Pharmacology

Nicotinic agonist

nicotine

Esterase-resistant agonist

Carbamylcholine

Endogenous neurotransmitter

Acetylcholine (ACh)

non-depolarizing muslce relaxant

tubocurarine

depolarizing muscle relaxant

succinylcholine

denervating neurotoxin

botulinum toxin

acetylcholineresterase inhibitor

neostigmine

physostigmine

muscarinic agonist

pilocarpine

muscarinic antagonist

atropine

scopolamine

agonist

binds to the receptor activating it and producing a similar response to the intended chemical and receptor

antagonist

binds to the receptor either on the primary site, or on another site, which all together stops the receptor from producing a response

nicotinic acetylcholine receptors

ligand-gated ion channels

5 subunits surrounding a central ion pore

Excitatory - transports Na+ K+

Prolonged exposure - refractory desensitized state

In autonomic ganglia of parasympathetic and sympathetic NS, CNS, and skeletal muscle

Nicotine

Nicotinic Receptor Agonist

Tertiary ammonium, resulting in increased skin permeability. Crosses the blood-brain barrier into the CNS.

Selective for nicotinic receptors

Drug of abuse

Acute toxicity (Generally occurs from ingestion of nicotine-based insecticides or ingestion of tobacco products by children)

Rapid onset of symptoms, including abdominal pain, nausea, diarrhea, disturbed hearing and vision, weakness, mental confusion

Stimulation of both branches of autonomic nervous system via activation of ganglionic receptors produces a complex mixture of sympathetic and parasympathetic effects. Initial autonomic stimulation can progress to ganglionic blockade as ganglionic receptors become desensitized

Central stimulation, which in severe poisoning may progress to convulsions, coma, respiratory arrest.

Skeletal muscle depolarization and contractions, which in severe poisoning may progress to paralysis (including respiratory paralysis), due to a combination of sodium channel inactivation and nicotinic acetylcholine receptor desensitization

Carbamylcholine

Nicotinic Receptor Agonist

Acetylcholinesterase-resistant analog of acetylcholine

Quaternary ammonium

Activates both nicotinic and muscarinic receptors

Acetylcholine

Nicotinic Receptor Agonist

Endogenous neurotransmitter; highly selective for nicotinic acetylcholine receptors

Quaternary ammonium; does not diffuse across membranes

Activates both nicotinic and muscarinic receptors

Rapidly inactivated by hydrolysis into choline and acetic acid by the enzyme acetylcholinesterase at the synapse, and by nonspecific esterases in blood

Tubocurarine

Nondepolarizing relaxant

Act as competitive antagonists of acetylcholine muscle nicotinic receptors, resulting in flaccid paralysis

May be indirectly antagonized by acetylcholinesterase inhibitors, resulting in increased levels of endogenous acetylcholine, which competes with the antagonist

sometimes used to speed postsurgical recovery of respiratory function

Adverse Effects - can also stimulate release of histamine, which can also contribute to hypotension, as well as producing pseudo-allergic reactions

succinylcholine

Depolarizing relaxant/nicotinic agonists

disorganized muscle fiber contractions due to non-synchronous activation of muscle nicotinic receptors progresses to flaccid paralysis due to a combination of acetylcholine receptor desensitization and voltage-gated sodium channel inactivation.

rapid onset and short duration of action, resistant to acetylcholinesterase but is rapidly hydrolyzed by plasma cholinesterase

Therapeutic uses: Surgical muscle relaxant, sometimes used to facilitate setting of fractures, Prevention of laryngospasm during tracheal intubation

Adverse Effects: Prolonged paralysis in patients with atypical plasma esterase; Hyperkalemia; Malignant hyperthermia

Botulinum toxin

enters cholinergic nerve terminals, degrades SNARE proteins required for vesicular fusion and acetylcholine release

Therapeutic uses: localized facial paralysis to reduce wrinkling; Treatment of focal dystonia, spasticity, nondystonic muscle activity disorder, localized muscle cramp, smooth-muscle hyperactive disorders and sweating disorders

Adverse Effects: Muscle weakness due to spread of the effect beyond the intended region. Due to the extended duration of botulinum toxin action, such unintended effects are long lasting. Use in the head and neck region sometimes results in dysphagia. Anaphylactic reactions have also been reported. Death may result from paralysis of respiratory muscles.

