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; 20-200; highly toxic drugs exempt

Phase 2 – 100-200; with placebo/positive drug control to determine desired efficacy; pharmaco-kinetics 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, positive-control

Single blind design: a study where the researcher knows the medication the subject is on but the subject doesn’t.

Double blind design: both the researcher and subject doesn’t 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 FDA’s 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 7-10 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 OR 0+1 > 2 eg., adrenaline + cocaine

Antagonism – 1+1=0 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. John’s 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 (body’s 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: there’s 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 Pregnancy ElderlyDecreased gastric emptying – increased absorption of drugs

Delayed gastric emptying and motility

Drug-drug interaction may alter absorption

Decreased acid secretion - increased absorption rate of acidic labile drugs (drugs that are easily destroyed in acidic conditions, if they’re not destroyed, more is available for absorption – penicillin)Immature organsDecreased microsomal enzymesDecreased plasma protein binding of drugs due to:Low albumin levelsAlbumin has decreased affinity for drugsBilirubin competes with drugs for albumin

Decreased albumin and other plasma proteins

Decreased albumin

Greater % of body water – increased Vd of water soluble drugs

Decreased % of total body water

Less body muscle and fat Increased maternal fat INCREASE in fatDECREASE in muscle mass

Decreased glomerular filtration (poor elimination)

Increased GFR Renal blood flow decreasesGlomerular filtration AND tubular secretion (another way to get rid of drugs) decrease

Decreased hepatic clearance = increased drug half-life.Toxicity can ariseLower doses are required, with longer dosage intervals.

Decreased splanchnic blood flow, less blood goes to liver = decreased 1st pass effect.Decreased phase I metabolismPreserved 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 errors1. 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 work2. Socioeconomic consequences3. 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 isn’t 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 drug-induced 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 animals2. 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 ADR’s are not clearly stated on the package.ii) Has an unusual or interesting ADRiii) It’s a traditional or herbal drug with serious ADR’siv) There was a serious reaction or interaction.v) It’s 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 product5. 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 doesn’t 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 John’s

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.