MED 2207 PHARMACOTHERAPEUTICS I

1. DRUG EVALUATION AND REGULATION

a. Outline the process of drug discovery
1. Numerous research is done on a disease to find a treatment target.
2. Various drugs are analysed until one is found which can reverse the effects of the disease by
binding to a specific target site lead compound.
3. ADMET studies are done on the drug.
4. Clinical trials
5. New drug application (NDA) approved.
b. Define a lead compound desired result of drug screening; a drug with pharmacological or
biochemical properties which suggest that it may have therapeutic potential and value as a starting
point for drug development.
c. Define IND Investigational New Drug Exemption Application
d. Describe the role of the NDA New Drug Application requests approval from FDA for general
marketing for prescribed use
e. Describe the phases of clinical trials -Phase 1-3 are premarketing surveillance and 4 is post.
Phase 1 Dose-response relationship & pharmacokinetics; Lethal/Toxic dose and Side effects; 20200; highly toxic drugs exempt
Phase 2 100-200; with placebo/positive drug control to determine desired efficacy; pharmacokinetics and dynamics
Phase 3 1000-5000; drug + placebo/positive drug control in double-blind crossover design;
toxicities, therapies and spectrum of benefits; compare with others
Phase 4 post-marketing surveillance; detect toxicities
f. Distinguish the various types of studies: single-blind, double-blind, placebo, crossover, positivecontrol
Single blind design: a study where the researcher knows the medication the subject is on but the
subject doesnt.
Double blind design: both the researcher and subject doesnt know what medication the subject is
on.
Randomized Cross-over clinical trial: Individuals with a chronic condition are randomly allocated
to one of two treatment groups, and, after a sufficient treatment period and often a washout period,
are switched to the other treatment for the same period. This design is susceptible to bias if carry
over effects from the first treatment occur.
Placebo: An inactive material, often in the form of a capsule, pill or tablet, that is visually identical
in appearance to a drug being tested in a clinical trial. The use of placebo control is a required
component of the FDAs drug approval process, as the agent must be proven more effective than the
placebo.

Positive control: an experimental set-up in which a change in the dependent variable is

observed/measured according to expectations. The independent variable is expected to have an effect
on the dependent variable.

2. DRUG INTERACTIONS
a. Describe pharmacokinetic drug interactions
Absorption GI absorption affected by agents affecting target surface area, that binding or
chelation, change pH or GI motility, or affect transport proteins; extent not rate of absorption
clinically significant
Distribution affected via competition for plasma binding protein (increases free [drug] but
increased elimination negates increased effect), displacement from tissue binding sites (transiently
increased [free drug]) and alterations in local tissue barriers
Metabolism drugs that induce CYP450 isozymes in liver and SI (slower process that peaks after 710 days and longer time to dissipate after it is stopped); drugs that increase activity of phase II
metabolism; inhibiting metabolism is faster
Excretion weak acid/base drugs affected by drugs that alter urinary pH; inhibition of transporters
into tubules (P-glycoprotein, organic anion and cation transporters) causes increased serum [drug]
b. Describe pharmacodynamic drug interactions
Additive Synergy 1+1=2 eg., aspirin + paracetamol
Potentiated / Super Additive Synergy 1+1 > 2
Antagonism 1+1=0

OR 0+1 > 2 eg., adrenaline + cocaine

eg., beta-blocker + Salbutamol

c. Define synergism and its types - when the therapeutic effect of one drug is enhanced by another
drug.
d. Describe antagonism and its types - Drugs with opposing pharmacologic effects may reduce the
response to one or both drugs.
Chemical 2 drugs react to form inactive product
Physiological - Two drugs act on different receptors or by different mechanisms, but have opposite
effect on the same physiological function
Receptor antagonist blocks receptor action of agonist
e. Identify inhibitors and inducers of the CYP 450 enzyme system
Inhibitors - Sodium valproate; Isoniazid; Cimetidine; Ketoconazole; Fluconazole; Alcohol - binge
drinking; Chloramphenicol; Erythromycin; Sulfonamides; Ciprofloxacin; Omeprazole;
Metronidazole; Grapefruit juice.

