (PAT)

Other uses for alpha adrenergics: nasal decongestion, adjunct to local anesthetics, maintenance of BP (eg in spinal anesthesia, shock), eye drops, mydriatic

Problems: some indirect effects

Proprietary names: Neo-Synephrine

Action: reversible substrate inhibitor of ChE; serves as substrate and forms more stable (but still reversible) enzyme-substrate complex
Clinical use: 

1. paralytic ileus or bladder atony (usually Neostigmine)

2. glaucoma

3. Alzheimer's disease

4. Myasthenia gravis (esp. Neostigmine)

Problems:

Contraindications:

Proprietary names: Antilirium

Action: muscarinic receptor agonist
Clinical use: tx of open angle glaucoma (Pilopine); relief of dry mouth owing to hypofunction of salivary glands (Salagen) for eg Sjogren's or cancer radiotherapy

Problems:

Contraindications:

Proprietary names: Pilopine, Salagen

Action: beta blocker with partial agonist at ALL beta adrenergic receptors with intrinsic sympathomimetic activity (provides a low resting stimulation of beta receptors so no decrease in resting HR, cf propanolol, which decr resting HR. Both block exercise-induced incr in HR)
Clinical use: HTN, angina, arrhythmia, ischemic heart dz, CHF

Potential advantages: less cardiac depression, less tendancy to cause bronchoconstriction, significantly reduces TPR

Problems:

Contraindications:

Proprietary names: Visken

Action: an oxime; pulls organophosphates off of cholinesterase to regenerate ChE; most effective in NMJ (nicotinic receptors) and peripheral PSNS (muscarinic receptors) but not CNS muscarinic receptors
Clinical use: acute organophosphate intoxication; often in conjunction with atropine (effective at both peripheral PSNS and CNS muscarinic receptors)

Problems: must treat quickly because of "aging" (stabilization of organophosphate-ChE complex over time renders 2-PAM ineffective)

Proprietary names: Protopam

Action: competitive inhibition of alpha-1 receptors (selective); decreased TPR and reduction of SNS-mediated stimulation of smooth muscle

Clinical use: HTN, CHF, BPH (Tamsulosin/Flomax)

Problems: "first dose phenomenon" - hypotension and/or syncope with first dose so take before bed

Contraindications:

Proprietary names: Minipress

Action:

• competitive antagonist of beta receptors (non-selective beta blocker) → immediate and sustained reduction in cardiac stimulation/output → baroreflex increases TPR and BP →  TPR falls over time → BP decreases
• depresses membrane excitability (membrane stabilizing activity)

Clinical use: HTN, angina, arrhythmia, ischemic heart dz, etc.

Problems: pharmacokinetic (first pass effect, short T1/2), pharmacodynamic (cardiac depression/heart failure; bronchoconstriction in asthmatics; hypoglycemia in susceptible pts; CNS effects/sedation, nightmares, insomnia).
*Beta blockers do not decrease BP in normotensive ppl*

Contraindications:

Proprietary names: Inderal, Innopran

Action: specific blocker of vesicular pump in monoaminergic neurons (VMAT); depletes stored NE
Clinical use: HTN (peripheral and central mechanisms)

Problems: periph & central sympatholytic effects (orthostatic hypotension, increased GI activity, sedation, severe depression, suicide)

Action: selective β-2 agonist; long acting (12 hrs) and slow onset
Problems:

Clinical use: bronchodilator (not for rescue therapy in asthma) 

Contraindications:

Proprietary names: Serevent

Action: organophosphate cholinesterase inhibitor
Clinical use: military nerve gas

Treat with atropine & 2-PAM!

Action: antimuscarinic with more CNS action than atropine (highly lipophilic)
Clinical use: transdermal application; effective tx of motion sickness

Problems: dry mouth, blurred vision, sedation, confusion and psychosis at high doses

Contraindications:

Proprietary names: Transderm Scop

Action: antimuscarinic with no apparent selectivity for different muscarinic receptor subtypes (prodrug)
Clinical use: tx of overactive bladder

Problems: still causes typical anticholinergic effects, but incidence significantly lower than with previous antimuscarinic drugs; dry mouth, constipation

Contraindications:

Proprietary names: Detrol

1. terminate exposure

2. maintain airway

3. atropine

4. 2-PAM

*treat quickly!

Description: Tyramine is a naturally occuring amine found in wine, beer, cheese, processed meats, etc. It is rapidly converted into octopamine (inactive) by MAO in the liver. It can displace NE in nerve terminal vesicles if not converted by MAO in the liver.

Contraindications: MAO-Inhibitors (leads to hypertensive crisis)

*If prescribing an MAO-I, must counsel pt on dietary restrictions*

Action: organophosphate cholinesterase inhibitor
Clinical use: military nerve gas

Treat with atropine & 2-PAM!

Action: an α4β2 neuronal nicotinic receptor partial agonist that binds in the CNS and:

1. produces low to moderate release of dopamine at reward centers in brain, mimicking nicotine's effect and reducing withdrawal symptoms

2. blocks the binding of nicotine and therefore the positive reinforcement obtained thru smoking
Clinical use: tobacco cessation (more effective than nicotine patch/gum and may be more effective than bupropion)

Problems: nausea (30%), headache, abnormal dreams, constipation, vomiting; possible psychosis or suicidal thoughts

Contraindications:

Proprietary names: Chantix

Elimination increases

Clearance stays the same

Half-life stays the same

Elimination stays the same (by definition)

Clearance decreases

Half-life increases

• Vd (volume of distribution) is important for determining the loading dose.
• Cl (clearance) is important for determining the maintenance dose.
• Half-life is important for determining the time to steady state.

DUMBELSS

• Diarrhea
• Urination
• Miosis
• Bradycardia
• Emesis
• Lacrimation
• Salivation
• Sweating

beta blocker

eg propanolol, atenolol, metoprolol, etc

beta 2 agonist

eg albuterol, salmeterol

local anesthetic

eg cocaine, lidocaine, novacaine

• angina
• cardiac arrhythmia
• hypertension
• post-MI
• CHF

alpha 1 antagonist

eg prazosin, tamsulosin (Flomax)

• clonidine (a2 agonist - decr secretion of IOF): vasoconstriction?
• timolol (b blocker - decr secretion of IOF): vasoconstriction?
• pilocarpine (muscarinic agonist): stimulation of glands?
• physostigmine/echothiophate (ChE inhibitor)