Cholinergic Agents

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Basic Sciences Pharmacology Agents

8 questions
0

Direct agonists: directly increase cholinergic stimulation

Direct agonists only require intact receptors to function. They will work even if the
target is denervated.
1) Bethanechol

Selective muscarinic receptor stimulation, especially the M3 receptor (no less

nicotinic effect)

Usually used to treat postoperative/neurogenic ileus and bladder atony

(urinary retention)
2) Carbachol

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Stimulates both muscarinic and nicotinic receptors
Quaternary ammonium compound positively charged and cannot cross the
blood brain barrier
Topical use for treatment of glaucoma, especially open-angle type
Used to relieve intraocular pressure
Used to constrict pupils (miosis) for cataract surgery

Sometimes used to stimulate bladder emptying

3) Pilocarpine

Nonselective muscarinic receptor agonist

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Used to treat glaucoma (open-angle and acute types) by causing miosis to
increase rate of aqueous humor efflux

- Contraction of the sphincter pupillae provides temporary relief in narrow-angle

glaucoma (acute angleclosure glaucoma). (Narrow-angle glaucoma is a medical
emergency.)

- Contraction of the ciliary muscle helps open the trabecular meshwork in the canal

of Schlemm to promote outflow of aqueous humor in open-angle (wide-angle)

glaucoma.
Used to treat xerostomia (dry mouth), for example, in patients having had
radiation therapy. Stimulates saliva and sweat secretion.
Used to diagnose cystic fibrosis by the sweat test
Adverse effects: cholinergic side effects
4) Methacholine
Nonselective muscarinic receptor agonist

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Primary usage: diagnostic agent to test for bronchial hyperactivity

(asthma, COPD)
Indirect agonists (cholinesterase inhibitors): indirectly increase cholinergic
stimulation by increasing acetylcholine levels

Thus, indirect cholinomimetics require an intact nerve to function.

1) Neostigmine
Reversible cholinesterase inhibitor
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Indirectly stimulates both nicotinic and muscarinic receptors
Quaternary nitrogen has a formal charge and cannot cross the blood brain

barrier.

Improves muscle tone for patients with Myasthenia Gravis

Improves postoperative/neurogenic ileus and urinary retention

Is also used post-operatively to reverse nondepolarizing NMJ blockers

2) Pyridostigmine

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Pyridostigmine is similar in all ways to neostigmine, except its longer acting,
in other words it:

- Is a reversible cholinesterase inhibitor

- Indirectly stimulates both nicotinic and muscarinic receptors
- Has a formal charge and cannot cross the blood brain barrier (quaternary
nitrogen).
- Improves muscle tone for patients with myasthenia gravis
- Improves postoperative/neurogenic ileus and urinary retention

3) Edrophonium

Similar in all ways to Neostigmine, except it is very short acting

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Due to its short acting property, it is used to differentiate myasthenia gravis

from cholinergic crisis. Contrast this with neostigmine and pyridostigmine, which are
used to treat myasthenia gravis symptoms.
4) Physostigmine
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Tertiary compound lacks a formal charge and can cross the blood brain
barrier (BBB) can produce CNS effects of cholinergic confusion
Physostigmine is the only cholinesterase inhibitor that works both
peripherally and can cross the BBB can be used to treat the CNS symptoms of
anticholinergic (e.g., atropine) overdose.

Recall:
Symptoms of anticholinergic overdose (e.g., atropine overdose):

Hot as a hare rapid pulse, increased body temperature

Dry as a bone dry mouth
Red as a beet dry, flushed skin
Cant pop a squat constipation, urinary retention (esp. in men with benign
prostatic hyperplasia)
Blind as a bat cycloplegia (paralysis of accomodation) blurry vision
Mad as a hatter disorientation, delerium

Contrast this with symptoms of cholinergic overdose (e.g., cholinesterase

inhibitor overdose)DUMBBELSS:
Diarrhea
Urination
Miosis
Bronchospasm

Bradycardia
Excitation (skeletal muscle, CNS)
Lacrimation
Sweating
Salivation
Since it crosses the BBB, it can produce CNS effects of cholinergic confusion

But can also treat CNS symptoms from anticholinergic drug overdose
5) Echothiophate
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Irreversible cholinesterase inhibitor

Used to treat glaucoma

Cholinesterase inhibitor poisoning

Symptoms of Cholinergic Crisis: diarrhea, urination, miosis, bronchospasm,

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bradycardia, excitation of skeletal muscle and CNS, lacrimation, sweating, and
salivation.(DUMBBELSS)
Due to excessive nicotinic and muscarinic acetylcholine stimulation
Produced by organophosphate insecticides (Parathion, Malathion) or
excessive irreversible cholinesterase inhibitor (Echothiophate)

Treatment : Atropine (muscarinic antagonist that crosses blood brain barrier)

and Pralidoxime (chemical antagonist that regenerates cholinesterase)
Donepezil (and physostigmine) are centrally acting cholinesterase inhibitors that is
used in the treatment of Alzheimers disease. They act to increase ACh in the basal
forebrain and cerebral cortex, thereby alleviating some of the symptoms of AD.

