Enzyme Kinetics

Enzyme-catalyzed reactions are saturable

o Are not linear in response to increasing substrate
o

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 enzyme's maximal rate, and Km
is the Michaelis constant.
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 (enzymes max rate)

Km = the substrate concentration at Vmax

o

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) [1]

o

Linear transformation of the Michaelis-Menten equation. Particularly useful

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:

o

Competitive inhibitors compete with substrate for the enzymes active site,
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:

o

Noncompetitive inhibitors bind outside the active site (and therefore do not
compete with the substrate).

Increasing substrate concentration will not relieve the noncompetitive

inhibition. Km stays constant while Vmax .

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Enzyme Kinetics

Lineweaver-Burk plot

Competitive inhibition

Noncompetitive inhibition

Pharmacokinetics

Describes how the body affects the drug

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

Vd is not a "real" number, it just reflects how a drug will distribute

throughout 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:

o

Ability to pass cellular membranes

Solubility in different biological compartments

Ability to bind to different constituents in tissues (ex. lipids, proteins)

Drugs bound to plasma proteins (albumin) are not available for:

o

Further distribution into tissues

Active pharmacological action

Glomerular filtration

Metabolism

Low Vd (4-8L) pharmacokinetics

o

High plasma protein bound

Stays in plasma blood

Example: Warfarin

Medium Vd (8-60L) pharmacokinetics

o

Hydrophilic

Distributes into extracellular fluid (10-20L) or total body water (30-45L)

Example: Ethanol

High Vd (Vd > 60L) pharmacokinetics

o

Lipophilic, strongly bound in intracellular sites

Sequestered into extracellular fluid, tissues (fat)

Example: Chloroquine

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

Half-life (T1/2) = time required to reduce the concentration of a drug by half.

o

T1/2 = 0.7 Vd / CL

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)
o

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

Drug Elimination

Zero-order elimination
o A constant amount of drug eliminated per unit of time
o

Drug plasma concentration decreases linearly with increased time

Examples: ethanol, phenytoin, high dose aspirin

First-order elimination
o

There is a constant fraction of drug eliminated per unit of time

Drug plasma concentration decreases exponentially with increased time

Most all drugs are eliminated in this order

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Zero Order elimination

First Order elimination

Phase I Versus Phase II Metabolism

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

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
o

Acetylation (Amino acid N acyl transferase)

Glucuronidation (UDP-glucuronosyltransferase)

Sulfation (sulfotransferase)

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

Pharmacodynamics

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:
o

Potency is decreased: Curve is shifted to the right

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

therefore efficacy remains unchanged

Noncompetitive antagonist:
o

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:
o

Partial agonists have a lower efficacy at all doses

Potency is an independent factor (partial agonist can have more, less, or

equal potency compared to the original agonist)

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Competitive antagonist

Noncompetitive antagonist

Partial agonist

Therapeutic Index

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

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Therapeutic index

Central And Peripheral Nervous System

Parasympathetic nervous system (PNS) - long pre ganglion fibers

o Short post ganglion fibers
o

Synapse close to effector organs

Sympathetic nervous system (SNS) - short pre ganglion fibers

o

Long post ganglion fibers

Synapse in paravertebral ganglia

Originate in thoracolumbar region

In the figure : Red - sympathetic nervous system

o

Only 1 type of preganglionic receptor: nicotinic acetylcholine

receptor

Several types of postganglionic receptors: 1) muscarinic

acetylcholine receptor

2) Alpha and beta receptors: norepinephrine and epinephrine

3) Dopaminergic 1 receptor: dopamine

In the figure: Blue - parasympathetic nervous system

o

Only 1 type of preganglionic receptor: nicotinic acetylcholine

receptor

Only 1 type of postganglionic receptor: muscarinic acetylcholine

receptor

Acetylcholine receptor signal mechanisms:

Nicotinic: ligand gated Na/K channel

Muscarinic: G protein coupled, 2nd messenger activation

CNS and PNS

G Protein Signal Transduction

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 Lipids broken down to phosphatidylinositol

biphosphate (PIP2)

PIP2 is metabolized to inositol triphosphate (IP3) and diacylglycerol

(DAG)

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:
o

G(i) = 2, M2, D2 {just memorize that 2 is by inhibition, G(i); rarely will

they test M2 or D2}

G(s) = 1, 2, H2, V2, D1 {need to memorize, but if u memorize G(q), this

will be easy}

G(q) = 1, H1, V1, M1, M3 {all the 1s except B1 and D1. Remember this
phrase, Bob and Dan are NOT Quiet}

