Module 3 (pharm)

Describe the synthesis of insulin (location, intermediate)

1. Preproinsulin is translated into proinsulin in the rough ER

2. A-chain ad B- chain fused together with 3 disulfide bond

3. Folded proinsulin goes to the golgi where its enzymatically cut into mature insulin

4. Gets packaged into secretory vesicles

Describe the mechanism through which insulin is secreted:

1. Glucose comes into through glut 2 (B cells)

2. ATP/ADP ratio increases causing K+ channel to shut (so K+ can’t go out)

3. Depolarizes the cell

4. Ca+ channel open and Ca2+ comes into the cell

5. Insulin-containing granule fuses with the membrane and insulin is released

Insulin receptor is what kind of receptor? Binding of insulin to this receptor does what?

kinase-linked receptor:

causes intracellular enzymatic activity of intracellular receptor domain and recruit other molecules intracellular to cause a action

How does insulin induce translocation of GLUT4 to plasma membrane in skeletal muscle and adipocyte?

1. Insulin bind to insulin receptor and becomes activated

2. Translocation of glucose transporter (GLUT4) occur to the plasma membrane

3. Glucose come in to cell via GLUT4

True or false: insulin-IRs binding does induce translocation of GLUT-4 in hepatocytes

False: insulin-IRs binding does not induce translocation of GLUT-4 in hepatocytes

How does insulin effect glucose uptake and glycogen production in skeletal muscle:

Skeletal muscle:
↑ glucose uptake
↑ glycogen production

How does insulin effect glucose uptake and fat storage production in adipose tissue:

Adipose tissue:
↑ glucose uptake
↑ fat storage

How does insulin effect glucose production and glycogen production in liver:

Liver
↓ glucose production (gluconeogenesis)
↑ glycogen production

Why does patients with diabetes experience frequent urination?

1. Not all glucose are reabsorbed by the SGLT in kidney

2. Glucose in lumen increases drawing water out

3. High volume of urine

Describe how A1C is used as glycemic test; does it require fasting?

Measure a Hb that is linked to a glucose (glycated Hb), measures average blood sugar level over the past 2 or 3 month

*Does not require to fast

1. Performed after 8-12 hours of fasting.

2. Single time-point measurement assessing glucose at that specific moment or condition

Fasting Plasma Glucose (FPG) Test

2 Test that measure Single time-point measurement assessing glucose at that specific moment or condition

1. Fasting Plasma Glucose (FPG) Test

2. Oral glucose tolerance test (OGTT)

How does insulin resistance effect circulating glucose, FFA, and glucose uptake in target organ:

Increased circulating glucose and FFA
Decreased glucose uptake in target organs

What 2 things causes low grade inflammation:

adipocytes undergoing

1.hypertrophy (adipocyte enlargement)

2. hyperplasia (proliferation of new adipocytes)

What’s low-grade inflammation?

It’s chronic low-grade production of pro-inflammatory
factors (adipokines, chemokines and free fatty acids) into the circulation

What’s Lipotoxicity?

accumulation of lipids (e.g. free fatty acids) in non-
adipose tissue, such as liver, muscles, pancreas

What happens when lipid accumulate in non-adipose tissue?

1. Insulin resistance

2. B-cell dysfunction

What are adverse effect of insulin treatment: (2)

1. Hypoglycemia

2. Weight gain

When do you use insulin as a treatment:

when B cell fails to produce insulin

What are insulin sensitizers used for?

lower glycemia by ↑ insulin sensitivity in target organs

What are insulin secretagogues used for?

To enhance insulin secretion

Insulin sensitizers effect on hyperinsulinemia and hypoglycemia

Insulin Sensitizers do not release insulin therefore they do not cause
hyperinsulinemia and hypoglycemia (unless given in combination with
secretagogues)

initial drug of choice for type 2 diabetes

Biguanides (metformin)- sensitizer

Mechanism of action for Biguanides (metformin)

1. ↓ postprandial and fasting glucose levels (does not promote insulin secretion)

2. ↑ glucose uptake (GLUT4-mediated)

3. ↑ glycogen production

4. ↓ hepatic gluconeogenesis

Adverse effect of Biguanides (metformin)

Largely gastrointestinal.