Acronym SICK FACES.COM Group

Inducers Barbituates; St. Johns wort; Carbemazepines; Rifampicin; Alcohol (chronic); Phenytoin;
Griseofulvin; Phenobarbitone; Sulphonylureas

Acronym BS CRAP GPS

3. PHARMACOGENOMICS
a. What is pharmacogenomics? - Pharmacogenetics is the study of how genetic differences influence
the variability in patients responses to drugs. It allows us to profile variations between individuals
DNA to predict responses to a particular medicine.
b. What are single nucleotide polymorphisms? SNPs occur when one nucleotide pair replaces
another, resulting in a wild type allele (determines phenotype) or variant allele.
c. What are the benefits of pharmacogenomics?
1. Improved medicines for better, safer starting drugs
2. More accurate methods of determining drug doses
3. Advanced screening for diseases
4. Availability of better vaccines
5. Improvements in Drug Discovery and Approval process
6. Decreases overall cost
1.

Predict patients response to certain drugs

2.

Improve rational drug development

3.

Screen and monitor diseases

4.

Develop more effective vaccines

d. What are some barriers to pharmacogenomics?

1. Investing millions of extra dollars into developing multiple pharmacogenomics products.
2. Emotional distress that stems from unexpected outcomes
3. Lack of controlled clinical trials
4. Lack of solid evidence of effectiveness
5. Poor accessibility
6. Complexity of finding gene variations that influence drug response
7. Limited availability of current treatment alternatives.
8. Pharming use of genetic engineering to insert genes that code for useful pharmaceuticals into
host animals or plants that would otherwise not express those genes, thus creating a genetically
modified organism.
9. Educating health care workers

4. VARIABILITY IN DRUG RESPONSES

a. What factors account for variation in drug responses?

Intrinsic factors Age, Gender, Race, Weight and body composition, Pregnancy and lactation,
Disease, Presence of food

Extrinsic factors - Smoking, Alcohol, Environment, Psychological factors, Drug tolerance (bodys
diminished response to a drug) and resistance (decreased effectiveness of drug)

Other factors - Circadian cycle (sleep cycle), Body temperature, Exercise, Stress, Nutritional status,
Genetics, Use of other drugs

b. What are the differences noted in biodisposition among elderly and neonates?
c. What are the differences noted in pregnancy?
Pregnancy: theres increased water and sodium retention increased plasma and blood volume
increased cardiac output and BF?
Increased hormone levels (estrogen and progesterone) disrupts enzymatic activity in pregnant
women.

Newborn/Premature Infants
Decreased gastric emptying increased
absorption of drugs
Decreased acid secretion - increased
absorption rate of acidic labile drugs (drugs
that are easily destroyed in acidic
conditions, if theyre not destroyed, more is
available for absorption penicillin)
Immature organs
Decreased microsomal enzymes
Decreased plasma protein binding of drugs
due to:
Low albumin levels
Albumin has decreased affinity for drugs
Bilirubin competes with drugs for albumin
Greater % of body water increased Vd of
water soluble drugs

Pregnancy

Elderly

Delayed gastric
emptying and motility

Drug-drug interaction may alter

absorption

Decreased albumin and

other plasma proteins

Decreased albumin

Decreased % of total body

water

Less body muscle and fat

Increased maternal fat

INCREASE in fat
DECREASE in muscle mass

Decreased glomerular filtration (poor

elimination)

Increased GFR

Renal blood flow decreases

Glomerular filtration AND
tubular secretion (another way
to get rid of drugs) decrease

Decreased hepatic clearance = increased

drug half-life.
Toxicity can arise
Lower doses are required, with longer
dosage intervals.

Decreased splanchnic blood

flow, less blood goes to liver =
decreased 1st pass effect.
Decreased phase I metabolism
Preserved phase II metabolism

5. MEDICATION ERRORS IN PRESCRIBING

a. Review common sources of error
- Choosing a medicine
- Writing a prescription
- Manufacturing the formulation to be used - wrong strength, contaminants, misleading packaging
- Dispensing the formulation wrong drug, wrong formulation, wrong label
- Administering or taking drug wrong dose, wrong route, wrong frequency or wrong duration.
- Monitoring therapy failure to alter therapy when required.
Knowledge, Rule, Action or Memory based Errors (Technical is subset of Action)
b. Describe consequences of medication errors
1. Health consequences
i.
Dose related (augmented - toxicity)
ii.
Non dose related and allergic reaction (bizarre)
iii.
Chronic prolonged exposure to a drug can cause negative side effects.
iv. Delayed adverse reaction to a drug is noticed some time after the drug was
administered.
v. Withdrawal symptoms
vi.
Failure of the drug to work
2. Socioeconomic consequences
3. Care consequences
Mental anguish/guilt; Disciplinary action; Job dismissal; Possible civil criminal charges; Loss of self
confidence
c. Identify ways to make medication use safe
- Proper communication
- Legible prescriptions
- Be aware of the patients allergies
- Keep patient medication list up-to-date
- Inform patient of potential side effects when giving them new medications
- Make sure the patient isnt pregnant when prescribing random drugs.

