Residency Week

Question 1

Tell me about the Na+/K+ pump

Answer 1

For every Na+ molecules that leave the cell, 2 K+ molecules enter. This facilitates the conversion of ATP for energy. Molecules want to go from high concentration to low concentration but this pump works against the gradient.
Higher concentration of sodium outside the cell, high concentration of potassium inside the cell.

Question 2

How and why does glucose enter the cell?

Answer 2

Na+ moves from high to low concentration via a passive mechanism: a symport to get glucose into the cell. Glucose is then used for energy.

Question 3

What is a ligand?

Answer 3

Any molecule that binds to a receptor.

Question 4

What is the purpose of albumin?

Answer 4

1) Colloid/osmotic pressure
2) Binds and transports drugs
3) Transports hormones

• Does not cross the cell membrane- stays in the extracellular environment

Question 5

What is the pathophysiology of CF at the cell membrane level?

Answer 5

Chloride transporter does not work which prevents chloride, sodium and water to move across the cell membrane.

Question 6

Discuss endocrine and exocrine communication.

Answer 6

Endocrine: uses hormones to travel through the bloodstream to a receptor in a distant location.
Exocrine: uses enzymes that can perhaps be in body cavities to migrate to receptor in distant location.

Question 7

Describe long distance communication of the nervous system.

Answer 7

Uses neurotransmitters to release a ligand that only travels a short distance to the receptor.

Question 8

What’s the difference between paracrine and autocrine signalling?

Answer 8

Paracrine: signals to its neighbouring cells (short distance). Example: interferon
Autocrine: releases a ligand that signals to itself.

Question 9

What’s the difference between short signalling in direct link and gap junction signalling?

Answer 9

Direct link: cell bears the ligand itself and goes directly to a cell that bears the corresponding receptor. Example: natural killer cells.
Gap junction: Tunnel between 2 cells where very small molecules can be transferred from 1 cell to the other. Example: cardiac cells.

Question 10

What is an amplifying enzyme?

Answer 10

3 types: cAMP, cGMP, phospholipase C
Produces further signalling in the cell by activating a cascade of response from one molecule to the other “second messengers”.
Example: second messengers trigger intracellular increases in Ca+ to stimulate muscle contractility.

Question 11

Differentiate the 3 types of feedback loops.

Answer 11

Positive feedback loop- drives the body further and further from homeostasis until the stimulus is removed. Example: stomach- pepsin- HCl acid and eating, more eating, more pepsin, until you stop eating.

Negative feedback loop- drives the body towards homeostasis. “self-limiting”
Example: Hypothalamus releases CRH, which stimulates the anterior pituitary to release ACTH, which stimulates the adrenal cortex to release cortisol which goes to the target and produces a response. Then, when the response is achieved it will signal to the hypothalamus and anterior pituitary to stop further stimulation.
Steps: stimulus – sensor – control system – effector

Feed forward loop- allows the body to anticipate change and maintain stability.
Example: hypothalamus is signalled that there is high osmotic pressure- posterior pituitary releases ADH and the hypothalamus also signals to drink more water. It would take a long time to release how much water has been consumed by the time it takes effect so there is receptors in our mouth that signal to the body that water has been consumed- decreasing thirst and ADH production.

Question 12

What is the difference between hyperplasia, hypertrophy and atrophy?

Answer 12

Hyperplasia: more cells (ex.endometriosis, pregnancy, calluses)
Hypertrophy: bigger cells (ex. muscle cells)
Atrophy: decrease in cell size (ex. muscle cells, uterus following pregnancy)

Question 13

What is the difference between dysplagia and metaplagia?

Answer 13

Dysplagia: abnormal changes in cell size, shape and organization. Related to hyperplasia. Example: cervical dysplagia.
Metaplasia: replacement of mature cell type with different cell type. Reprogramming of stem cells due to altered growth factors and/or cytokines in cellular environment. Typical of chronic insults. Example: bronchial metaplasia.

Question 14

What are the 4 types of cellular injury?

Answer 14

Hypoxic: loss of ATP
Free Radical: atoms with unpaired electrons (unstable), cause destruction of plasma membrane, fragmentation of peptides, DNA cleavage and lipid peroxidation
Reperfusion: re-introduction of O2 creates reactive oxygen species and the loss of antioxidant systems due to hypoxia
Chemical: can cause cell membrane destruction, DNA destruction or manipulation, and irreversibly bind to proteins inside and outside of the cell. (Example: lead poisoning, CO, ethanol)

Question 15

What are the mechanisms used to protect cells from free radicals?

