Pharmacology Exam One

Steps of drug development

1. Discovery and development

2. Preclinical research

3. Clinical development

4. FDA review

5. Post-market monitoring

Phases of a clinical trial

• Preclinical

• Phase 1: Safety

• Phase 2: Safety and dosing

• Phase 3: Safety and efficacy

• FDA Approval

• Phase 4: Post marketing safety and efficacy

It takes ______ years from development of a drug to when it hits the market for consumers

7-10

Primary reason for clinical trials

testing drug safety

Pure food and drug act (1906)

meat industry/wet market

• COVID is believed to have possibly arisen from a wet market

Food, drug, and cosmetic act (1938)

Strep-elixer made from sulfonamide+antifreeze, 100 people died

FDA amendments act (2007)

Anti-inflammatory drug Rofecoxib (Vioxx)- fatal coagulopathy

• MI and strokes (CVA), 60,000 deaths

• return to market as treatment for hemophilic arthropathy (HA)- spontaneous bleeding disorder

Thalidomide

antiemetic for hypermedia gravidarum

• babies born to these mothers were born with phocomelia

Phocomelia

birth defect of “seal like” condition in infants

Tertatogenesis

creation of abnormalities and abnormal cells (defects)

• Accutane causes teratogenesis

Accutane in teratogenesis

high amounts of retinoic acid (vitamin A) that causes 100% chance of birth defects

Consent required to participate in a clinical trial

informed consent

Preclinical testing

testing before clinical studies occur

IND

Investigational new drug

• passes through initial pre-clinical testing

• between the pre-clinical and stage 1 of a clinical trial

Phase I trial

• normal, healthy volunteers (10-50)

• people who relapsed typical therapies

• newly diagnoses disease with no therapy

Phase II trial

• 100-500 patients studied

• therapy is given over several months to evaluate response

Phase III trial

• 100-10,00o pts

• compare effect of newer drug to established therapies

• file NDA (New Drug Application) once successfully completed

NDA

New drug application

• happens between the Phase III and Phase IV

• applying to release to public

Adverse event

any untoward medical occurrence associated with the use of a drug, whether dose related or not

• nausea, vomiting, diarrhea

Serious adverse event

• Stevens Johnson syndrome with rash- Antibiotics

• Bronchospasm after use of BP reducing medication- Propranolol

• Priapism- Sildenafil

Life threatening event

death, hospitalization, persistent or significant disability, congenital/birth defect

Statins can cause

Rhabdomyolysis

1. Breakdown of muscles (myopathy) in myoglobulin

2. Myoglobulin in blood is filtered in kidney

3. Leading to acute renal failure and possible death of patient

Codeine is a

Prodrug

• inactive at time given, converts to active form when metabolized

• Codeine metabolizes into morphine

Cytochrome P450 allele CYP2D6

metabolizing enzyme and oxidation reactions in the liver

• 7% of caucasians are missing this which makes metabolizing drugs difficult and ineffective

Drugs with narrow therapeutic windows

• Lithium: bipolar mood stabilizer

• Digoxin: CHF

• Theophylline: severe bronchoconstriction

Aminoglycoside antibiotics

Ototoxic, nephrotoxic, NM toxicity

• Gentamicin

Pharmacokinetics- ADME

• A: Absorption

• D: Distribution

• M: Metabolism

• E: Excretion

Half-life

time required for serum concentration of a drug to decrease by half after absorption and distribution are complete

• Drug A: half life of 5 hrs

  • Gone from the body in 25 hrs (half life (hrs)*5=time to be gone from the body)

Hepatic 1st pass effect

a drug given orally needs to pass through this organ before it reaches its site of action

Physiologic barriers

• epithelial lining

• pH difference

• BBB/blood placental barrier

• Bi-Lipid layer: phospholipid, glycolipid

• Transmembrane proteins (2nd messenger system- G Protein)

• Hydrophobic/Hydrophilic

Oral drug administration

Enteral (PO)

Inhalation drug administration

Vapors, gas, smoke

Parenteral

medication administration everywhere besides orally

Mucous membrane drug administration

• Intranasal

• Sublingual

• Rectal suppository

• Vaginal pessary

Injection drug administration

• Intravenous

• Intramuscular

• Subcutaneous/intradermally

• Intraperitoneal

• Intra-arterial

• Intra-articular

pKa

pH at which 50% of dirge molecules are ionized

pH trapping

ppens when a drug moves across a membrane, becomes ionized in a different pH environment, and then can’t easily cross back, so it gets “trapped” there

Oral drug administration pros and cons

• Pros: safe, economical, practical, reversible

• Cons: first pass effect, activation/inactivation problems

Absorption is more rapid in

injections vs orally

• Injection does not undergo hepatic first pass effect

• rapid absorption can be bad in cases of overdose- usually irreversible

Bioavailability

the fraction of an administered dose that actually reaches the blood stream

• diet

• age and gender

• interactions with other drugs

• gastric emptying rate

• fasting state

• drug formulation

Passive transport

1. Filtration- aminoglycosides (gentamicin)

2. Diffusion

3. Facilitated diffusion- glucose

• Depends on concentration gradient

Active Transport

1. ABC transporters- Levodopa (L-Dopa)

2. Pinocytosis- Insulin

Aqueous solubility

drugs given in solid form mist dissolve in the aqueous bio-phase before they are absorbes

• Griseofulvin: non-water soluble anti fungal

Route of administration affects

drug absorption, because each route has its own peculiarities

• Acid drugs (aspirin) absorption from the stomach is faster due to non-ionized properties