Sympathomimetics
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A) 8 Direct agents
1) Epinephrine: agonist to all receptors (1, 2, 2, mild 1)

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Clinical applications: asthma, hypotension, cardiac resuscitation, anaphylaxis
2) Norepinephrine: agonist to 1, 2, and mild 1; no effect on 2
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Clinical Applications: hypotension such as in sepsis, but can decrease renal
and mesenteric perfusion
Note: because NE has no effect on the 2 receptor and therefore cannot elicit the
bronchodilatory or vasodilatory effects of 2 receptors, NE cannot be substituted

clinically for epinephrine in situations such as anaphylaxis, cardiac arrest, or

emergent bronchospasm
3) Isoproterenol: equal agonist 1 = 2 activity

Clinical applications: bradycardia due to AV block, used to increase heart rate

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after cardiac transplant
4) Dopamine: D1 = D2, mild 1 & 2 and mild 1

Clinical applications: heart failure, hypotension. There is some support for less
dopamines role in preserving renal perfusion.
5) Dobutamine: 1 > 2

Clinical applications: heart failure since it increases inotropic cardiac outputless

but it can also cause hypotension
6) Phenylephrine: 1 > 2

Clinical applications: hypotension, nasal congestion

7) Albuterol, Terbutaline, Salmeterol, Metaproterenol: 2 > 1

Clinical applications: acute asthma (albuterol); premature labor (terbutaline)

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8) Ritodrine: 2 only

Clinical application: premature labor, decreases uterus contractions

B) 3 Indirect agents
1) Ephedrine

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Is a mixed agent: weak, direct agonist of both alpha and beta receptors
Strong indirect effect of inducing presynaptic release of stored
catecholamines

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Clinical application: hypotension, bradycardia

2) Amphetamine
Indirect effect by inducing presynaptic release of stored catecholamines

Clinical application: attention deficit disorder, narcolepsy, depression

3) Cocaine

Inhibits the reuptake of norepinephrine, thereby indirectly causes an

increased norepinephrine availability in synapse

Clinical application: local vasoconstriction and local anesthesia effects

C) 2 agonist: clonidine, methyldopa, dexmedetomidine, guanfacine

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Decreases presynaptic release of norepinephrine or epinephrine

Clinical application: hypertension, pain syndromes

Side effect: sedation, hypotension, dry mouth, can have withdrawal symptoms

NMJ Blocking Agents

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Basic Sciences Pharmacology Agents

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1 question
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There are 2 basic classes of NMJ blockers: nondepolarizing and depolarizing agents.

Non-depolarizing agents: Achieve blockade by physically limiting accessless

of
the agonist to the receptor (i.e. functions as a competitive antagonist).

These represent the majority of NMJ blocking agents that are clinically used.

Depolarizing agents: Achieve blockade of the NMJ by over activation of the

normal agonist pathway.

The only depolarizing agent currently used in the US is succinylcholine.

Depolarizing agents work in 2 phases: depolarizing phase and desensitizing phase

Phase I Block (Depolarizing Phase): Succinylcholine binds the receptor

depolarizesthe membrane; causes an initial discharge that produces
fasciculations followed by a flaccid paralysis.

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Because succinylcholine is metabolized slowly, the membrane

becomes unresponsive to further impulses.

Phase II Block (Desensitizing phase): Eventually, the membrane repolarizes,

however remains unresponsive because it is desensitized.

During later phase II, desensitizing agents are susceptible to reversal by ACh
esterase inhibitors.
Non-depolarizing agents are competitive antagonists of ACh at the nicotinic AChR
(most commonly those at the NMJ).

d-Tubocurarine: Prototypical non-depolarizing agent.

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Uses: Because of long duration of action, useful for surgical paralysis. Use has been
supplanted by newer agents.

Adverse effects: Causes weak muscarinic ACh antagonism and histamine release.
Atracurium: Similar to tubocurarine in duration of activity but does not have
anticholinergic or histaminergic effects.

Because atracurium is eliminated by ester hydrolysis, it is the drug of choice in

patients with renal impairment.
Rocuronium: Useful in patients with renal impairment (hepatic excretion)

Uses: 20-40 min duration useful for surgical procedures.

Vecuronium: Intermediate duration of activity
Mivacurium: Rapid onset with a short duration of activity (10-20 mins)

Metabolism: Plasma cholinesterase

Because the non-depolarizing agents are competitive antagonists of the

AChR, their effect can be reversed by acetylcholine esterase inhibitors such
as neostigmine andpyridostigmine.

Blockers
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1 question
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Metoprolol, atenolol, propranolol, timolol, esmolol, labetalol, carvedilol, acebutolol,

betaxolol, pindolol
General rules for -blocker nomenclature:
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-olol ending for all general -blockers
-alol, -ilol drugs are combined blockers
sotalol: potassium channel and -blocker
labetalol: / blocker

carvedilol: / blocker
Selectivity:

Nonselective 1 and 2 antagonists Can be remembered with mnemonic:less

Better Try Pretty Nonselective PIlls:

Beta:
Timolol
Propranolol
Nadolol
PIndolol

1 selective antagonists can be remembered with

mnemonic A BEAM = Acebutolol,Betaxolol, Esmolol, Atenolol
(no CNS entry), Metoprolol
Partial -agonists (fewer side effects, minimal change in plasma lipid profile):
pindolol, acebutolol.

Because these drugs can have sympathomimetic effects which can exacerbate
angina, they are contraindicated in patients with angina.

Nonselective and antagonist = labetalol and carvedilol (will decrease

blood pressure and heart rate)
-Blockers action on the heart:
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Decreases AV conduction velocity; treatment for supraventricular tachycardia

All -blockers are Class II antiarrhythmics

Notes regarding blockade:
Treatment for angina due to decreased myocardial O2 consumption
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Decreases mortality after a myocardial infarct
Slows progression of congestive heart failure by decreasing renin activation

Toxic side effects: asthma exacerbation, AV block, acute heart failure,

sedation, impotence

Blockers
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5 questions
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Nonselective (blocks 1 and 2 receptors)

Examples: phenoxybenzamine (irreversible blockade) and phentolamine less

(reversible blockade) both used to treat hypertension

Phenoxybenzamine is the drug of choice for hypertension due to

pheochromocytomas:
- it has a slower onset and a longer lasting effect compared to other blockers,
which
minimizes the likelihood of severe hypertension during surgery
Clinical application: urinary retention in patients with benign prostatic hyperplasia,
hypertension
Selective 1 blockade: Prazosin, Terazosin, Doxazosin
All 1 blockers will have the side effect of orthostatic hypotension

Note: Prazosin is associated with a first-dose response of significant

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orthostatic hypotension and syncope (fainting), especially after the first dosesimilar
effects can occur if:

- dosage is rapidly increased

- therapy is interrupted for a few days and then resumed

- or prazosin is combined with another antihypertensive drug (particularly

vasodilators) or a phosphodiesterase type 5 inhibitor (PDE-5 inhibitor)e.g.,
sildenafil citrate (Viagra).
Selective 2 blockade: Mirtazapine
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Increased release of norepinephrine and serotonin from presynaptic vesicles

Clinical application: depression, anorexia with depression (side-effect of

weight gain)

Glaucoma Treatment
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Basic Sciences Pharmacology Agents

3 questions
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Glaucoma is caused by intraocular pressure (IOP), which can lead to blindness if

left untreated. Goal of treatment: IOP.

