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First Aid USMLE Step 1: Pharmacology

Terms in this set (65)

In the Michaelis-Menten kinetics what do the following mean:
Km
Vmax

Draw a typical hyperbolic curve on a Michaelis-Menten Plot, then draw how the addition of a competitive and non-competitive inhibitor would change the kinetics of the reaction.
In the Michaelis-Menten kinetics what do the following mean:

Km:
- the concentration of substrate at 1/2 Vmax
- this is INVERSELY related to the affinity of enzyme for its substrate

Vmax:
- maximal velocity at which enzymatic reaction occurs
- is directly proportional to the enzyme concentration

Competitive inhibitor: would raise Km but Vmax is the same

Non-competitive inhibitor: would lower Vmax?
Draw a Lineweaver-Burke plot. What information do the following intercept points correspond to?

X axis
Y axis
slope
y intercept
x intercept

How do a competitive and non-competitive inhibitor would change the plot?
Draw a Lineweaver-Burke plot. What information do the following intercept points correspond to?

X axis: 1/ [S]
Y axis: 1/V
slope: Km/Vmax
y intercept: 1/Vmax
x intercept: 1/-Km

How do a competitive and non-competitive inhibitor would change the plot?
- reversible competitors cross each other competitively
- non-competitive inhibitors DO NOT!
FOR:
reversible competitive inhibitors
irreversible competitive inhibitors
non-competitive inhibitors

Explain the following properties:
- do they resemble their substrate?
- overcome by an increase in [S]
- bind to the active site of the enzyme
- have an effect on Vmax
- have an effect on Km
- how does it alter kinematics of the original substrate?
What is bioavailability (F)?

What is F for an IV drug?

What is F for an oral drug?
What is bioavailability (F)?
- the fraction of an administered drug reaching systemic circulation unchanged

What is F for an IV drug?
- F = 100%

What is F for an oral drug?
- usually < 100% due to incomplete absorption and first-pass metabolism
What is the volume of distribution (Vd) of a drug? How do you calculate it?

How does the apparent Vd of a plasma-protein bound drug change in disease states?


For the following compartments, what would Vd be approximated as and what kinds of drugs are primarily found in these compartments?
- Blood
- ECF
- All tissue (including fat)
What is the volume of distribution of a drug? How do you calculate it?
- the theoretical volume occupied by a total amount of drug in the body relative to its plasma concentration

Vd = amount of drug in the body/plasma drug concentration

How does the apparent Vd of a plasma-protein bound drug change in disease states?
- apparent Vd of a plasma-protein bound drug can be altered by liver and kidney disease
- decreased protein binding leads to increased Vd

For the following compartments, what would Vd be approximated as and what kinds of drugs are primarily found in these compartments?
See image included
What is the definition of drug clearance (CL)? How is it calculated?

What disease states can affect drug clearance?
What is the definition of drug clearance? How is it calculated?
- volume of plasma cleared of drug per unit time

CL= rate of elimination of drug/plasma drug concentration = Vd x Kc (elimination constant)

What disease states can affect drug clearance?
What is the definition of drug half life?

What is the equation for T1/2 in a first-order kinetics reaction?
What is the definition of drug half life?
- the time required to change the amount of drug in the body by 1/2 during elimination

What is the equation for T1/2 in a first-order kinetics reaction?

t1/2 = (0.693 x Vd)/CL
What is the equation for calculating loading dose?

What is the equation for calculating maintenance dose?

In renal or liver disease however is maintenance dose and loading dose changed?

What factors influence the time to steady state of a drug?
What is the equation for calculating loading dose?

What is the equation for calculating maintenance dose?

In renal or liver disease however is maintenance dose and loading dose changed?
- maintenance dose is usually decreased
- loading dose is usually unchanged

What factors influence the time to steady state of a drug?
- depends primarily on t1/2 and is independent of dose and dosing frequency

Note the Cp = target plasma concentration at steady state
What is an additive drug interaction?

What is an permissive drug interaction?

What is an synergistic drug interaction?

What is an tachyphylactic drug interaction?