Loss of appetite and weight loss

what happens if Biguanides (metformin) is taken with insulin?

Hypoglycemia

Thiazolidinediones is what type of anti-diabetic drug? and its mechanism of action?

It’s a senitizers, mechanism of action:

1. Activates PPARγ

2. PPARγ receptor regulates transcription of genes resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle

3. ↓ postprandial and fasting glucose levels (does not promote insulin secretion)

4. ↑ glucose uptake (GLUT4-mediated)
   

5. ↑ glycogen production

6. ↓ hepatic gluconeogenesis

Adverse effect of Thiazolidinediones

1. Weight gain

2. Fluid retention

Sulfonylureas is what type of anti-diabetic drug? and its mechanism of action?

It’s a secretagogue (GLUCOSE-INDEPENDENT)

1. Sulfonylureas block ATP-sensitive K+ channels,

2. resulting in depolarization, Ca2+ influx

3. insulin exocytosis

Adverse effect of Sulfonylureas

1. Hypoglycemia

2. Weight gain

Glinide is what type of anti-diabetic drug? and its mechanism of action?

It’s a secretagogue (GLUCOSE-INDEPENDENT)

1. block ATP-sensitive K+ channels

2. resulting in depolarization

3. Ca2+ influx

4. insulin exocytosis

Adverse effect of glinide:

1.Hypoglycemia

2. Weight gain

What are the 2 incretin secreted by GI tract?

1. Glucagon-like peptide 1 (GLP-1)

2. Glucose-dependent insulinotropic polypeptide (GIP)

GLP-1/GIPR agonist is what type of anti-diabetic drug? and its mechanism of action?

It’s a secretagogue (GLUCOSE-DEPENDENT)

1. incretin bind to GPCR (Gs-coupled GLP-1R/GIPR in the β-cells)

2. Gctivation of GLP-1R/GIPR is responsible for
   GLUCOSE DEPENDENT RELEASE of insulin

What inactives GLP-1/GIP?

Dipeptidyl peptidase 4 (DPP-4)

When can GLP-1/GIP become resistant to DPP-4? And its effect on GLP-1/GIP concentration:

Selective modification of key amino acids renders these peptides resistant to DPP-4 degradation, thereby extending their circulating half-life

Incretin- and incretin related drugs are what kind of molecule and what improves their oral bioavailability?

—> they are polypeptides

—> Salcaprozate sodium and related compound improve oral bioavailability of peptides

Adverse effect of Incretins and Incretin-related drugs:

1. Weight loss

2. GI issue: nausea, vomiting

3. Low incidence of hypoglycemia

Why does Incretin-related drugs cause nausea and vomiting:

it acts on the GLP-1R → Nausea- promoting in the Chemoreceptor trigger zone (CTZ)

Why is it dangerous to give incretin-related drugs and general anesthesia?

1. Protective airway reflexes may be lost

2. risk of regurgitation & aspiration

3. ↑ risk of pneumonia or acute respiratory
   distress

DPP-4 inhibitor is what type of anti-diabetic drug? and its mechanism of action?

It’s a secretagogue (GLUCOSE-DEPENDENT)

1. Prevent GLP-1/GIP inactivation

2. produce 2- to 3-fold levels of active GLP-1/GIP

3. GLP-1/GIP binds to GLP-1R/GIPR

4. Allows insulin to be secreted

DPP-4 inhibitors adverse effect:

1. doesn’t cause satiety, or fullness

2. Upper respiratory infections

α-Glucosidase Inhibitors mechanism of action:

1. α-glucosidase is an intestine enzyme which breaks down carbohydrates into glucose and other simple sugars that can be absorbed

2. α-glucosidase inhibitors block the intestinal breakdown of complex carbohydrates and interferes with their absorption, resulting in lower postprandial glucose levels