Open angle glaucoma: normal ocular angle. Occurs due to acutely reduced or
obstructed outflow from the canal of Schlemm.
Closed angle glaucoma: generally from excessive pupillary dilation; posterior
chamber pressure pushes iris forward, closing the ocular angle prevents drainage
of aqueous humor. This is a medical emergency
Eye innervation:

1 stimulation: contraction of pupil dilator/radial muscles (mydriasis)

M3 stimulation: contraction of pupil constrictor/circular muscles (miosis).

M3 agonists can also open the trabecular meshwork outflow of aqueous humor.
Miotic agents (parasympathomimetics)
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Examples: pilocarpine, carbachol, echothiophate, physostigmine
These agents contract the ciliary muscles and open the trabecular meshwork
increased outflow of aqueous humor with resultant decrease in IOP

Causes miosis and cyclospasm. Retinal detachment is an uncommon but

dangerous side effect.
Carbonic anhydrase inhibitors
Example: Acetazolamide

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less

Decreases aqueous humor production due to decreased HCO3 . Bicarbonate

is required for aqueous humor production.
Topical -antagonist
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Example: Timolol
Decrease aqueous humor production by ciliary epithelium
-

-blocker side effects include: asthma exacerbation, impotence, fatigue,

bradycardia, hypotension
Prostaglandins

Example: Lantanoprost
Prostaglandins are thought to IOP by outflow of aqueous humor.

Useful for the treatment of open angle glaucoma.

Anticholinergics: Muscarinic Receptors

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4 questions
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Atropine

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Causes mydriasis and cycloplegia

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Treatment for bradycardia, asystole, heart block: at high or toxic doses, HR
(note that at low doses, the effect is bradycardia secondary to atropine-induced Ach
release from inhibitory neurons)

These effects are due to the inhibition of parasympathetic tone on the heart
increase HR
Inhibits salivary/sweat/mucus gland airway secretions
Decreases stomach acid secretions
Decreases gut motility
Can be used to treat symptoms of organophosphate poisoning
Overdosage can produce an anticholinergic toxidrome (hot as a hare, blind
as a bat, dry as a bone, red as a beet, and mad as a hatter)
Crosses the blood brain barrier and can result in CNS manifestations of
anticholinergic toxidrome
Beware: can cause acute angle closure glaucoma or urinary retention in men
with prostatic hyperplasia
Benztropine
Centrally acting anticholinergic with antihistamine properties
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Treatment for Parkinsons symptoms (decreases cholinergic stimulation)

Treatment for dystonia, akathisia

Glycopyrrolate

Similar to atropine except it is a quaternary amine and polar, so it doesnt less

cross blood brain barrier
Ipratropium
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Treats asthma and COPD by counteracting parasympathetic
bronchoconstriction
Methscopolamine
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Used in combination with other drugs to treat peptic ulcers

Decreases stomach acid, relaxes muscles in stomach and intestines

Oxybutynin
Reduces bladder spasms

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Treats urge incontinence

Scopolamine
Treats motion sickness
Causes mydriasis and cycloplegia. Can also cross blood brain barrier and
result in CNSmanifestations of anticholinergic toxidrome.

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Enzyme Kinetics
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5 questions
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Enzyme-catalyzed reactions are saturable

Are not linear in response to increasing substrate

Most enzymatic reactions can be described by the Michaelis-Menten
equation, which relates the initial velocity of the enzymatic reaction (V) to the
substrate concentration ([S]). Vmax is the enzymes maximal rate, and Km is the
Michaelis constant.

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V = (Vmax[S]) / (Km + [S])

At low substrate concentrations, V (reaction rate) increases along with the
substrate concentration.
However, as substrate concentration gets higher, enzyme becomes saturated
and rate reaches Vmax, the maximum rate at which the reaction can occur.
Km = the substrate concentration at Vmax
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Reflects the AFFINITY of enzyme for its substrate

So if Km is low, the affinity of enzyme for substrate is high

If Km is high, then the affinity of enzyme for substrate is lower

Lineweaver-Burk plot (double reciprocal plot)
Linear transformation of the Michaelis-Menten equation. Particularly usefulless
for
evaluating mechanism of inhibition. Km and Vmax can be obtained from the linear
regression.
1/V (reciprocal of the initial velocity of the enzymatic reaction) is plotted vs. 1/
[S] (reciprocal of the substrate concentration). The linear regression is described by:

(1/V) = [(Km/Vmax) * (1/[S]) ] + (1/Vmax)

The equation given above is of the form y = mx + b

- the slope of the Lineweaver-Burk plot is Km/Vmax

- the y-intercept is 1/Vmax
- the x-intercept is -1/Km
For competitive inhibitors:

Competitive inhibitors compete with substrate for the enzymes active site, less
therefore Km because it takes more substrate to reach 1/2 Vmax
Inhibition can be completely overcome by increasing substrate, therefore
Vmax is unchanged
For noncompetitive inhibitors:

Noncompetitive inhibitors bind outside the active site (and therefore do notless
compete with the substrate).