For the following drug interactions, state what kind of interaction it is:
- aspirin and acetaminophen
- clopidogrel with ASA
- MDMA and LSD
- cortisol on catecholamine responsiveness
What is an additive drug interaction?
- effect of A and B together is equal to the sum of their individual effects

What is an permissive drug interaction?
- presence of substance A is required for full effects of substance B

What is an synergistic drug interaction?
- effect of A and B together is greater than sum of their parts

What is an tachyphylactic drug interaction?
- acute decrease in response to a drug after initial/repeated administration

For the following drug interactions, state what kind of interaction it is:
- aspirin and acetaminophen
- clopidogrel with ASA
- MDMA and LSD
- cortisol on catecholamine responsiveness
What is zero order elimination? How does this affect Cp?

What are examples of zero order elimination drugs?
What is zero order elimination? How does this affect Cp?
- when the rate of elimination of a drug is constant regardless of Cp (the steady state plasma concentration)
- note that in zero-order elimination, Cp will decrease linearly with time

What are examples of zero order elimination drugs?
- PEA --> phenytoin, ethanol, aspirin (at high or toxic concentrations)
What is first order elimination? How does this affect Cp?
What is first order elimination? How does this affect Cp?
- when the rate of elimination is directly proportional to the drug concentration (ie: a constant fraction of drug is eliminated per unit of time)
- Cp decreases exponentially with time
- this applies to MOST drugs
weak acids and bases
...
What is phase I and phase II drug metabolism?

Which is usually impaired in geriatric patients?
What is phase I and phase II drug metabolism?

PHASE I:
- reduction, oxidation, hydrolysis with cytochrome P-450 to yield a slightly polar, water soluble metabolite (often still active)

PHASE II:
- Conjugation (via: Methylation, Glucoronidation, Acetylation, Sulfation)
- usually yields very polar, inactive metabolites (renally excreted)

Which is usually impaired in geriatric patients?
- geriatric patients lose phase I first

"Geriatric paitnest have More GAS (phase II)"
What is the difference between efficacy and potency?
What is the difference between efficacy and potency?

Efficacy:
- is the maximal effect a drug can produce
- unrelated to potency
- represented by the y value, with increased y = increased Vmax = increased efficacy
- note that partial agonists have less efficacy than full agonists

Potency:
- the amount of drug needed for a given effect
- represented by the X value (EC50)
- left shifting = decreased EC50 = increased potency = decrease amount of drug needed
- again, unrelated to efficacy.
Describe the effect of combining an agonist with a:
- competitive antagonist
- noncompetitive antagonist
- partial agonist
What is the therapeutic index of a drug? How is it measured?


What is the therapeutic window of a drug?
What is the therapeutic index of a drug? How is it measured?
- a measurement of drug safety
- calculated by TD50/ED50
- TD50 is median toxic dose
- ED50 is median effective dose
- Remember "TITE
Therapeutic Index = TD50/ED50"*


What is the therapeutic window of a drug?
- the dose at which a drug can be given safely and effectively
- safer drugs have higher TI values while drugs with lower TI values frequently require monitoring
For the following autonomic fibers, provide the type of NT used and the type of receptor/target of innervation:

Pre-ganglionic parasympathetic fibers
Post-ganglionic parasympathetic fibers

Pre-ganglionic sympathetic fibers:
- to sympathetic chain
- to adrenal medulla
Post-ganglionic sympathetic fibers:
- to sweat glands
- to cardiac/smooth muscle, gland cells, nerve terminals
- renal vascular smooth muscle
What kinds of receptors are nicotinic cholinergic receptors? What are the two subtypes and where are they primarily found?


What kinds of receptors are muscarinic ACh receptors?
What kinds of receptors are nicotinic cholinergic receptors? What are the two subtypes and where are they primarily found?
- nicotinic Ach receptors are ligand-gated Na/K channels
- the two subtypes are Nn and Nm
- Nn = found in autonomic ganglia and adrenal medulla
- Nm = found at neuromuscular junction in skeletal muscle