Muscarininc Acetylcholine Receptors

G-protein coupled

odd-numbered subtypes - couple through activation of phospholipase C (2nd messengers inositol triphosphate (IP3) and diacylglycerol). M3 (“glandular”) muscarinic receptors are predominantly responsible for glandular secretion, nitric oxide (NO) release in vasculature, bronchial smooth muscle contraction, bladder contraction & sphincter relaxation

even-numbered subtypes - couple through inhibition of adenyl cyclase, reducing 2nd messenger cAMP. In addition, they also produce Ca2+ channel inhibition and K+ channel activation mediated by the G-protein -subunit. Activation of M2 (“cardiac”) receptors decreases heart rate and contractility.

Muscarinic Agonists - Nonselective

Nonselective (nicotinic + muscarinic) – acetylcholine and carbamylcholine

Muscarinic Agonists - Selective

Muscarinic-selective – pilocarpine, muscarine, bethanechol

Therapeutic uses of muscarinic agonists

Promote bladder emptying (bethanechol)

Stimulation of GI activity in GI disorders (bethanechol)

Treatment of xerostomia (dry mouth)

Contraction of pupil (miosis) for ophthamlogical surgery (acetylcholine, carbachol)

Reduce intraocular pressure in open-angle glaucoma by contracting ciliary body, facilitating drainage of aqueous humor (pilocarpine, carbachol)

Physiological Effects - Muscarinic Agonists

Contraction of pupil (miosis) and ciliary muscle (accommodation)

Decreased heart rate

Vasodilation, mediated by release of EDRF (nitric oxide) by vascular endothelium

Bronchial smooth muscle contraction

Gastric acid secretion

Increased GI tone and peristalsis

Bladder contraction and sphincter relaxation

Glandular secretion

Penile erection

Muscarinic Toxicity

(SLUDGE)

Salivation

Lacrimation

Urination

Diarrhea

GI upset

Emesis

Bronchoconstriction/bronchospasm

Muscarinic Antagonists (Belladonna alkaloids)

Atropine (little CNS effect at moderate doses)

Scopolamine (CNS depression in addition to peripheral autonomic effects)

Therapeutic Effects of muscarinic antagonists

Reducing excessive salivation

Treatment of overactive bladder

Reducing tremor (CNS action)

Treatment of Parkinson’s disease

Reduces extrapyramidal side effects of antipsychotic drugs

Prevention of motion sickness (scopolamine; CNS action)

Ophthalmology, for mydriasis and cycloplegia

Relief of acute rhinitis

Treatment of bradycardia due to excess vagal tone in acute myocardial infarction

Bronchodilation (treatment of asthma, COPD)

Relaxation of GI smooth muscle for endoscopy or treatment of irritable bowel syndrome

Antidote for poisoning with cholinergic agonists or esterase inhibitors

Physiological Effects - Muscarinic Antagonists

Eye

Dilation of pupil (mydriasis)

Paralyzes accomodation by blocking contraction of ciliary muscle

Increase heart rate by blocking vagal control of heart rate

Decreased salivary and gastric secretion

Inhibition of sweating

Inhibition of GI motility

Bronchial dilation

Antimuscarinic Toxicity

“Dry as a bone, blind as a bat, red as a beet, mad as a hatter”

Dry mouth

Dry, hot skin

Dilated pupils

Blurred near vision

Flush

Hallucinations and delirium

Hyperthermia (especially with atropine in children)

Tachycardia (greater with atropine than scopolamine)