Increasing substrate concentration will not relieve the noncompetitive

inhibition. Km stays constant while Vmax .

Drug Elimination
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2 questions
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Zero-order elimination

A constant amount of drug eliminated per unit of time

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Drug plasma concentration decreases linearly with increased time

Examples: Can be remembered with mnemonic: a PEA has zero calories.

Phenytoin
Ethanol
Aspirin
First-order elimination
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There is a constant fraction of drug eliminated per unit of time
Drug plasma concentration decreases exponentially with increased time
Most drugs are eliminated in this manner

Phase I vs. Phase II Metabolism

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3 questions
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The smooth endoplasmic reticulum of liver cells is the principal organelle of drug
metabolism
Phase I

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Oxidation (cytochrome P450, monoamine oxidase, alcohol dehydrogenase)
Reduction (NADPH)
Hydrolysis

Some drugs are activated by Phase I metabolism.

For drugs that are inactivated, if they are sufficiently polar they can be excreted
renally. Most will undergo subsequent Phase II metabolism.
Phase II

Acetylation (Amino acid N acyl transferase).

Note that there are generally 2 types of acetylation:
1) Fast acetylation
2) Slow acetylation

Those who are slow acetylators are at increased risk for druginduced SLE (Hydralazine > Procainamide > INH)
Glucuronidation (UDP-glucuronosyltransferase)
Sulfation (sulfotransferase)

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Results in inactive metabolites that are very polar, and therefore readily
renally excreted

Pharmacodynamics
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5 questions
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Describes the effect of the drug on the body

Expressed through a Dose-Response Curve
Efficacy point: the highest level of % maximal response attained
Potency: indicated by the location of the dose-response curve along the X-axis

Higher potency when curve is left shifted

Competitive antagonists:
Potency is decreased: Curve is shifted to the right

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100% of maximal response can still be attained by adding more agonist,

therefore efficacy remains unchanged
Noncompetitive antagonist:

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Efficacy is decreased: Curve is shifted downward
Potency may or may not be affected by a noncompetitive antagonist.
A) If efficacy of endogenous agonist is low, low receptor density, and/or poor
coupling of receptors antagonist has no effect on potency: curve does not shift to
the right

B) If efficacy of endogenous agonist is high, high receptor density, efficient

coupling of receptors, and/or high receptor reserve potency is decreased: curve
shifts to the right
Partial Agonist:
Partial agonists have a lower efficacy at all doses relative to a full agonist less
Potency is an independent factor (partial agonist can have more, less, or
equal potency compared to the original agonist)

Extracellular Receptor And Functions

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11 questions
0

1: vasoconstriction, constricts uterus, contracts pupillary dilator (mydriasis),

constricts sphincters in intestine as well as internal urethral sphincter
2: decreases sympathetic outflow, decreases insulin release
1: increases contractility, increases chronotropic (heart rate), increases conduction
at AV node, increases renin, increases lipolysis via HSL (hormone sensitive lipase)
2: vasodilation, bronchodilation, relaxes uterus, increases liver glycogenolysis and
gluconeogenesis, inhibits mast cell release
M1: gastric acid secretion, found in CNS (but role undefined)
M2: decreases HR, decreases contractility, decreases AV node conduction
M3: increases peristalsis, increases bladder contraction, increases exocrine gland
secretions, bronchoconstriction, contracts the sphincter pupillae (miosis)
D1: renal vasodilation
D2: dopamine control in brain
H1: mast cell degranulation, nasopharyngeal/bronchial mucus production, bronchial
smooth muscle constriction (bronchospasm).
H2: increases gastric acid secretion
V1: increases vascular smooth muscle contraction
V2: vasopressin receptor in collecting tubules H2O reabsorption

Acetylcholine Synthesis & Degradation

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5 questions
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ACh is synthesized in the presynaptic nerve terminal via the combination

of choline withAcetyl CoA.

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The enzyme choline acetyltransferase (ChAT) catalyzes this step.
Newly formed ACh is then packaged into presynaptic vesicles via the ACh
transporter.
When the vesicle is released, ACh enters the synaptic cleft where it can bind
to the postsynaptic receptors.

AChE (ACh Esterase) is an enzyme that degrades ACh in the synapse choline +
acetic acid.

Choline is then recycled back into the presynaptic neuron via a

Na dependent transporter, where it is reused.
+

There are several drugs that can interfere with the ACh synthesis or degradation
pathway:
Hemicholinium = prevents intracellular influx of choline by reuptake
Vesamicol = prevents ACh from being packaged into intracellular vesicles
Botulinum = prevents presynaptic vesicle release of ACh by cleaving synaptobrevin
Black widow spider toxin = increases presynaptic vesicle release of ACh
Cholinesterase inhibitors = prevents the breakdown of ACh in the synaptic channel,
by inhibiting the enzyme acetylcholinesterase

Spare Receptors and Curve Shifting

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Basic Sciences Pharmacology Physiology

3 questions
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Spare receptor theory states that a maximal physiological effect of a drug is often
met when a proportion of the receptors remain unbound by the drug.

Striking experimental evidence: An irreversible antagonist can be bound toless

90% beta adrenergic myocardial receptors in the presence of catecholamines and
still produce a maximal effect!
The mechanism is related to the fact that the receptor occupancy and
pharmacological effect is infrequently directly proportional.

With ligand gated ion channels, this is the case. The percentage of channels
less
bound by the ligand is proportional to the ion flow and to the effect.
But with the case of G-protein coupled receptors and others that
use downstream effectors, the effect is often magnified.
So that means that drug X can bind to receptor A, trigger a cascade,
disassociate and then bind to receptor B, while receptor A is still activating its effect.
Thus all receptors neednt be temporally occupied to create a maximal downstream
effect.

