141 Post Midterms

Which has a higher risk of immunogenicity, small molecule drugs or biologics?

Biologics

Which is generally more circulated in the body, small molecule drugs or biologics?

Small molecule drugs

Which may be eliminated from the body via immune response or phagocytosis, small molecule drugs or biologics?

Biologics

Which typically has a higher half life, small molecule drugs or biologics?

Biologics

True or false. All biologic drugs are made with living organisms

False. This is true for most but some biologic drugs are made without living organisms (wholly synthetic peptides)

The active pharmaceutical ingredient in many HUMALOG preparations

Insulin lispro

How is insulin lispro created?

By inverting the natural Pro-Lys sequence in human insulin (at positions 28 and 29 in the C terminal portion of the B-chain)

Why is insulin lispro absorbed more rapidly than regular insulin?

A change amino acid sequence slightly modifies the physicochemical properties such that insulin lispro self-associates less and dissociates into its monomeric form more rapidly than regular insulin

Insulin lispro has a _________________ (shorter/longer) duration of action than regular insulin

Shorter

An embolism in the brain will cause a...

Stroke

An embolism in the heart will cause a...

Heart attack

"Clot busters"

Drugs that promote the break-up of blood clots to restore normal bloodflow

Plasmin is a ______________ that breaks down fibrin and fibrinogen in clots

protease

Plasminogen is converted to _____________________ by ___________________________________

Plasmin; tissue plasminogen activator (tPA)

________________________ is the leading fibrinolytic agent in the treatment of thromboembolic conditions and is involved in the activation of plasminogen

Streptokinase

Reteplase is a recombinant alteplase but is smaller and non-glycosylated, resulting in a ____________ half-life

Longer

True or false. Both alteplase and tinecteplase are non-glycoslyated proteins created by recombinant DNA technology and used for their anticoagulant effects

False, both are glycosylated

First fully human monoclonal antibody drug approved by the FDA

Adalimumab (Humira)

First monoclonal antibody

muromonab-DC3

How was adalimumab derived?

Antibody libraries displaying millions of different antibodies on phage to isolate highly specific therapeutic antibody leads for development

Adalimumab binds to ___________, preventing activation of TNFR2 on immune cells and treating inflammatory conditions

TNFα

True or false. Antibodies are insoluble

False

Which is not a class of immunoglobulin?

- IgM

- IgA

- IgE

- IgG

- IgD

- None of the above

None of the above

Almost all antibody drugs are ________clonal and most of these are the IgG1k ("kappa") subclass

Mono

On-target antibody binding

Binding to antigen

Antibodies typically have a ___-shape structure

Y

Order the following by murine (mice) content

- Humanized

- Chimeric

- Human

- Murine

1. Murine

2. Chimeric

3. Humanized

4. Human

Match the naming convention suffix to the type of antibody

i) Humanized

ii) Chimeric

iii) Human

IV) Murine

a) -mab

b) -mumab

c) -zumab

d) -ximab

i) and c)

ii) and d)

iii) and b)

iv) and a)

Saturable metabolism

Past a certain dose a drug is not metabolized at the same rate which increases plasma concentration of the drug

________________________ drug response: unusual or unexplained and often dramatic

Idiosyncratic

True or false. Most variation in drug response is qualitative in manner

False. Typically quantitative

Thalidomide and atropine have adverse effects in humans. This was not detected in animal testing due to this concept of variation...

Species variability

A drug abnormally crossing the blood-brain barrier due to the patient having meningitis is an example of drug response variation due to...

Disease state

True or false. Most drug variation occurs in the very young and the very old

True

GFR is _________________ (increased/decreased) in infants compared to adults

Decreased

Which is not a cause of drug variation between sexes?

- Men respond better to NSAIDs

- Women respond better to opioids

- Rate of gastric emptying is faster in women

- Pain perception and intensity tends to be higher in women

Rate of gastric emptying is faster in women

______________ is inhibited by grapefruit juice

CYP3A4

High vitamin __ intake reduces warfarin efficacy

K

True or false. The impact of pharmacogenetics on pharmacokinetics is more well-studied than pharmacodynamics

True

Pharmacogenomics

Using tools to survey the genome and assess multigenic determinations of drug response

Pharmacogenetics

Study of the genetic basis for variation in drug response

____________________ metabolizers are typically the largest group in the population

Extensive

________ metabolizers have fewer copies or dysfunctional metabolic enzymes

Poor

__________________ metabolizers typically have multiple copies of the metabolic gene

Ultra-rapid

True or false. Extensive metabolizers and intermediate metabolizers are sometimes grouped together

True

Most variable drug metabolizing enzyme

CYP2D6

Second most common drug metabolizing enzyme

CYP2D6

True or false. The "poor metabolizer" CYP2D6 phenotype is rare in certain Asian populations but more common in Northern Europeans.

True

True or false. The "ultra-rapid metabolizer" CYP2D6 phenotype is very low in countries in the Middle-East and East Africa but is very high in Northern European populations

False.

The "ultra-rapid metabolizer" phenotype is very high in countries in the Middle-East and East Africa but is very low in Northern European populations

CYP2C19 has ________ that may have base switches causing drug response variation

exons

True or false. Warfarin is a racemic mixture

True

S-warfarin is more potent and is a substrate for this drug metabolism enzyme

CYP2C9

Which would not affect a person's response to S-warfarin

- Vitamin K intake

- CYP2C9 phenotype

- CYP2A6 phenotype

- Vitamin K reductase

CYP2A6 phenotype.