May trigger acute symptoms in narrow-angle glaucoma

Urinary retention, exacerbation of benign prostatic hyperplasia (BPH)

Constipation

Acetylcholinesterase inhibitors

reduce the enzymatic activity of acetylcholinesterase at both nicotinic and muscarinic synapses - increases the effective concentration of acetylcholine and extend duration of action

physostigmine - slowly reversible

parathion, malathion, sarin - effectively irreversible bond *poisons (insecticides, nerve gas)

neostigmine - cannot enter CNS

Therapeutic uses: overlap with the uses of muscarinic agonists and also to accelerate reverse of paralysis by nondepolarizing muscle relaxants

Acetylcholinesterase inhibitors Toxicity (e.g. pesticide or nerve gas poisoning)

Muscarinic toxicity (“SLUDGE”; treated with atropine)

Neuromuscular blockade

Respiratory failure

Confusion, ataxia, convulsions, coma

Treatment of acute toxicity: atropine to treat muscarinic symptoms, artificial respiration, benzodiazepine to relieve convulsions (if atropine fails to do so), pralidoxime to regenerate esterase.

Molecules that can passively diffuse across the membrane

small, lipid-soluble, nonpolar meds

drug with a carboxylate group (weak acid) at low pH or drug with an amine group (weak base) at high pH - uncharged and lipophilic

facilitated diffusion transporter

SLC

active transporter protein

ABC

Example of ABC protein

PGP (inhibited by grapefruit juice)

Example of SLC protein

OATP (statin drugs to hepatocytes)

IV Route of Administration

100% bioavailability

fastest possible time-course

First-pass effect

Oral (PO) - absorbed in the small intestine and carried to the liver through the portal circulation, substantial portion of drug may be transformed rapidly

Enzymatic inactivation of drug in cells of intestinal lumen, liver

Conditions that affect blood flow to the liver or the activity of liver enzymes, such as chronic liver disease, will change the magnitude of the first pass effect

process by which drug molecules leave the site of administration and gain access to the systemic circulation (plasma)

*bioavailability, half-life

absorption

pharmokinetics

absorption

distribution

metabolism

excretion

factors effecting distribution

blood flow

vascular permeability

molecules that can freely diffuse across the BBB

Gases and small lipophilic molecules

The amount of drug available to enter a target tissue depends on both

total concentration of drug and the affinity of its binding to a plasma protein

albumin

most abundant plasma protein

AGP protein

levels can increase during acute or chronic inflammatory reactions and stress, increasing binding of basic drugs

Apparent volume of distribution (Vd)

Vd = Dose / Cp0

volume of the body into which a drug appears to have distributed

Factors that increase Vd will tend to decrease the plasma concentration of a drug

a very high plasma drug concentration indicates a low Vd, while a very low drug concentration indicates a high Vd

can exceed total body weight due to preferential accumulation in fat

half–time for clearance (t1/2)

the time for the concentration of drug to fall by half

slope of the line

t1/2 = 0.693(kel) or 0.693(Vd/CIT)

2 methods of clearance

drugs are either cleared without modification (excretion) or after one or more modifications (metabolism), generally followed by excretion of the metabolic products

total clearance (ClT)

defined as the volume of plasma completely cleared of drug per unit time by all routes and mechanisms

the sum of clearance values for each elimination route

biotransformation

the alteration of a drug by chemical modification, usually catalyzed by an enzyme

can be made active, less active, or inactive or toxic

prodrug

inactive form of a drug that must be transformed to the active therapeutic agent

Ex: codeine to morphine by CYP2D6, a cytochrome P450 liver enzyme

Enzymatic activity is generally highest in _____

the liver

Phase I reactions (biotransformation)

often the first step

products may have therapeutic or toxic activities

Types: Oxidations (primary enzymes: cytochrome P450s, CYP enzymes), Reductions, Hydrolyses