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PIP2 structure and PLC cleavage site

G(s) signal transduction pathway

Other Types Of Receptors

Ligand-gated ion channels: nicotinic cholinergic receptor, GABA, Gln, 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)
o

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

pass 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)

Extracellular Receptor And Functions

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

2: decreases sympathetic outflow, decreases insulin release

1: increases contractility, increases chronotropic (heart rate), increases conduction

at AV node, increases renin, increases lipolysis

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

H2: increases gastric acid secretion

V1: increases vascular smooth muscle contraction

Acetylcholine Synthesis & Degradation

Drugs that interfere with acetylcholine (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

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

Ach synthesis and degradation

V2: vasopressin receptor in collecting tubules H2O reabsorption

Norepinephrine Synthesis And Degradation

Regarding norepinephrine synthesis: The hydroxylation of tyrosine and formation

of dopamine takes place in the cytoplasm
o Dopamine then enters the storage granules where it is converted to
norepinephrine
o

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)

o

Phe Tyr catecholamines

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

Note: BH4 is a cofactor for both reactions.

Other fates of tyrosine:

- Tyr DOPA (several steps) melanin (key enzyme: tyrosinase)
- 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 NE/serotonin/dopamine into vesicles the neurotransmitters never
reach the synapse

Guanethidine: prevents presynaptic vesicle release of NE

Cocaine or tricyclic antidepressants: prevents presynaptic reuptake of NE

Amphetamine: increases presynaptic vesicle release of NE and, to a lesser extent,

acts as a reuptake inhibitor [1]

NE synthesis and degradation

Cholinergic Agents

Direct agonists: directly increase cholinergic stimulation

1) Bethanechol

2) Carbachol
o

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 [1] [2]

o

Nonselective muscarinic receptor agonist

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 narrowangle 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
o

Nonselective muscarinic receptor agonist

Primary usage: diagnostic agent to test for bronchial hyperactivity (asthma,

COPD)

Indirect agonists (cholinesterase inhibitors): indirectly increase cholinergic

stimulation by increasing acetylcholine levels

1) Neostigmine

Reversible cholinesterase inhibitor

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

2) Pyridostigmine
o

Pyridostigmine is similar in all ways to neostigmine, except it's 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
o

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

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
o

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
"Can't 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

5) Echothiophate
o

Irreversible cholinesterase inhibitor

Used to treat glaucoma

Cholinesterase inhibitor poisoning

o

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

bradycardia, excitation of skeletal muscle and CNS, lacrimation, sweating,
and salivation. (DUMBBELSS)

Due to excessive nicotinic and muscarinic acetylcholine stimulation

Produced by organophosphates (Parathion, Malathion) or excessive

irreversible cholinesterase inhibitor (Echothiophate)

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

and Pralidoxime (chemical antagonist that regenerates cholinesterase)

Tacrine and Donepezil are centrally acting cholinesterase inhibitors that are used in
the treatment of Alzheimer's disease. They act to increase ACh in the basal forebrain
and cerebral cortex, thereby alleviating some of the symptoms of AD.

Anticholinergics

Atropine
o Causes mydriasis and cycloplegia
o

Treatment for bradycardia, asystole, heart block: at high or toxic doses, HR

(note that at low doses, the effect is bradycardia secondary to atropineinduced Ach release from inhibitory neurons)

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

Treatment for Parkinsons symptoms (decreases cholinergic stimulation)

Treatment for dystonia, akathisia

Glycopyrrolate
o

Ipratropium
o

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

cross blood brain barrier

Treats asthma and COPD by counteracting parasympathetic

bronchoconstriction

Methscopolamine
o

Used in combination with other drugs to treat peptic ulcers

Decreases stomach acid, relaxes muscles in stomach and intestines

Oxybutynin
o

Reduces bladder spasms

Treats urge incontinence

Scopolamine
o

Treats motion sickness

Causes mydriasis and cycloplegia. Can also cross blood brain barrier and
result in CNS manifestations of anticholinergic toxidrome.

Glaucoma Treatment

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, usually steroid induced. 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:
o

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

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

Miotic agents (parasympathomimetics)

o

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

o

Example: Acetazolamide

Decreases aqueous humor production due to decreased HCO3-. Bicarbonate

is required for aqueous humor production.