What kinds of receptors are muscarinic ACh receptors?
- G protein coupled receptors that usually act through 2nd messengers
- there are 5 subtypes --> M1-5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands
For the following SYMPATHETIC GPCR subtypes, name the associated G-protein class and the major function of receptor activation:

alpha 1

alpha 2

beta 1

beta 2

beta 3
alpha 1:
- Gq
- increases vascular smooth muscle contraction
- increases pupillary dilator muscle contraction (mydriasis)
- increased intestinal and bladder sphincter muscle contraction

alpha 2:
- Gi
- decreased adrenergic outflow
- decreased insulin release, lipolysis
- increased platelet aggregation
- decreased aqueous humor production

beta 1
- Gs
- increased HR, contractility, renin release, lipolysis

beta 2
- Gs
- vasodilation, bronchodilation
- increased lipolysis, insulin release
- decrease uterine tone (tocolysis)
- ciliary muscle relaxation
- increased aqueous humor production

beta 3
- Gs
- increased lipolysis
- increased thermogenesis in skeletal muscle
For the following PARASYMPATHETIC GPCR subtypes, name the associated G-protein class and the major function of receptor activation:

M1

M2

M3
M1
- Gq
- CNS, enteric nervous system

M2
- Gi
- decreased heart rate and contractility of atria

M3
- Gq
- increased exocrine gland secretions
- increased gut peristalsis
- increased bladder contraction
- bronchoconstriction
- increased pupillary sphincter muscle contraction (miosis)
- ciliary muscle contraction (accomodation)
For the following DOPAMINERGIC GPCR subtypes, name the associated G-protein class and the major function of receptor activation:

D1

D2
D1
- Gs
- relaxes renal vascular smooth muscle

D2
- Gi
- modulates transmitter release, especially in the brain
For the following HISTAMINERGIC GPCR subtypes, name the associated G-protein class and the major function of receptor activation:

H1

H2
H1
- Gq
- increased nasal and bronchial mucus production
- increased vascular permeability
- contraction of bronchioles
- pruritus
- pain

H2
- Gs
- increased gastric secretion
For the following VASSOPRESSIN GPCR subtypes, name the associated G-protein class and the major function of receptor activation:

V1

V2
V1
- Gq
- increased vascular smooth muscle contraction

V2
- Gs
- increased H2O permeability and reabsorption in collecting tubules of the kidney (V2 is found in the 2 Kidneys)
Useful mnemonic for remembering the which GPCRs correspond to which intracellular signaling cascades:
Draw the intracellular signaling cascades for:
- Gq activation
- Gs activation
- Gi activation

Which of the GPCRs receptor subtypes correspond to each signaling cascade?
- Gq activation = HAVe 1 M and M
- Gs activation = everything else
- Gi activation = MAD 2's
Draw a cholinergic nerve terminal, noting where the following drugs act:
- hemicholinium
- vesamicol
- botulinum
- acetylcholinesterase inhibitors


Draw an noradrenergic nerve terminal, noting where the following drugs act:
- metyrosine
- reserpine
- bretylium, guanethidine
- amphetamine, ephedrine
- cocaine, TCAs, amphetamines
Explain how dietary tyramine can result in altered sympathetic transmission in patients taking MAO inhibitors


What is the classic symptom of tyramine excess?
Explain how dietary tyramine can result in altered sympathetic transmission in patients taking MAO inhibitors
- tyramine is normally degraded by monoamine oxidase
- levels of tyramine are increased in patients taking MAO inhibitors who digest tyramine rich foods (cheese, wine)
- excess tyramine enters presynaptic vesicles and displaces other neurotransmitters resulting in an increase in active presynaptic NTS --> increased diffusion of NT into synaptic cleft --> increased sympathetic stimulation

What is the classic symptom of tyramine excess?
- hypertensive crisis
Bethanechol

type of drug:
action:
application:
type of drug:
- direct agonist cholinergic receptors
- cholinomimetic agents

action:
- activates *B*owel and BBctivates *B*owel and *B*ladder smooth muscle
- resistant to AChE

remember: "BETHANY, CALL (bethanecol) me to activate your BLADDER"

application:
- postop ileus
- neurogenic ileus
- urinary retention


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Carbachol

type of drug:
action:
application:
type of drug:
- direct agonist of cholinergic receptors
- cholinomimetic agents

action:
- "CARbon copy of acetylcholine

application:
- constricts pupil and relieves intraocular pressure in open-angle glaucoma


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Methacholine

type of drug:
action:
application:
type of drug:
- direct agonist of cholinergic receptors
- cholinomimetic agents

action:
- stimulates Muscarinic receptors in airways when inhaled

application:
- challenge test for diagnosis of asthma


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Pilocarpine

type of drug:
action:
application:
type of drug:
- direct agonist of cholinergic receptors
- cholinomimetic agents

action:
- potent stimulator of sweat, tears and saliva
- contracts ciliary muscle of eye (open-angle glaucoma)
- pupillary sphincter (closed-angle glaucoma)
remember:
"You cry, drool and sweat on your PILOw"

application:
- open angle and closed angle glaucoma
- xerostomia (mouth dryness) in Sjogren's