S-Warfarin is metabolized by CYP2C9

True or false. Most drug interactions are negative

False. Most are neutral (no clinical impact)

Pharmacodynamic drug interaction

When one drug or substance interferes with the pharmacodynamic actions of another drug or substance

Most common example of a pharmacodynamic drug interaction

A GPCR agonist and an antagonist

Pharmacokinetic drug interactions

When one drug or substance changes the absorption, distribution, metabolism, or excretion of another drug or substance

Taking two CNS depressants with distinct mechanisms of action, e.g. a benzodiazepine and an opioid is an example of a ____________________________ drug interaction

Physiological

Additive drug effect

The consequence of a drug interaction is the sum of the effect of 2 drugs with similar actions

Physiological Drug Interactions

When two drugs act on the same pathway to increase or oppose each others' physiological response

If a drug interaction increases the drug's effect more than taking both drugs separately, it is termed ____________-additive

Supra

Why are stages of embryogenesis and fetal development more susceptible to exogenous compounds?

There is rapid cellular growth and division and many tissues are in the process of differentiation

Which is not true about teratogens?

- Organ specific

- Stage of development specific

- Dose dependent

- Typically act before the embryonic period

Typically act before the embryonic period

True or false. A substance that is fetopathic causes adverse fetal outcomes in a non organ specific manner

True

Which is not a mechanism of teratogenesis?

- DNA mutation

- Impaired meiosis

- Chromosomal breaks

- Macro nutrient deficiency

Impaired meiosis

True or false. Preclinical animal testing of a drug's ability to cross the placenta is typically highly accurate to what will happen in humans

False. Placental structure varies considerably between species

Drugs with a molecular weight of ________ (less/more) than 500 will struggle to cross the placenta

More

A drug that is highly protein bound and highly ionized ___________ (will/wont) cross the placenta easily

wont

True or false. Fetal blood is _________ (less/more) basic than maternal blood

Less

True or false. Maternal genetics are not known to have an impact on specific adverse fetal outcomes

False

eg. cleft lip/palate

What older FDA risk category do most drugs fall in

Class C

Older FDA risk categories for drugs in pregnancy

A, B, C, D , X where A is no risk and X is absolute contraindication

Pregnancy and Lactation Labeling Rule (PLLR)

Removed the FDA risk categories but is intended to provide more comprehensive, drug-specific information for pregnant or breastfeeding individuals

In Prescription Drug Labeling Sections 8.1-8.2 on pregnancy and lactation, what section is always required

Risk summary

Section 8.3 Females and Males of Reproductive Potential

Provides data on effects of reproductive systems including fertility

Diethylstilbestrol

Used to prevent miscarriage by stimulating hormonal production in the placenta but female offspring presented with vaginal cancer at age 15-22 (long term effect)

Why should retinoids not be taken during pregnancy?

The concentration gradient of retinoids in the retina is disrupted during a period of neuronal mobility. Retinoids are crucial for development

Most consistent adverse effect with smoking and pregnancy

Lower birth weights (due to aromatic hydrocarbons)

Triad of abnormalities with fetal alcohol syndrome

Craniofacial abnormalities

CNS dysfunction

Pre and/or post natal stunting of growth

True or false. Fetal alcohol syndrome is very common in children of heavy drinkers

False, still just 5%

FAE and FASD are partial phenotypes of...

FAS (fetal alcohol syndrome)

True or false. Most anticonvulsants such as phenytoin are not associated with causing fetal abnormalities

False

True or false. Folic acid __________________ (increases/decreases) risk of neural tube defects eg. spina bifida

Decreases

Why is folic acid recommended in sexually active women of child bearing age?

Because neural tube defects occur approximately 1 month (23-26 days) after conception (before pregnancy might be identified)

Gross fetal abnormalities occur at a base rate of ~ _____

1%

True or false. The developed infant is relatively less susceptible to drug toxicity than the embryo or fetus

True

Hale's Lactation Risk Category indicates L1 as _____________________ and L5 as _______________________

Safest; contraindicated

Which is not a component of breast milk?

- Red blood cells

- Colloidal proteins dispersions

- White blood cells

- Oil-water emulsions containing triglycerides

Red blood cells

True or false. There is a brief period (~72 hours postpartum) where cells and larger proteins including antibodies can pass into the breast milk before lactocytes form tighter junctions

True

If a drug transfers readily into the milk and the concentrations in the plasma and milk are the same, the milk/plasma ratio is __

1

Drugs that accumulate in milk at higher concentrations than the plasma have milk/plasma ratios ___________ (less/greater) than 1

Greater

True or false. Most drugs have a milk/plasma ratios greater than 1

False

Relative infant dose (RID)

Gives a % dose to the infant based on the maternal dose and the milk/plasma ratio

Histamine has a(n) ___________________ ring

Imidazole

____-receptors present in smooth muscles mediate histamine response

H1

Ethanolamine ethers (e.g. diphenhydramine) are a class of ________-generation antihistamines

First

This first-generation antihistamine class has a pyridine ring

Alkyl amines

Alkyl amines have a _________ (short/long) duration of action and _________________ (increased/decreased) CNS and cholinergic side effects compared to ethanolamine ethers

Long; decreased

__-enantiomers of alkyl amines exhibit greater affinity toward H1-receptors

S

True or false. For first generation antihistamines, a two or three carbon spacer provides optimum activity

True