Answer 15

1) Antioxidants: block formation or scavenge free radicals (ex. Vit C, E, transferrin, glutathione)
2) Enzymes: convert free radicals into more peaceful creatures. (Ex. catalase)

Question 16

What is the difference between pharmacodynamics and pharmacokinetics?

Answer 16

Pharmacodynamics: affect of the drug on the body. Drug-receptor interaction, patient functional state, placebo effect.
Pharmacokinetics: affect of the body on drugs. Absorption, distribution, metabolism, excretion.

Question 17

What factors affect absorption?

Answer 17

1) Rate of dissolution
2) Surface area (primarily microvilli in small intestine)
3) Blood flow (compromising factors: HF)
4) Lipid solubility (drugs must pass through biologic membranes, phospholipid membranes which is easier for lipid-soluble drugs to do)
5) pH (charged vs. uncharged state “like absorbs like”)
6) External vs. parenteral

Question 18

What is the first pass effect?

Answer 18

When the liver inactivates a large portion of the drug which decreases therapeutic effects.
GI system –> portal circulation –> liver –> bloodstream

In order to bypass the first pass effect you can use modalities such as, parental routes, sublingual, transdermal

Question 19

Describe distribution.

Answer 19

Flows through the vasculature to reach the target site.
The BBB poses an issue for some drugs as it only allows free drugs to go through. Protein-bound drugs will not be able to cross.

Question 20

Describe metabolism.

Answer 20

• liver*
• drug inactivation (first pass effect)
• increased therapeutic action (slower metabolism of drug)
• activation of prodrugs

Question 21

Describe excretion.

Answer 21

Renal excretion of drugs:

• All drugs of LMW- not protein-bound drugs
• GFR plays big factor
• passive reabsorption of lipid-soluble drugs
• active transport (charged, acidic drugs are pushed from blood to urine)
• competition
• age plays a factor (elderly may have increased drug accumulation)
• can also be excreted via bile, blood, breast milk and saliva

Question 22

What is the plateau phase of drug metabolism?

Answer 22

4-5 half lives to get to plateau.

Once drug has been d/c’d it will take 4-5 half lives to have the drug completely out of the system.

Question 23

Tell me about cytochrome P450.

Answer 23

• Main process for drug metabolism in the liver
• Cytochrome P450 families encompass 57 isoenzymes, with CYP1, CYP2, and CYP3 being responsible for the metabolism of ⅔ of all known drugs
• Drugs that interact with this metabolic pathway can be categorized as CYP450 inhibitors (slowing metabolism of other drugs which can lead to toxicity) or CYP450 inducers (causing increased metabolism of other drugs)
  Example: amio is a CYP450 inhibitor and when given with warfarin may cause increased levels of this drug which could lead to increased risk of bleeding.
• As the main driver of metabolism, CYP450 enzymes are also the main site of altered metabolism through:
  Environmental influences (drug-drug/drug-food
  interactions)
  Biological factors (sex, hormonal status, and disease)
  Genetic differences in cytochrome P450 genes
• Grapefruit and some herbs causes altered CYP450 metabolism

Question 24

What are the implications of pregnancy and lactating on ADME?

Answer 24

Depends on stage of pregnancy:

• Increased renal blood flow
• Increased hepatic metabolism
• Decreased bowel tone and motility
• Placental drug transfer

Breast milk:

• nearly all drugs can enter so dose immediately after breastfeeding and don’t choose drugs with long half-life.
• lipid soluble drugs tend to be present in breastmilk at higher concentrations

Question 25

How does the paediatric population influence ADRs?

Answer 25

• Organ system immaturity
• ADR may be intense and last longer
• Increased sensitivity
• BBB not fully developed *
• Increased metabolism

Infants:

• Drug absorption changes depending on route of administration
• Decreased protein binding of drugs result in high levels of free drugs
• Low hepatic drug metabolism
• Reduced renal drug excretion
• BBB not fully developed

Question 26

How does renal failure influence ADME?