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Donezepil
Galantamin
Rivastigmine

type of drug:
action:
application:
type of drug:
- indirect ACh agonists (anticholinesterases)

action:
- increases acetylcholine in the synapse

application:
- Alzheimer disease


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Ephodrium

type of drug:
action:
application:
type of drug:
- indirect ACh agonists (anticholinesterases)

action:
- increases acetylcholine in the synapse

application:
- diagnosis of myasthenia gravis (extremely short acting) but myasthenia now diagnosed by anti-AChR Ab test


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Neostigmine

type of drug:
action:
application:
type of drug:
- indirect ACh agonists (anticholinesterases)

action:
- NEO CNS = NO CNS penetration (quaternary amine)

application:
- post-operative and neurogenic ileus and urinary retention, myasthenia gravis, reversal of neuromuscular junction blocks


Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Physostigmine

type of drug:
action:
application:
type of drug:
- indirect ACh agonists (anticholinesterases)

action:
- increased acetylcholine
- "PHYsostigmine "PHYxes" atropine overdose

application:
- anticholingeric toxicity
- crosses blood brain barrier leading to CNS

Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Pyridostigmine

type of drug:
action:
application:
type of drug:
- indirect ACh agonists (anticholinesterase)

action:
- increased acetylcholine
- increased muscle strength
-"Pyridostigmine gets ride of Myasthenia Gravis"

application:
- used for myasthenia gravis, non-CNS penetrating

Note: as with all cholinomimetic agents, watch for exacerbation of COPD, asthma and peptic ulcers
Cholinergic toxicity

Causes:
Symptoms:
Treatment:
Causes: absence of cholinergic signaling, occurs with cholinesterase inhibitors, organophosphates that irreversibly inhibit AChE leading to a cholinergic excess

Symptoms:
- see picture

Treatment:
- atropine (a competitive inhibitor of muscarinic acetylcholinergic receptors)
- pralidoxime - an antidote for organophosphate poisoning.

[pralidoxime is an antidote to organophosphate pesticides and chemicals. Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme. If given within 24 hours,after organophosphate exposure, pralidoxime reactivates the enzyme cholinesterase by cleaving the phosphate-ester bond formed between the organophosphate and acetylcholinesterase.]
Anticholinergic toxicity
"The bowel and bladder act alone" --> urinary retention
- flushing
- anhydrosis
- miosis (pupillary constriction)

Causes:
- anticholingeric drugs (ie: atropine)
- jimson weed (gardener's pupil, due to plant alkaloids)
Atropine, homatropine, tropicamide

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
- EYE

application:
- results in mydriasis and cycloplegia (paralysis of the ciliary muscle of the eye, resulting in a loss of accommodation. Because of the paralysis of the ciliary muscle, the curvature of the lens can no longer be adjusted to focus on nearby objects.)
Atropine

type of drug:
organ system and effect on it:
- eye
- airway
- stomach
- gut
- bladder
adverse effects:
type of drug: muscarinic antagonist, use to treat bradycardia and for ophthalmic applications

organ system and effect on it:
- eye: increased pupil dilation, cycloplegia
- airway: decreased secretions
- stomach: decreased acid secretions
- gut: decreased motility
- bladder: urgency in cystitis

adverse effects:
- elicits anticholinergic toxicity symptoms
BENZtropine

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
- CNS

application:
- Parkinson's ("PARK my BENZ")
- acute dystonia (2/2 antipsychotics)
Glycopyrrolate

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
- GI, respiratory

application:
- pareneteral: preop use to reduce airway secretions
- oral: drooling, peptic ulcers
Hyoscyamine, dicyclomine

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
GI

application:
antispasmodic for IBS
Ipratropium

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
- respiratory

application:
- COPD, asthma, ("I pray I can breath soon")
Oxybutynin, solifenacin, tolterodine

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
GU

application:
- reduce bladder spasms and urge urinary incontinence (overactive bladder)
Scopolamine

type of drug:
organ system:
application:
type of drug:
- muscarinic antagonist

organ system:
CNS

application:
motion sickness
type of drug:
action:
application:
type of drug:
action:
application:
For the following direct sympathomimetics, provide the primary receptor of action and their applications.