CYP enzymes

primarily active in the liver and carry out most Phase I reactions

Phase II reactions (biotransformation)

involve the coupling of a drug or its oxidized metabolite to endogenous conjugating agent derived from carbohydrate, protein or sulfur sources

product is ALWAYS greater in molecular weight than the parent compound

more water–soluble than the parent compound, and therefore more readily excreted in urine or bile

products generally have less therapeutic activity than parent drug

Excretion

elimination of drug in body fluid or breath

What is given to patient to increase excretion of a weak acid (ie: aspirin)

sodium bicarbonate - makes urine more basic

What is given to patient to increase excretion of a weak base (ie: amphetamine)

ammonium chloride - makes urine more acidic

Routes of excretion

urine - most important; rate can be altered by conditions that effect blood flow to the kidneys or their normal function, such as chronic renal disease; charged compounds are much more readily excreted in urine (more acidic than plasma)

bile - important route for drugs and their metabolites that are transported by hepatocytes. Once in the small intestine, compounds with sufficient lipophilicity are reabsorbed and cleared again by liver through the enterohepatic circulation. More polar substances may be biotransformed by bacteria, e.g. hydrolysis of drug conjugates, and products reabsorbed.

feces - unabsorbed drugs and metabolites

Minor routes of excretion include in sweat, tears, reproductive fluids, and (breast) milk

area under the curve (AUC)

dependent on dose (D), the fraction of the dose absorbed (F) and the total clearance ClT

AUC = FD/CIT

elimination rate constant (kel)

fraction of drug eliminated per unit of time

slope of the ln Cp vs. time

duration of action

amount of time the Cp is above the MECdesired line, when it is having the desired action

therapeutic window

space between MECdesired and MECadverse

therapeutic level

the minimum concentration required for the drug to have the desired effect (MECdesired)

MECadverse

the minimum concentration that causes toxic or adverse effects

bioavailability (F)

The fraction of the dose absorbed into the systemic circulation

100% for a drug given intravenously

Relative bioavailability

compare generic to proprietary

steady-rate (CSS)

drug is administered at a constant rate (k0) and its elimination follows first-order kinetics, the concentration of drug in the plasma rises exponentially and reaches a plateau level

INPUT RATE (k0 = D/T) = OUTPUT RATE (CSSVd*kel)

CSS = k0/ Vd*kel

CIT and CSS

CIT = kel*Vd

plasma concentration at steady-state (CSS) is directly proportional to the input rate (k0) of the drug and inversely proportional to its plasma clearance (ClT)

CSS = k0/ ClT

rate of achieving steady state

depends only on the elimination half-life of the drug

Half the CSS level is achieved in one t1/2, and about 94% of CSS in four t1/2

a loading dose may be given to achieve a therapeutic effect more quickly (long elimination half-life = delay in reaching steady-state)

loading dose (continuous infusion)

Loading dose = CSS•Vd

The plasma concentration will instantaneously reach the steady-state level, and that level will be maintained while the infusion continues. As drug is eliminated from the loading dose, it is replaced by drug in the infusate.

determined by the infusion rate and is NOT affected by the size of a loading dose

repeated oral doses

administered PO repeatedly to maintain their therapeutic effects

maintenance dose (D) is given at a constant dosing interval (τ): CSS “average” = F•D/τ/ ClT

Between doses the concentration fluctuates between CmaxSS and CminSS

at steady state, the drug in (dosing rate) equals the drug out (total clearance). Therefore, to achieve a specific desired CSS, the clearance is the most important factor.

cholinergic agonists and antagonists effect the ____ nervous system

Parasympathetic Nervous System

1) Ganglia typically close to target organ

2) Neurotransmitter:

Ganglionic synapse: Acetylcholine released by preganglionic neuron, and acting at neuronal nicotinic receptors of postganglionic neuron

Postganglionic neuron: Acetylcholine released by postganglionic neuron, and acting at muscarinic acetylcholine receptors on target organ

adrenergic agonists and antagonists effect the ____ nervous system

Sympathetic Nervous System

1) Ganglia predominantly located near spinal cord

Adrenal medulla is the sole organ innervated directly by preganglionic sympathetic neurons