Answer 26

• Decreased absorption due to Gi disturbances (due to high levels of urea)
• Decreased distribution due to edema and ascites, reduced colloid pressure so less protein for drugs to grab onto.
• Metabolism: affects hepatic enzyme function that usually plays a big role in drug metabolism
• Decreased excretion (increased GFR)

Question 27

What is CrCl used for?

Answer 27

• Indicator of renal fxn and ability to excrete the drug
• Used to adjust dose of drugs
• Unreliable measurement if renal function is changing
• If CrCl is <50ml/min this indicates significant renal dysfunction and one’s ability to eliminate the drug

Question 28

What’s the difference between linear and non-linear kinetics?

Answer 28

Linear: check level after 4-5 half lives of first dose (ex. vanco)
Non-linear: Half life not applicable, protein-binding drugs follow this pattern (ex. valporic acid , phenytoin)

Question 29

What are the 3 approaches to hypothesis formation when developing differential diagnoses?

Answer 29

Probabilistic approach- most likely dx
Prognostic approach- how serious if left untreated
Pragmatic approach- conditions more responsive to tx

Question 30

What is one pneumonic for hx taking?

Answer 30

O- onset
P- provoking factors/palliating factors
Q- quality
R- region/radiation
S- severity
T- timing/treatment
U- understanding

Question 31

What’s the difference between efficacy and potency?

Answer 31

• Efficacy is the maximal response a drug can have

- Potency is the amount of drug needed to get a desired response

Question 32

What are the risk factors for ADR’s?

Answer 32

• Advanced age
• Polypharmacy (especially for older adults)
• Co-existing liver disease and renal dysfunction
• Alcohol misuse

Question 33

What are the 3 types of ADR’s?

Answer 33

1) Side effects- secondary effects occurring at normal drug doses
2) Idiosyncratic reactions- uncommon drug responses due to genetic predisposition
3) Hypersensitivity reactions- a non-immune or immune response that requires prior sensitization of the immune system separate from the dose of medication administered. These type of true allergen responses represent less than 10% of ADR’s. Hypersensitivity reactions must occur within the first 24 hours of exposure to the allergen.

Question 34

What patient factors influence drug therapy selection?

Answer 34

• Age, gender, genetics, pregnancy, weight (frailty)
• Allergy history
• Co-morbidities: DM, CKD/CrCl (creatinine clearance), liver impairment
• Nutritional status
• Potential for drug interactions - polypharmacy
• Complexity of a drug regimen (has an impact on non-adherence)
• Cost (drug coverage)

Question 35

Discuss dependance and tolerance (pharmacodynamic and pharmacokinetic).

Answer 35

• Tolerance: occurs when a given dose of a drug yields a weaker effect compared to previous doses of the same drug, thereby necessitating larger doses to produce effects of the same magnitude.
  Pharmacodynamic tolerance: a high concentration of drug is constantly binding to receptors and leading to desensitization.
  Pharmacokinetic tolerance: a reduced volume of drug reaches the site of action due to up-regulation of enzymes such as CYP450 enzymes.
• Dependence: develops in the presence of withdrawal symptoms when the drug is removed. These withdrawal symptoms are associated with dopaminergic deficits leading to aversive effects on brain function.
• Addictive substances (opioids, ETOH, nicotine, etc.) affect pathways in the brain in the reward/reinforcement centre and involve the release of dopamine. Both genetic and environmental influences in addiction.

Question 36

How does addiction differ from misuse, abuse and diversion?

Answer 36

• Addiction: primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. 4 C’s: Craving, loss of control of amount or frequency of use,
  compulsion to use, use despite consequences
• Misuse: the use of a drug in a manner or for a purpose other than indicated
• Abuse: using a drug in a fashion inconsistent with medical or social norms and that is harmful to the individual or society
• Diversion: any intentional act that results in transferring a drug product from lawful to unlawful distribution or possession

** Proper term: substance use disorder

Question 37

How does the older adult population have different ADME factors?

Answer 37

• Absorption: Slowed rate of absorption and delayed responses
• Distribution: Increase in free drug distribution and resultant intensified drug effects
• Metabolism: Decline in liver metabolism which can increase drug half-lives prolonging responses BUT this degree of decline is widely varying so difficult to adjust dose base off this assumption
• Excretion: Decline in renal function results in toxic drug accumulation secondary to the changes (considered the most important cause of ADRs in elderly clients)