Thus, it isnt a maximal binding of a drug to its receptor sites which causes a
max effect, but rather a downstream effector (like PKA) that becomes the limiting
reagent.
When graphically portrayed on a dose response curve, the effect of spare receptors
with the addition of a irreversible antagonist in the presence of an agonist would
show a direct translation to the right. In other words, the pharmacodynamics
would remain unchanged. The only change would be the EC50 (concentration of the
drug that produces 50% maximal response), would increase.

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As you experimentally increase this antagonist concentration, the curve would
keep shifting right until too many receptors are occupied, at which point the curve will
behave like a irreversible agonist dose curve, with Emax decreasing.
Take home point: Since drug effect is a direct result from the activity of downstream
effectors (a cascade), a cell can increase its expression of surface receptors to
produce a more sensitive response. If you have many more receptors, then you
need less drug to bind the same amount of receptors and produce the same
downstream effect.

Pharmacokinetics
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8 questions
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Describes how the body affects the drug

Volume of distribution Vd = (total amount of drug in body) / (plasma drug
concentration)

Vd is not a "real" number, it just reflects how a drug will distribute throughout
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the body based on solubility, charge, size, etc

Can be altered by kidney disease, liver disease, obesity, drug-drug

interactions, and age
Distribution of drugs in a body is a function of:

Solubility in different solutions (lipid or aqueous) and therefore body

compartments (adipose or non-adipose tissue).
Concentration gradient
Ability to bind to different constituents in tissues (ex. lipids, proteins)

Surface area and vascularity of affected area (more blood flow, more drug
delivery; more surface area, more drug entry into the circulation)
Drugs bound to plasma proteins (albumin) are not available for:
Further distribution into tissues
Active pharmacological action
Glomerular filtration

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Metabolism
Low Vd (4-8L) pharmacokinetics
High plasma protein bound

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Example: Warfarin
Medium Vd (8-60L) pharmacokinetics
Water soluble molecules
Distributes into extracellular fluid (10-20L) or total body water (30-45L)

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Example: Ethanol
High Vd (Vd > 60L) pharmacokinetics

Lipophilic, strongly bound in intracellular sites

Sequestered into adipose tissue. High Vd low protein binding.

Example: Chloroquine

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Clearance (CL) = (rate of elimination of drug) / (plasma drug concentration)

Clearance (CL) = Constant (k) * Volume of Distribution (Vd)
Half-life (T1/2) = time required to reduce the concentration of a drug by half.

T1/2 = 0.7 Vd / CL
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Steady state (Css) = equilibrium point where amount of drug administered exactly
replaces the amount of drug excreted. It takes about 4 x T1/2 to reach steady state.

Css = (F x D) / (CL x Tau)

Css is directly proportional to

D dose of drug
F fraction of the dose absorbed
T1/2- half life of drug
Css is inversely proportional to
Tau time interval between the doses

CL clearance of drug

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Therapeutic Index
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4 questions
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Every drug has a dose-response curve of effectiveness and a curve for toxicity. A
comparison of these two curves will give you the drugs therapeutic index.
Therapeutic index: (dose at which 50% of subjects develop a toxic effect) / (median
effective dose) = (TD50) / (ED50). Historically, the TI was defined using the lethal dose
(LD50) rather than the toxic dose (TD50).
In the image: Therapeutic index = 10/0.3 = 33
A higher therapeutic index value indicates a safer drug

Norepinephrine Synthesis And

Degradation
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6 questions
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Norepinephrine synthesis: The hydroxylation of tyrosine and formation of dopamine

takes place in the cytoplasm

Dopamine then enters the storage granules where it is converted to

norepinephrine

Inactivation of norepinephrine is achieved by metabolism in the synaptic cleft

by COMT(1/3rd) or by reuptake into the proximal axon (2/3rd) once back in the
cytoplasm, it is either repackaged into vesicles or metabolized by cytoplasmic MAO
Metyrosine: inhibits tyrosine hydroxylase (this is the rate-limiting step)

Phe Tyr catecholamines

- first step: phenylalanine hydroxylase
- second step: tyrosine hydroxylase

Note: BH4 is a cofactor for both reactions.

Other fates of tyrosine

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- Tyr DOPA (several steps) melanin (key enzyme: tyrosinase)

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- Tyr T3 and T4 (directly by iodination)

- Tyr catabolism yields acetoacetate and fumarate (proceeds via homogentisate
intermediate)
Reserpine: inhibits VMAT (vesicular monoamine transporter), thereby preventing the
entry of dopamine into presynaptic vesicles intracellular concentration of
dopamine degradation by MAO
Guanethidine: prevents presynaptic vesicle release of NE
Cocaine or tricyclic antidepressants: prevents presynaptic reuptake of NE.

Cocaine also enhances transmission of other monoamines such as dopamine and 5HT by blocking presynaptic re-uptake. This mediates the effects of cocaine in the
mesolimbic reward center.
Amphetamine: increases presynaptic vesicle release of NE and, to a lesser extent,
acts as a reuptake inhibitor

Other Types Of Receptors

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3 questions
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Ligand-gated ion channels: nicotinic cholinergic receptor, GABA, Glu, Asp & Gly
receptors
G-protein-coupled receptors: several classes, including those for most peptide
hormones, eicosanoids, and biogenic amines (example: catecholamines)
Signal transmission through transcription factors: receptors for lipophilic molecules
(example: steroid hormones, thyroid hormone, vitamin D, retinoids)

Lipophilic molecules (steroids, thyroid hormone, vitamin A and D) easily pass

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through lipid bilayer of cell membrane. Once intracellular, they bind to specific
cytoplasmic protein and pass into nucleus where they change the rate of mRNA
transcription.
Signal transmission through receptor tyrosine kinases. Examples: insulin, growth
factors (e.g.EGF, PDGF)

G Protein Signal Transduction

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4 questions
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3 types of G protein linked 2nd messenger pathways