Topical -antagonist
o

Example: Timolol

Decrease aqueous humor production by ciliary body

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

bradycardia, hypotension

Sympathomimetics

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

2) Norepinephrine: agonist to 1, 2, and mild 1; no effect on 2

o

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

rate after cardiac transplant

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

o

Clinical Applications: hypotension such as in sepsis, but can decrease renal

and mesenteric perfusion

3) Isoproterenol: equal agonist 1 = 2 activity

o

Clinical applications: asthma, hypotension, cardiac resuscitation,

anaphylaxis

Clinical applications: heart failure, hypotension. There is some support for

dopamines role in preserving renal perfusion.

5) Dobutamine: 1 > 2

6) Phenylephrine: 1 > 2
o

Clinical applications: hypotension, nasal decongestion

7) Albuterol, Terbutaline: 2 > 1

o

Clinical applications: heart failure since it increases inotropic cardiac output

but it can also cause hypotension

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

8) Ritodrine: 2only
o

Clinical application: premature labor, decreases uterus contractions

B) 3 Indirect agents

1) Ephedrine

Is a mixed agent: weak, direct agonist of both alpha and beta receptors

Strong indirect effect of inducing presynaptic release of stored

catecholamines

Clinical application: hypotension, bradycardia

2) Amphetamine
o

Indirect effect by inducing presynaptic release of stored catecholamines

Clinical application: attention deficit disorder, narcolepsy, depression

3) Cocaine
o

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

o

Decreases presynaptic release of norepinephrine or epinephrine

Clinical application: hypertension, pain syndromes

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

symptoms

Selective 2 Agonists

Selective 2 agonists: salmeterol (longer-acting), metaproterenol, albuterol (shortacting), terbutaline, ritodrine

Use these agents for patients with heart disease (such as aortic stenosis). However,
note:
o

Salmeterol has a black box warning for causing increased asthma-related

deaths.

Repeated and excessive use of albuterol may cause tachyphylaxis and

paradoxical bronchoconstriction. Albuterol should only be used as a
rescue medication.

Alpha Blockers

Nonselective (blocks 1 and 2 receptors)

o Examples: phenoxybenzamine (irreversible blockade) and phentolamine
(reversible blockade) both used to treat hypertension
o

Selective 1 blockade: Prazosin, Terazosin, Doxazosin

o

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

All 1 blockers will have the side effect of orthostatic hypotension

o

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

orthostatic hypotension and syncope (fainting), especially after the first dose
similar 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).
[1] [2] [3]

Selective 2 blockade: Mirtazapine

o Increased release of norepinephrine and serotonin from presynaptic vesicles
o

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

weight gain)

Notable Drug Toxicities

Agranulocytosis
o Carbamazepine
o

Procainamide

Clozapine

Colchicine

Propylthiouracil and Methimazole

Aplastic anemia
o

Chloramphenicol

NSAIDS

Benzene

Propylthiouracil and Methimazole

Adrenocortical insufficiency
o

Long-term treatment with high doses of corticosteroids causes suppression

of the adrenal gland's production of endogenous steroids.
Pathophys: High doses of exogenous steroids negative feedback on the
HT less ACTH 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
o

Anticholinergics, e.g. atropine, scopolamine

Tricyclics

Cough
o

ACE Inhibitors

Not seen with Angiotension Receptor Blockers such as Losartan

Coronary vasospasm
o

Cocaine

Cholinergic syndrome
o

Cholinesterase inhibitors: neostigmine, physostigmine

Organophosphates (Sarin, Soman)

Pilocarpine

Carbachol, Bethanechol

Cutaneous flushing
o

Adenosine

Vancomycin

Niacin

Digoxin

Dihydropyridine calcium channel blockers (e.g. amlodipine, nifedipine)

Morphine

Rifampin

Sildenafil

Dilated Cardiomyopathy
o

Doxorubicin

Daunorubicin

Direct Coombs positive hemolytic anemia

o

Sumatriptan

Methyldopa

Disulfiram like reaction (especially when combined with alcohol)

o

Metronidazole

Sulfonylureas, 1st generation

Griseofulvin

Some cephalosporins
[1]

Gout
o

Furosemide

Thiazides

Gingival hyperplasia
o

Phenytoin

Dihydropyridine Ca2+ channel blockers: amlodipine, nifedipine, etc.