Adverse effect of α-Glucosidase Inhibitors

1. GI effects, e.g. flatulence, diarrhea, and abdominal cramping.

2. Doesn’t cause hypoglycemia when used as monotherapy.

3. When used with insulin secretagogues or insulin, hypoglycemia may
   develop

Mechanism of action of SGLT-2 Inhibitors:

1. decrease reabsorption of glucose,

2. increase urinary glucose excretion

3. lower blood glucose

Adverse effect of SGLT-2 Inhibitors

1. weight loss

2. Urinary tract infections (especially in women)

Lack of drug efficacy for organism/ neoplastic cell

natural resistance

Loss of drug efficacy over course of treatment in a patient or in a population

Acquired resistance

Acquired resistance develop 3 ways, what are they?

1. Gene amplification

2. Gene mutation

3. Gene transfer in bacteria

What are the 3 form of gene transfer? describe each:

Conjugation: transfer of R plasmid between bacterial cells

Transposons: transfer of resistance gene between plasmid and plasmid, chromosome

Transduction: transfer of resistance gene from bacteriophage and bacteria

What are 4 drug target sites in bacteria?

1. Folate synthesis in cytoplasm

2. Protein synthesis by ribosome

3. Nucleic acid synthesis

4. Cell wall synthesis

Funny People Need Coffee

what does B lactams do

kill bacteria by inhibiting cell wall synthesis

Function of B-lactamases

enzyme that inactive B-lactams ring (penicilin) by cutting opening the ring —> drug can no longer bind to the active site

Transpeptidases that cross-link peptidoglycan polymer in final step of cell formation—> giving cell wall rigidity, what drug messes with this function?

Penicillin binding protein —> penicilin

2 class of drug that bind to transpeptidases and block cross-linking of peptidoglycan polymers in cell wall synthesis

1. penicilins

2. Cephalosporins

penicilins and Cephalosporins which are both used to block cell wall synthesis in bacteria, how do they differ? (3)

1. Spectrum

2. Susceptibility to B-lactamases

3. Oral bioavailability

Who has more peptidoglycan layer and what does this mean?

Gram + and it provides high structural integrity against osmotic pressure

True or false: both gram (+) and (-) have penicillin binding protein (PBP)

True

required cofactor in the synthesis of pyrimindine dTMP for DNA replication

THF

In bacteria THF is formed from

PABA

In human THF formed FROM

DHF

What enzyme converts DHF to THF?

DHF reductase

What is function of sulfonamides?

Analogues of substrate PABA which inhibit DHF synthetase in bacteria

Bacterial Protein synthesis inhibitors interact with what

30 S or 50 S ribosomal subunit

Treatment of infection, documented by culture of microbes and determination of susceptibility to drugs is what type of treatment

Definitive

Treatment of infection based on most likely microbes and their probable susceptibility/ you don’t know what’s causing the problem but making a best guess in terms whats likely to help is what type of treatment

Empiric

Therapy to prevent infection

Prophylactic

What are some mechanism of resistance? (4)

1. Reduce intercellular level of the drug by decreasing uptake and increasing reflux

2. Inactivation of the drug

3. Alter drug target by increasing amount and decreasing affinity to drug

4. Increase repair of the drug effect

True or false ; overuse of anti-bacterial medication contributes to resistance

True, estimated 30% inappropriate antibacterial prescribing, especially anti-vectorial agents for viral infection

What is the function of reverse transcript test in HIV?

A retrovirus with two identical, single-stranded RNA replicated by reverse transcriptase into DNA to be incorporated into the host DNA

What are some site of actions of anti-HIV agent (4)

1. Entry inhibitor

2. reverse transcription inhibitor

3. integrase inhibitor

4. protease inhibitor

What’s zidovudine (AZT) and what is it used for?