• Basic drugs (morphine) largely ionized in the stomach and are only absorbed in the duodenum

Enteric coated tablets

acid resistant coating and sustained released preparations to overcome acid ability and gastric irritancy

Tetracyclines cannot be taken with

calcium or milk

Drugs altering the gut wall

• Motility: Atropine, metoclopramide

• Mucosal damage: methotrexate

• Gut flora: Clindamycin

Fat soluble vitamins

A, D, E, K (Ileum)

Water soluble vitamins

B and C

Depot preparations

preparations with a long action

• Benzyl penicillin and protamine zinc insulin

PPD skin test for TB is given

intradermally

Drugs that significantly penetrate intact skin

• Nitroglycerine, scopolamine, estradiol

• Glucocorticoids can produce systemic effects and pituitary adrenal suppression that can cause adrenal insufficiency

Active form of a drug

“Free form”

• Unbound drug= not working

2 -compartment pharmacokinetic model

oral medication route model

1- compartment pharmacokinetic model

IV medication route model

Apparent volume of distribution (Vd)

Vd= dose administered/plasma concentration

• Closer to 1= high concentration in the blood

• Closer to 100= drug not in blood

Drugs with high Vd

Digoxin (CHF)- present in heart

BBB

lipid based and limits the entry of non-lipid soluble drugs

• inflammation of the meninges can increase the permeability of drugs

Placental barrier

lipid soluble and allow free passage of lipophilic drug and restrict hydrophilic drugs

• incomplete barrier

• Penicillins, azithromycin, clarithromycin used in pregnancy

  • NO ERYTHROMYCIN

Drugs accumulating in organs

• Heart and skeletal muscles- Digoxin

• Liver- Chloroquine

• Kidney- NSAIDs

• Thyroid gland- Iodine

• Brain- Isoniazid

• Retina- Choloroqiune

• Bones and teeth- tetracyclines and heavy metals

• Adipose tissue- DDT (insecticide)

Metabolism (biotransformation)

Chemical alteration of drugs in the body

• Primary site is the liver; followed by the kidneys, intestines, lungs, plasma

1. Inactivation

2. Active metabolite from an active drug- Codeine→ Morphine

3. Activation of inactive drug: PRODRUG (Levodopa)

Phase I non-synthetic reactions- Oxidation

Most important drug metabolizing reaction

• most is carried out by Cytochrome P450

Oxidation reaction example- Inhibitor

CYP3A4/5 enzyme

• Substrate: Nifedipine for pts HTN

• Inhibitor (Fluconozole, Ketoconazole): Pt takes for fungal infection and decreases the CYP3A4/5 enzyme

• Result: Increased CCB in blood and pt has adverse drug reactions due to an increased presence

Oxidation reaction example- Inducers

CYP3A4/5 enzyme

• Substrate: Nifedipine for pts HTN

• Inducer (Hydrocortisone, dexamethasone): These medications induce the production of CYP3A4/5 enzyme that metabolizes nifedipine more

• Result: Decreased CCB in blood and pt has HTN despite taking meds

Reduction reaction

Converse of oxidation and involves the CYP450 enzymes working in the opposite direction- Levodopa

• Levodopa (DOPA)—-DOPA-decarboxylase→Dopamine

Hydrolysis

Cleavage of a drug molecule by taking up a molecule of water

Ester+H2O—Esterase→Acid+alcohol

• Ester= local anesthetics (benzocaine) and cocaine

• Occurs in liver, intestines, plasma and other tissues→ lidocaine and oxytocin

De-cyclization

opening of a ring structure of the cyclic molecule

• Phenytoin

All oral medications must go through

“First Pass” through the intestines/liver

• Propranolol, verapamil, albuterol, nitroglycerine

• In pts with severe liver disease drugs will not break down well which leads to cumulative toxicity

Excretion

Passage of systemically absorbed drugs out of the body

• Urine (kidney)

• bile and feces

• exhaled air

• saliva

• sweat

• milk

• skin

Urinary/Renal excretion

• Aminoglycosides- gentamicin

• Quinolones- “floxacin”

• Nitrofurantoin (Macrobid)- severe UTI

Hepatic excretion

• Macrolides- azithromycin, clarithromycin, erithromycin

• Tetracyclines- doxycycline, aminocycline

Pulmonary excretion

• General inhalation anesthetics

• Nicotine

• Albuterol

• Alcohol

• Cannabis

Salivary excretion

• Nicotine

• Phenytoin (Dilantin)- can cause gingival hyperplasia

• Nifedipine- can cause gingival hyperplasia

First order (exponential) kinetics

• 90% of drugs

• Drugs are removed at the rate at which they are absorbed

Zero order (linear) kinetics

• Ethanol, phenytoin, warfarin

• Drugs are removed at a constant rate that is independent of plasma concentration

• Causes toxicity

• Can start as first order and progress to zero order kinetics

First vs Zero order elimination

• First Order elimination

  • drug decreases exponentially with time

  • rate of elimination is proportional to drug

  • t ½ is constant regardless of drug

• Zero order elimination

  • drug decreases linearly with time

  • rate of elimination is constant (same with 2 beers vs 10)

  • rate of elimination is independent of drug

  • NO true t ½

Plasma half life (t½)

• Adenosine <2 sec

• Diazepam <12 hrs

• Alendronate =10 yrs (type of bisphosphonate that goes straight to bones)