Non-dihydropyrirdine Ca2+ channel blockers: verapamil, diltiazem

Cyclosporine

Gynecomastia
o

Chloramphenicol

G6PD hemolysis
o

Isoniazid

Aspirin and NSAIDs

Sulfonamides

Primaquine

Nitrofurantoin

Hepatitis
o

Can be remembered by mnemonic: Some Drugs Create Awesome Knockers

Spironolactone
Digitalis
Cimetidine
Alcohol
Ketoconazole

Gray baby syndrome

o

Procarbazine

Isoniazid

Hepatic Necrosis
o

Acetaminophen

Valproic Acid

Halothane

Amanita phalloides (mushroom)

Hemorrhagic cystitis
o

Cyclophosphamide

Interstitial nephritis
o

NSAIDS

Methicillin

Nephrogenic Diabetes Insipidus

o

Lithium

Demeclocycline

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

Ototoxicity
o

Aminoglycosides

Furosemide

Cisplatin

Photosensitivity
o

Tetracycline and sulfonamides

Amiodarone

Quinolones

Pulmonary fibrosis
o

Amiodarone: pulmonary fibrosis will not resolve despite discontinuation of

the drug

Bleomycin: pulmonary fibrosis can occur several years after therapy

Busulfan

Nitrofurantoin

SLE-like syndrome
o

Hydralazine

Phenytoin

Procainamide

Isoniazid

Sulfa allergy
o

Sulfonylureas

Bactrim (trimethoprim and sulfamethoxazole)

Thiazides

Furosemide

Celecoxib

Tendonitis
o

Torsades des pointes

o

Fluoroquinolones

Any antiarrhythmic agents, but mostly Sotalol and Quinidine

Tardive dyskinesia
o

Antipsychotics

Metoclopramide

CYP450 Interactions

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

reaction)
Location: inner membrane of mitochondria or smooth endoplasmic reticulum
Drugs that induce P450 (and are contraindicated in porphyrias!) use the
mnemonic "Barb-E Steals Smokin Phen-phen, INDUCES vomiting, and Refuses
Greasy Gluttonous Carbs Chronically"
*[NOTE: although First Aid 2010 claims Quinidine is also an inducer of
cytochrome P450 and even incorporates quinidine into a cytochrome P450 inducer
mnemonic we cannot find any articles (pubmed, uptodate, emedicine, etc) to
support the role of Quinidine in the induction of cytochrome P450. True, Quinidine
is a substrate of CYP3A4, and so the level of quinidine in the body is affected by
inducers and inhibitors of CYP3A4, however quinidine doesn't act as an inducer
just because its a substrate. If you find a legitimate article that states quinidine is
an inducer, please let us know.]

Barbiturates

Ethosuximide

St. Johns wort

Smoking (aromatic hydrocarbons)

Phenytoin

Rifampin

Griseofulvin

Glucocorticoids

Carbamazepine

Chronic ethanol use/abuse

Drugs that inhibit P450 use the mnemonic "Right-O, Quin INHIBIT yourself
from drinking a KEG of quinolones and chloramphenicol because it will make
you Acutely Very SICk"
o

Ritonavir
[1]

o
o

Omeprazole
Quinidine*
- potent inhibitor of CYP2D6
*[Note: although First Aid 2010 claims Quinidine is also an inducer of
cytochrome P450 and even incorporates quinidine into a cytochrome P450
inducer mnemonic we cannot find any articles (pubmed, uptodate,
emedicine, etc) to support the role of Quinidine in the induction of
cytochrome P450.]
[2] [3]

o
o

Ketoconazole
Erythromycin (macrolide antibiotics)

Grapefruit juice

Quinolones (e.g., ciprofloxacin, norfloxacin)

Chloramphenicol

Acute alcohol intoxication

Valproate

Sulfonamides

Isoniazid

Cimetidine

Alcohol Metabolism

Three types of alcohol substrates:

o Ethylene glycol (found in antifreeze and bleach products)
o

Methanol (found in industrial solvents)

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.

3) Fomepizole: inhibitor of alcohol dehydrogenase enzyme

Methanol is metabolized into formaldehyde and formic acid

o

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:

1) Correct acid/base status

2) Folic acid: cofactor in conversion of formic acid to CO2

3) Ethanol: to competitively inhibit methanol breakdown

4) Fomepizole: inhibits alcohol dehydrogenase

[1]

Ethanol is metabolized by alcohol dehydrogenase enzyme to produce acetaldehyde.