Reverse transcriptase inhibitor and it is used as an antiviral agent drugs for HIV

Courteous inhibitors are cleared by

CYP3 A4 which is a enzyme in the liver and intestinal track that metabolizes drug

What is the benefit of giving prose inhibitors along with CYP3 A4 inhibitors as well

It increases the efficacy of protein, inhibitors by slower, elimination, causing boosting of the drug effect

Highly active oral antiretroviral therapy (HAART) is used for

long term regimen treatment for HIV and it requires different drugs from different classes

Non-B hepatitis affecting blood transfusion, recipients and IV drug users and it is a single stranded RNA virus

HCV infection

Cause of liver failure, liver, cancer, and need for transplant

HCV infection

Name three treatment for HCV

1. Protease inhibitor

2. NS 5A replication complex in inhibitor

3. NS 5B polymerase inhibitor

How does protease inhibitor in HCV treatment work?

It binds and inhibits the viral NS3/4A protease blocking the release of viral protein required for replication from large precursor

Mechanism of NS 5B polymerase inhibitor in HCV treatment

Block RNA dependent RNA polymers, preventing the synthesis of new viral RNA

-chain Terminator

Mechanism of NS 5A replication complex in inhibitor in HCV treatment

Block viral RNA replication and assembly

What are three antimalarial agent?

1. chloroquine e type (chloroquine)

2. Artemisinins

3. Primaquine-type (primaquine)

What is a possible treatment of respiratory illness COVID-19 due to SARS-CoV-2 infection

Protein inhibitor with CYP3 A4 inhibitor

What are 2 treatment targets for malaria?

1. Target schizonts in erythrocytes

2. Target hypnozoites in liver

Chloroquine e type (chloroquine) used as anti-parasitic drug. How does it work?

• Parasite digests hemoglobin

  • Inside RBCs, Plasmodium breaks down hemoglobin for nutrients.

  • This releases free heme (Fe²⁺-protoporphyrin IX) → toxic to the parasite.

• Parasite detoxifies heme

  • It normally converts toxic heme → hemozoin (non-toxic crystal).

• Chloroquine blocks this detox step

  • Chloroquine accumulates in the parasite’s acidic food vacuole.

  • It inhibits conversion of heme → hemozoin.

• Toxic buildup → parasite death

  • Free heme + chloroquine–heme complexes damage membranes and proteins.

  • This leads to oxidative damage and parasite death

Artemisinins is antimalarial agent, describe its mechanism of action:

1. Heme induced endoperoxide opening generates toxic free radicals

2. Toxic for radicals are lethal for parasites

Targets liver stages (hypnozoites) of:

• Plasmodium vivax

• Plasmodium ovale

• Prevents relapse

primaquine

Efficacy of anti-malarial drug—>primaquine is due to

CYP2D6 hydroxylation and CYP-reductase generation of H2O2

poisons made by plants and animals

Toxins

any toxic substance, including man-made poisons

Toxicants

Regulatory agency responsible for overseeing pesticides, industrial chemicals, hazardous waste, pollutants in air, water, and soil from manufacturing waste.

Environmental Protection Agency (EPA)

Regulatory agency responsible for overseeing Safety Data Sheets
for each hazardous chemical in standard format to communicate information on hazards in workplace

Occupational Safety and Health Administration (OSHA)

Provides EPA with authority to require reporting, record-keeping and testing requirements, and restrictions relating to chemical substances and/or mixtures

Toxic Substance Control Act

Importance in setting allowable levels of chemicals in air, water, workplace by EPA and OSHA

Regulatory Risk Assessment

Challenge of extrapolation from Regulatory Risk Assessment:

1. Animals to human

2. Experimental dose

High acute toxicity does not necessarily equal

high chronic toxicity

Low acute toxicity does not necessarily equal

low chronic toxicity

Define LD50

Amount of a toxic substance required to kill an individual

How does electrophilic alkylating agents cause toxicity? (mechanism)

They alkylate DNA, which then does not uncoil properly.
• Results in cytotoxicity, inhibition of cell growth, initiation of apoptosis, and risk of carcinogenic mutations.

How does oxidative stress cause toxicity:

1. Xenobiotic foreign to body

2. Goes through bioactivation —> generate free radical—> Lipid radical—> damages cell membrane