Albuterol, Salmeterol
Dobutamine
Dopamine
Epinephrine
Fenoldopam
Isoproterenol
Midodrine
Norepinephrine
Phenylephrine
Indirect Sympathomimetics

Amphetamines
Cocaine
Ephedrine
...
SEE LANGE CARDS FOR REMAINDER OF ADRENERGIC AGONISTS
...
Tetrodotoxin

Source:
Action:
Symptoms:
Treatment:
Source:
- Pufferfish

Action:
- highly potent toxin that binds fast-voltage gated Na+ channels in cardiac and nerve tissue preventing depolarization

Symptoms:
- nausea, diarrhea, paresthesias, weakness, dizziness, loss of reflexes

Treatment:
- primarily supportive
Ciguatoxin

Source:
Action:
Symptoms:
Treatment:
Source:
- reef fish such as barracuda, snapper and moray eel


Action:
- Opens Na channels causing depolarization

Symptoms:
- mimics cholinergic poisoning

Treatment:
- primarily supportive
Histamine (scombroid poisoning)

Source:
Action:
Symptoms:
Treatment:
Source:
- spoiled dark meat fish such as tuna, mahi-mahi, mackerel and bonito

Action:
- bacterial histidine decarboxylase converts histidine to histamine
- frequently misdiagnosed as a fish allergyy

Symptoms:
- mimics anaphylaxis: acute burning, sensation of mouth, flushing of face, erythema, urticaria, itching
- may progress to bronchospasm, angioedema, hypotension

Treatment:
- antihistamines
- albuterol and epi if needed
For the following toxins (overdoses) please name the treatment for them.

Acetaminophen

AChE inhibitors, organophosphates

Amphetamines (basic)

Antimuscarinic, anticholingeric agents

Arsenic

Benzodiazepines

Beta-blockers

Carbon monoxide

Copper

Cyanide

Digitalis (digoxin)

Gold

Heparin

Iron

Lead

Mercury

Methanol, ethylene glycol

Methemoglobin

Opioids

Salicylates

TCA

Warfarin
For the following drug reactions, name the causal agents:

Coronary vasospasm:
Cutaneous flushing:
Dilated cardiomyopathy:
Torsades des Pointes:
Coronary vasospasm:
- cocaine
- sumatriptan
- ergot alkaloids

Cutaneous flushing:
"VANCE"
- vancomycin
- adenosine
- niacin
- Ca2+ channel blockers
- echinocandins

Dilated cardiomyopathy:
- anthracyclines (ex: doxorubicin, daunorubicin)
- prevent with dexrazoxane

Torsades des Pointes:
- "ABCDE"
- anti-Arrythmics
- anti-Biotics
- anti-"C"ycotics (haloperidol)
- anti-"D"epressants
- anti-"E"metics (ondansetron)
Drug reactions - endocrine/reproductive
...
Drug reactions - GI
...
Drug reactions - hematologic
...
Drug reactions - musculoskeletal/skin/connective tissue
...
Drug reactions - neurologic
...
Drug reactions - renal/GU
...
Drug reactions - respiratory
...
Drug reactions - multiorgan
...
Cytochrome P450 interactions

INDUCERS

SUBSTRATES

INHIBITORS
*INDUCERS:
Chronic alcoholics Steal Phen-pHen and NEver Refuse Greasy Carbs

Chronic alcohol use
St. John's wort
Phentyoin
Phenobarbital
Nevirapine
Rifampin
Carbazepine

*SUBSTRATES:
Always Think When Outdoors*
Anti-epileptics
Theophylline
Warfarin
OCPs

*INHIBITORS:
AAA RACKS IN GQ M*agazine

Acute Alcohol Abuse
Ritonavir
Amiodarone
Cimetidine/ciprofloxacin
Ketoconazole
Sulfonamides
Isoniazide (INH)
Grapefruit juice
Quinidine
Macrolides (except azithromycin)
Sulfa Drugs
"*S*cary Sulfa *P*hS*cary *S*ulfa Pharm FACTS"

Sulfonamide antibiotics
Sulfasalazine
Probenecid
Furosemide
Acetazolamide
Celecoxib
Thiazides
Sulfonyluras
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