Acetaldehyde is further metabolized by acetaldehyde dehydrogenase to produce
harmless acetic acid.
o Disulfiram: irreversibly inhibits oxidation of acetaldehyde by competing
with cofactor NAD for binding sites on acetaldehyde dehydrogenase.
o

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

unpleasant nausea, headache, vomit, and flushing symptoms.

Toxicology

Acetaminophen
o Symptoms: abdominal pain, increased liver function enzymes, coagulopathy
o

Normal conjugative metabolism becomes saturated so liver uses P450 to

metabolize acetaminophen into toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI) which causes zone III centrilobular liver necrosis.

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

glutathione to conjugate NAPQI)

Aspirin
o

Symptoms: anion gap metabolic acidosis, respiratory alkalosis, tinnitus

Antidote: Bicarbonate to treat acidosis and dialysis

Amphetamines
o

Symptoms: tachycardia, arrhythmia, mydriasis, seizures

Antidote: NH4Cl (acidify urine to enhance secretion)

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

o

Symptoms: dysphagia, drooling, metabolic alkalosis

Antidote: Milk, water, NPO to prevent further esophageal erosion

Anticholinergics
o

Symptoms: hot as a hare (fever), blind as a bat (mydriasis), dry as a bone,

red as a beet, and mad as a hatter (delirium)

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

Anticholinesterase and Organophosphates

o

Symptoms: DUMBBELSS: diarrhea, urination, miosis, bronchospasm,

bradycardia, excitation of skeletal muscle and CNS, lacrimation, sweating,
and salivation

Antidote: Atropine and Pralidoxime

Arsenic
o

Symptoms:
-Garlic smelling breath
-CNS sxs: seizures, altered mental status, coma
-Mees's lines (white horizontal lines on fingernails)
seizures

Antidote: Dimercaprol, gastric lavage

Benzodiazepines
o

Symptoms: apnea, drowsiness, excessive amounts can also cause cardiac

depression

Antidote: Flumazenil

Beta Blockers
o

Symptoms: bradycardia, hyperkalemia, hypoglycemia, pulmonary

vasoconstriction

Antidote: Glucagon

Carbon Monoxide
o

Physical signs: cherry red skin and mucous membranes, confusion

Antidote: 100% oxygen, hyperbaric oxygen

Copper, Gold, Mercury

o

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

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
o

Symptoms:
- 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: Inhaled Amyl Nitrite or intravenous Sodium Thiosulfate. These

nitrites oxidize hemoglobins iron from ferrous to ferric state, converting
hemoglobin into methemoglobin. Cyanide preferentially bonds to
methemoglobin rather than cytochrome oxidase.

Digoxin
o

Symptoms: yellow red halos in vision, nausea, heart block or

supraventricular tachycardia

Antidote: Antidigoxin Fab-antibodies

Heparin
o

Symptoms: bleeding, thrombocytopenia

Antidote: Protamine

Iron
o

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
o

Symptoms: confusion, peripheral neuropathy, hepatotoxicity, seizures

Antidote: Pyridoxine

Lead
o

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

peripheral neuropathy (wrist and foot drop), ataxia

Antidote: EDTA, Penicillamine, Dimercaprol

Methemoglobin
o

Symptoms: cyanosis, fatigue, confusion, coma

Antidote: Methylene blue

Opioids

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

Antidote: Naloxone

Phenobarbital
o

Symptoms: sedation, hypotension, cardiac depression

Antidote: Charcoal, Bicarbonate to improve renal secretion

Quinidine
o

Symptoms:
- torsades des pointes, thrombocytopenia, tinnitus
- cinchonism
- cytochrome P450 inhibitor

Antidote: Intravenous magnesium for torsades des pointes

Tricyclics
o

Symptoms: "the 3 C's" due to muscarinic blockade:

1) Convulsions
2) Coma
3) Cardiotoxicity e.g., arrhythmias, torsades des pointes
Note: the drugs that can precipitate "the 3 C's" due to muscarinic blockade
can be remembered with the mnemonic "All These Queers Are Muscarinic
Antagonists":
Antihistamines (1st generation)
TCA's
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
o

Symptom: bleeding

Antidote: Aminocaproic acid

Warfarin
o

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

S deficiencies)

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