6. PHARMACOVIGILANCE
a. Define Pharmacovigilance - Pharmacovigilance is defined as the science and activities concerned
with Detecting, Assessing, Understanding and Preventing adverse reactions to medicines i.e. adverse
drug reactions (ADRs).
b. Define an adverse drug reaction - Adverse Drug Reactions (ADR) is defined as a response to a
medicine used in humans or animals, which:
- Is noxious and unintended, including lack of efficacy
- Occurs at any dosage
- Results from overdose, misuse or abuse of a medicine.

c. Why is pharmacovigilance conducted? - Pharmacovigilance is needed for the prevention of druginduced human suffering and to avoid financial risks associated with unexpected adverse effects.
Clinical trials are insufficient with regards to the safety of the drug since:
1. Most tests are done on animals
2. There are selected and limited number of patients, and the way the drug is used is completely
different from how it would be used when marketed.
3. Tests are rarely ever done on children, elderly or pregnant women, however, they still use these
drugs and adverse drug reactions can surface.
d. Describe the system of adverse drug reaction reporting in Guyana.
1. Reception of ADR reports. Drugs are reported because:
i)
The ADRs are not clearly stated on the package.
ii)
Has an unusual or interesting ADR
iii)
Its a traditional or herbal drug with serious ADRs
iv)
There was a serious reaction or interaction.
v)
Its a new drug and has an ADR.
2. Inspection of drugs, cosmetics and medical device import and wholesalers/distributor bands.
3. Examination of import licenses and custom entries
4. Collection of samples of product
5. Submission to the FDA or the CRDTL for analysis and examination
6. Report findings

7. DIETARY SUPPLEMENTS AND HERBAL MEDICATIONS

a. What is a dietary supplement?
A dietary supplement is a product intended for ingestion that contains a "dietary ingredient" intended
to add further nutritional value to (supplement) the diet. It doesnt require a prescription, thus proof
of efficacy and safety before marketing is not needed. It is not tested for toxicity or carcinogenicity
making it harder for the FDA to prove that a supplement is harmful.
b. What is a botanical? - Any drug or pesticide that is made from parts of a plant.
c. What is the role of the DSHEA? - The Dietary Supplement Health and Education Act of 1994
("DSHEA"), is a 1994 statute of United States Federal legislation which defines and regulates dietary
supplements.
-

Manufacturers and distributors of dietary supplements and dietary ingredients are prohibited
from marketing products that are adulterated or misbranded. That means that these firms are
responsible for evaluating the safety and labelling of their products before marketing to
ensure that they meet all the requirements of DSHEA and FDA regulations.

FDA is responsible for taking action against any adulterated or misbranded dietary
supplement product after it reaches the market.

d. What are some of the properties of Coenzyme Q10?

-

Fat-soluble

OXIDIZED as ubiquinone, plays a role in the ETC

REDUCED as Ubiquinol, is an ANTIOXIDANT

Produced naturally by our body and found in every cell.

Has a neuroprotective effect on the brain in infarction induced by ischemia; cardiologic and
neurologic disorders

Reduced muscle pain in patients with statin-related myopathy.

ADRs include GI disturbances

Rare effects include rash, thrombocytopenia, irritability, dizziness, and headache.

Has a similar structure to vitamin K and can decrease the effects of warfarin.

e. What are the pharmacologic effects and likely drug interactions associated with St Johns
Wort?
Pharmacologic effects:
-

Anti-depressant

Anti-viral

Anti-carcinogenic

Drug interactions:
-

Too much serotonin syndrome (excessive accumulation of serotonin can be fatal) or

MAO crisis (Monoamine Oxidase)

Induce hepatic CYP enzymes and P-glycoprotein drug transporters leading to sub therapeutic
effects of many drugs.