G(i) inhibits Adenylyl Cyclase inhibits cAMP production decreases protein
kinase A activity
G(s) activates Adenylyl Cyclase increases cAMP production increases protein
kinase A activity
G(q) stimulation phospholipase C stimulates the hydrolysis of PIP2

PIP2 is metabolized to IP3 (inositol triphosphate) and DAG (diacylglycerol) less

IP3 is released into cytoplasm where it binds to endoplasmic reticulum and
increases intracytoplasmic [Ca2+]

DAG stays bound to cell membrane and, together with Ca2+ liberated from
the endoplasmic reticulum due to IP3, activates protein kinase C
The way to remember which receptor types use which G protein pathway is:

G(i) = 2, M2, D2 (just memorize that 2 is by inhibition, G(i); rarely will theyless
test M2 or D2)
G(s) = 1, 2, H2, V2, D1 (need to memorize, but if you memorize G(q), this will
be easy)
G(q) = 1, H1, V1, M1, M3 (all the 1s except 1 and D1. Remember this
phrase: Bob andDan are NOT Quiet Ones)

Alternatively, use the mnemonic: QISS and QIQ till youre SIQ of SQS

1 Q
2 I
1 S
2 S
M1 Q
M2 I
M3 Q
D1 S
D2 I
H1 Q
H2 S
V1 Q
V2 S

CYP450 Interactions
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Basic Sciences Pharmacology Toxicology

3 questions
0

Cytochrome P450 is the most important element of oxidative metabolism (Phase I

reaction)

Note: The list of inducers and inhibitors here is not meant to be a list of all less
drugs that affect the P450 system, but a select few that are high yield for exam
purposes and for clinical settings.
Drugs that induce P450
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Barbiturates are P450 inducers.
Nevirapine is a P450 inducer.
St. Johns wort is a P450 inducer.
Smoking (aromatic hydrocarbons) is a P450 inducer.
Phenytoin is a P450 inducer.
Rifampin is a P450 inducer.
Griseofulvin is a P450 inducer.
Carbamazepine is a P450 inducer.
Chronic ethanol use/abuse is a P450 inducer.

Modafinil is a P450 inducer.

Drugs that inhibit the P450 system:

Ritonavir is a P450 inhibitor.

Quinidine is a P450 inhibitor.
Ketoconazole is a P450 inhibitor.
Macrolides (erythromycin) is a P450 inhibitor.
Grapefruit juice is a P450 inhibitor.
Ciprofloxacin is a P450 inhibitor.
Acute alcohol intoxication is a P450 inhibitor.
Sulfonamides are P450 inhibitors.
Isoniazid is a P450 inhibitor.
Cimetidine is a P450 inhibitor.
Amiodarone is a P450 inhibitor.

Gemfibrozil is a P450 inhibitor.

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Alcohol Metabolism
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Basic Sciences Pharmacology Toxicology

4 questions
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Three types of alcohol substrates:

Ethylene glycol (found in antifreeze and bleach products)

Methanol (found in industrial solvents)

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Ethanol (found in college)

All three types are initially metabolized by alcohol dehydrogenase
Ethylene glycol is metabolized by alcohol dehydrogenase into oxalic acid. Oxalic acid
combines with metal ions to deposit crystals in kidney tubules, resulting in metabolic
acidosis and acute renal failure.

Treatment for Ethylene glycol toxicity:

1) Correct acid/base status
2) Ethanol: allows competitive inhibition. Alcohol dehydrogenase will
metabolize ethanol and allow ethylene glycol to be filtered without metabolism;
thereby preventing toxic byproduct production.

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3) Fomepizole: inhibitor of alcohol dehydrogenase enzyme

Methanol is metabolized into formaldehyde and formic acid
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Formic acid is broken down into formate byproduct. This byproduct is toxic
because it inhibits mitochondrial cytochrome c oxidase, can result in optic nerve
injury.
Treatment for methanol toxicity:
Correct acid/base status
Folic acid: cofactor in conversion of formic acid to CO2
Ethanol: to competitively inhibit methanol breakdown
Fomepizole: inhibits alcohol dehydrogenase

Ethanol is metabolized by alcohol dehydrogenase enzyme to produce acetaldehyde.

Acetaldehyde is further metabolized by aldehyde dehydrogenase to produce
harmless acetic acid.

Disulfiram: Irreversibly inhibits oxidation of acetaldehyde by competing with

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cofactor NADfor binding sites on acetaldehyde dehydrogenase.

Results in a buildup of acetaldehyde. It is the acetaldehyde that produces the

unpleasant nausea, headache, vomit, and flushing symptoms.

Toxicology
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Basic Sciences Pharmacology Toxicology

15 questions
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Acetaminophen

Symptoms: abdominal pain, increased liver function enzymes, coagulopathy

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Normally, acetaminophen is conjugated in the liver to inactive metabolites.
However, a fraction of acetaminophen becomes hydroxylated to Nacetylbenzoiminoquinone (NAPQI), a toxic metabolite which can react with the
sulfhydryl groups of hepatic proteins, forming covalent bonds, which can lead to
zone III centrilobular hepatic necrosis.
At normal therapeutic doses, this is not clinically significant because
the NAPQI reacts with the sulhydryl group of glutathione molecules and forms a
nontoxic metabolite which can be excreted in the urine.

However, with an overdose of acetaminophen, glutathione molecules in the liver are

depleted, and accumulating quantities of NAPQI react with the sulfhydryl groups of

hepatic proteins and cause hepatic necrosis, which can potentially become lifethreatening.

Antidote: N-acetylcysteine (precursor of glutathione, increases available

glutathione to conjugate NAPQI); avoid using this agent with patients that have
preexisting liver failure.
Aspirin

Symptoms: anion gap metabolic acidosis, respiratory alkalosis, tinnitus less

Mechanism of respiratory alkalosis: aspirin and other salicylates uncouple the
ox-phos pathway, which leads to elevated [CO2] and subsequently respiratory
rate.