2) Neurotransmitter:

Preganglionic neuron: Acetylcholine, acting at neuronal nicotinic receptors of postganglionic neuron

Postganglionic neuron: Norepinephrine (α1>α2>ß1>>ß2), acting at adrenergic receptors

(Exceptions: sweat glands innervated by cholinergic sympathetic fibers; dopamine in renal vasculature smooth muscle)

Adrenal medulla: Epinephrine (α1 = α2; ß1 = ß2), released into circulation

A1 selective agonist

phenylephrine

α1>α2

A2 selective agonist

clonidine

α2 (centrally active)

beta selective agonist

isoproterenol

ß1=ß2

b1 selective agonist

dobutamine

b2 selective agonist

albuterol

ß1>ß2

indirect agonist (false transmitter)

tyramine

indirect agonist/central stimulant

cocaine

alpha antagonist

phentolamine

a1 antagonist

prazosin

beta antagonist

propranolol

b1 antagonist

metoprolol

beta and alpha 1 antagonist

carvedilol

a1 receptor

vascular and genitourinary smooth muscle contraction

intestinal smooth muscle relaxation

radial muscle (eye contraction)

liver

a2 receptor

pancreas (decrease insulin secretion)

nerve terminals (decrease NE release)

CNS (decrease sympathetic tone)

platelets

b1 receptor

heart (increase force, rate, AV conduction velocity)

kidney (increase renin release)

b2 receptor

smooth muscle relaxation

skeletal muscle

liver

d1 receptor

dilates renal vasculature

Tyramine

when MAO is inhibited—can precipitate hypertensive crisis by releasing norepinephrine from nerve terminals

Can be converted to octopamine (false transmitter, released but little action at receptors) and stored in synaptic vesicles, replacing norepinephrine

long-term administration of MAO inhibitors can impair the function of the sympathetic nervous system

Dextroamphetamine

Releases norepinephrine and dopamine, also acts directly at adrenergic receptors

Orally active, marked CNS effects: wakefulness, anorexia, euphoria, locomotor stimulation, stereotyped behavior

Primary clinical use for ADHD

Methylphenidate

Effects similar to amphetamine

Primary clinical use for ADHD

Cocaine

Inhibits reuptake of norepinephrine and dopamine

Can precipitate fatal cardiovascular and CNS events, sometimes at moderate doses

Ephedrine and Pseudoepinephrine

Releases norepinephrine and directly activates α and ß receptors

Controversial ingredient of many “nutritional supplements” - use restricted by FDA

Tricyclic antidepressants

Inhibit catecholamine and serotonin reuptake. Also have antimuscarinic side effects at high doses.

MAO inhibitors

increase catecholamine levels in nerve terminals; potentiate effects of tyramine

systemic administration of norepinephrine normally results in a reflex _______ in heart rate

Baroreceptor-mediated autonomic reflex effects on heart rate and cardiac output may amplify or oppose the adrenergic receptor mediated effects of adrenergic drugs on heart rate.

Most notably, systemic administration of norepinephrine normally results in a reflex, vagal-mediated decrease in heart rate even though the direct b1-mediated effect of norepinephrine is to increase heart rate.

Therapeutic uses of adrenergic agonists - Cardiovascular

Nasal decongestants (α1 (e.g., phenylephrine, pseudoephedrine)

Slowing absorption of local anesthetics (α1, epinephrine)

Resuscitation after cardiac arrest (probably mainly α1; epinephrine)

Restoring blood pressure during:

• Overdose of hypotensive agents (α1)

• Spinal damage or anesthesia (α1)

• Cardiogenic shock (ß1; dopamine, dobutamine)

Therapeutic uses of adrenergic agonists - Ophthalmology

Mydriasis (radial muscle α1)

Treatment of wide angle glaucoma (α1 for vasoconstriction; α2 for reduced secretion)