High aspirin doses affect the medullary respiratory center, which leads to
hyperventilation and a respiratory alkalosis that can usually compensated by
excretion of H and NH4 as well as reabsorption of bicarbonate.

Note: toxic doses of aspirin can lead to respiratory paralysis, and respiratory acidosis
can then ensue instead due to decreased ventilation and increased CO 2 production

Antidote: Bicarbonate to treat acidosis and dialysis

Amphetamines

The major pharmacological effects of amphetamine are due to it causing less

release of both dopamine and NE
CNS symptoms: insomnia, dizziness, tremor, irritability, confusion, panic,
delirium, and suicidal tendencies are possible.

Chronic amphetamine usage can produce symptoms that appear similar to the
psychotic episodes associated with schizophrenia, which makes sense due to its
mechanism of action dopamine and NE release. Rather than try and memorize
the list of CNSeffects, if you recall its mechanism of action, a list of its side effects
should be easy to generate.
Cardiovascular symptoms: arrhythmias, hypertension, angina, palpitations,
headache, chills, hyperhidrosis
Antidotes: treat overdoses with chlorpromazine or haloperidol -blocking
properties which relieve both CNS and cardiovascular side effects.

NH4Cl (acidify urine to enhance secretion)

Alkali agents (found in batteries, drain cleaners, detergents)

Symptoms: dysphagia, drooling, metabolic alkalosis

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Antidote: Milk, water, NPO (nothing by mouth) to prevent further esophageal

erosion
Anticholinergics
Symptoms: hot as a hare (fever), blind as a bat (mydriasis), dry as a bone,less
red as a beet, and mad as a hatter (delirium)

Antidote: Physostigmine (crosses the blood brain barrier to treat delirium)

Anticholinesterase and Organophosphates

Symptoms: DUMBBELSS:
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diarrhea, urination, miosis, bronchospasm, bradycardia, excitation of skeletal muscle
andCNS, lacrimation, sweating, and salivation

Antidote: Atropine and Pralidoxime

Arsenic

Symptoms:

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-Garlic smelling breath

-CNS sxs: seizures, altered mental status, coma
-Meess lines (white horizontal lines on fingernails)

Antidote: Dimercaprol, gastric lavage

Benzodiazepines

Benzodiazepines target the GABAA receptors and the frequency of their less
chloride channel opening, causing postsynaptic hyperpolarization and inhibiting
action potential generation.
Symptoms: apnea, drowsiness, excessive amounts can also cause cardiac
depression

Antidote: Flumazenil, a GABA-receptor antagonist

Beta Blockers

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Symptoms: Hypotension, bradycardia, hyperkalemia, hypoglycemia,
bronchiolar smooth muscle constriction (bronchoconstriction airway resistance,
especially in asthmatics)

Antidote: Glucagon
Carbon Monoxide

Physical signs: cherry red skin and mucous membranes, confusion

Antidote: 100% oxygen, hyperbaric oxygen

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Copper, Gold, Mercury

Symptoms: anemia, convulsions, liver failure, myopathy, skin discoloration,less

peripheral neuropathy
Copper poisoning yellow discoloration of skin, Wilsons liver disease
Mercury poisoning consumption of fish, improper disposal of fluorescent
light bulb or spills
Antidote: Dimercaprol
Cyanide
Symptoms:

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- almond scent breath

- trismus

- apnea, seizures, coma, cardiac arrest

Cyanide poisoning from nitroprusside causes metabolic acidosis with
increased mixed venous PO2 (tissues are not able to utilize bound oxygen). Early
sign is tachyphylaxis to nitroprusside infusion.
Antidote:
1. Amyl nitrite and sodium nitrite are given. The combination of these causes
oxidation of hemoglobin and intentional formation of methemoglobin.
2. Sodium thiosulfate is then given which acts as a sulfur donor, to increase the
production of thiocyanate (SCN-) which can be excreted.
3. Hydroxocobalamin has been recently approved in the US. It combines with CN to
form cyanocobalamin (Vit B12), which is renal excreted.
Digoxin
Decreased levels of potassium in the blood can increase the potential for less
cardiotoxicity with digoxin; this is most commonly seen in patients who are
concurrently on thiazide or loop diuretics. Patients on digoxin should be treated with
potassium-sparing diuretics or given supplemental potassium.
Simultaneous treatment with digoxin and a variety of drugs including
quinidine, amiodarone, erythromycin, tetracycline, and verapamil can dramatically
increase the serum concentration of digoxin both through competition with digoxin for
renal excretion and by displacement of digoxin from protein-binding sites in tissue.
Care should be taken to reduce dosage when administering any of the above
medications along with digoxin.
Symptoms: yellow red halos in vision, nausea, heart block or supraventricular
tachycardia

Antidote: Antidigoxin Fab-antibodies

Heparin
Symptoms: bleeding, thrombocytopenia

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Antidote: Protamine sulfate; combines ionically in a 1:1 ratio with heparin to

form an inactivated compound.
Iron
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Symptoms: confusion, bloody diarrhea (acute GI bleed) or metabolic acidosis
(chronic iron exposure). With chronic iron overload hemachromatosis may develop: a
disease causing restrictive cardiomyopathy, joint pain, brittle diabetes and bronze
coloring of the skin (all due to iron deposits).
Antidote: Deferoxamine
Isoniazid

Symptoms: confusion, peripheral neuropathy, hepatotoxicity, seizures

Antidote: Pyridoxine

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Lead

Symptoms: microcytic anemia, abdominal pain, purple lines on gingivae, less

peripheral neuropathy (wrist and foot drop), ataxia

Antidote: EDTA, Penicillamine, Dimercaprol

Methemoglobin

Symptoms: cyanosis, fatigue, confusion, coma

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Antidote: Methylene blue

Opioids
Symptoms:

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- apnea
- miosis (except meperidine, an opioid which can cause mydriasis due to muscarinic
antagonism)
- sedation
- constipation

Antidote: Naloxone
Phenobarbital
Symptoms: sedation, hypotension, cardiac depression

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Antidote: Charcoal, Bicarbonate to improve renal secretion

Quinidine
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Symptoms:

- torsades des pointes, thrombocytopenia, tinnitus

- cinchonism
- cytochrome P450 inhibitor

Antidote: Intravenous magnesium for torsades des pointes

Tricyclics

Symptoms: the 3 Cs due to muscarinic blockade:

1. Convulsions
2. Coma
3. Cardiotoxicity e.g., arrhythmias, torsades des pointes

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Note: the drugs that can precipitate the 3 Cs due to muscarinic blockade can be
remembered with the mnemonic All These Quirks Are Muscarinic Antagonists:
Antihistamines (1st generation)
TCAs
Quinidine
Amantadine
Meperidine (the oddball of the opioids that causes mydriasis due to muscarinic
block)
Antipsychotics chlorpromazine, thioridazine

Antidote: Charcoal; Bicarbonate to improve renal excretion

tPA, Streptokinase
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Symptom: bleeding

Antidote: Aminocaproic acid

Warfarin

Symptoms: bleeding, skin necrosis (especially in patients with protein C orless

S
deficiencies)
Antidote: FFP (rapid), Vitamin K (requires several hours)

Notable Drug Toxicities

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Basic Sciences Pharmacology Toxicology

22 questions
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Agranulocytosis
Carbamazepine
Procainamide
Clozapine
Colchicine

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Propylthiouracil and Methimazole

Aplastic anemia
Chloramphenicol
NSAIDS
Benzene

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Propylthiouracil and Methimazole

Adrenocortical insufficiency

Long-term treatment with high doses of corticosteroids causes suppressionless

of
the adrenal glands production of endogenous steroids.

Pathophys: High doses of exogenous steroids negative feedback on the HT

lessACTH release from pituitary less stimulation of adrenal cortex atrophy.
Sudden cessation of glucocorticoid treatment will lead to acute adrenocortical
insufficiency.

In times of stress, infection or surgery, this can cause adrenal crisis and shock.
Anticholinergic syndrome

Muscarinic antagonists can be remembered with the first letters of the

mnemonic "All These Quirks Are Muscarinic Antagonists":

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Antipsychotics, TCAs, Quinidine, Amantadine, Meperidine, Antihistamines

Cough

ACE Inhibitors
Not seen with Angiotension Receptor Blockers such as Losartan
Coronary vasospasm

Cocaine

Sumatriptan
Cholinergic syndrome

Cholinesterase inhibitors: neostigmine, physostigmine

Organophosphates (Sarin, Soman)
Pilocarpine

Carbachol, Bethanechol

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less

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Cutaneous flushing

Adenosine
Vancomycin (caused by histamine)
Niacin (caused by prostaglandins, hence NSAIDs are the treatment)
Digoxin
Dihydropyridine calcium channel blockers (e.g. amlodipine, nifedipine)
Morphine
Rifampin
Sildenafil
SSRIs (e.g. escitaprolam, citaprolam, paroxetine)
Dilated Cardiomyopathy
Doxorubicin

Daunorubicin
Direct Coombs positive hemolytic anemia

Methyldopa
Disulfiram like reaction (especially when combined with alcohol)

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Metronidazole
Sulfonylureas, 1st generation
Griseofulvin
Some cephalosporins

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less
less

Procarbazine
Gout from uric acid excretion
Furosemide

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Thiazides
Gingival hyperplasia
Phenytoin
Dihydropyridine Ca2+ channel blockers: amlodipine, nifedipine, etc.
Non-dihydropyrirdine Ca2+ channel blockers: verapamil, diltiazem

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Cyclosporine
Gynecomastia
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Can be remembered by mnemonic: Some Drugs Create Awesome Knockers
Spironolactone
Digitalis
Cimetidine
Alcohol
Ketoconazole
Gray baby syndrome
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Chloramphenicol
G6PD hemolysis. Mnemonic: PAINS.
Primaquine
Aspirin and NSAIDs
Isoniazid
Nitrofurantoin

Sulfonamides
Hepatitis

Isoniazid
Hepatic Necrosis
Acetaminophen
Valproic Acid
Halothane

Amanita phalloides (mushroom)

Hemorrhagic cystitis

Cyclophosphamide
Interstitial nephritis
NSAIDS

Lithium
Demeclocycline

Aminoglycosides
Furosemide
Cisplatin

Tetracycline and sulfonamides

Amiodarone

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less

less

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Quinolones
Pulmonary fibrosis
Amiodarone: pulmonary fibrosis will not resolve despite discontinuation of the
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drug

Bleomycin: pulmonary fibrosis can occur several years after therapy

Busulfan

Nitrofurantoin

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Vancomycin
Photosensitivity

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Drugs that may cause hypercalcemia (e.g. thiazides)

Ototoxicity

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Methicillin
Nephrogenic Diabetes Insipidus

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SLE-like syndrome

Drugs commonly associated with drug-induced lupus (use the

mnemonic Q CHIMPP pronounced Cute Chimp):
Quinidine
Chlorpromazine
Hydralazine
Isoniazid
Methyldopa
Penicillamine/Phenytoin
Procainamide

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Note: the 4 classically tested drugs are:

Hydralazine
Isoniazid
Procainamide
Phenytoin
Sulfa allergy

Sulfonylureas
Bactrim (trimethoprim and sulfamethoxazole)
Thiazides
Furosemide

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Celecoxib
Tendonitis

Fluoroquinolones
Torsades des pointes

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Any antiarrhythmic agents, but mostly Sotalol and Quinidine

Tardive dyskinesia

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Antipsychotics

Metoclopramide

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