Pharmacology leture notes PDF

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Learnin outcome 1. Critique the professional, sociocultural and politico-legal context of medicines’ management. 2. Demonstrate understanding of pharmacokinetics. 3. Demonstrate understanding of pharmacodynamics. - Pharmacolog PHMY Medicine Management 4. Demonstrate understanding of pharmacotherapeu...

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Pharmacolog PHMY701 Learnin outcome 1.

Critique the professional, sociocultural and politico-legal context of medicines’

management. 2. Demonstrate understanding of pharmacokinetics. 3. Demonstrate understanding of pharmacodynamics. 4. Demonstrate understanding of pharmacotherapeutics. Medicine Management ☆ Preclinical testing - using animals Clinical trials ƒ☆ Clinical trials (Phase 3) ☆ Randomisation ☆ Double-blinded ☆ MEDSAFE - NZ Regulatory Body ☆ 4th phase of a clinical trial Affordability Appropriate use

3 4 5 6 6 7 9 11 13 17

Pharmacokinetics Absorption Tutorial - Absorption Distribution Distribution - Tutorial Metabolism Elimination

19 19 22 25 30 31 34

Infections and Anaphylaxis Antibiotics

36 36

Pharmacodynamics Infections/ Anaphylaxis Antibiotics: Concepts Antibacterial agents Review Questions: Basic Concepts Antifungals Antivirals Unwanted effect 1: Antimicrobial Resistance Review Question Unwanted effect 2: Superinfection LO4

38 45 45 47 48 49 50 52 56 57

Review Questions Unwanted effect 3: Hypersensitivity Review Questions

58 59 62

Respiratory Functions Asthma ☆MoA: Short-Acting Beta-2 Agonists (SABAs) ☆MoA: Long-acting beta 2 agonists (LABAs) Tolerance - No longer has the same effect on you ☆ Corticosteroids ☆MoA: Corticosteroids Use of systemic Corticosteroids Antimuscarinic Agents Other conditions Drug delivery to lungs Smoking cessation

63 64 67 68 69 70 70 73 75 76 77 78

Central Nervous System, Part 1 Neurotransmitters Review neurophysiology and neurotransmitters Antidepressants Anti-psychotics Antiemetics Dopaminergic agents Acetylcholinesterase Inhibitors Anxiolytics and hypnosedatives Anticonvulsants

82 82 83 89 92 94 96 96 98

Central Nervous System Part 2: Analgesics, Anaesthetics & Gout Non-opioid analgesics Paracetomol Non-Steroidal Anti-inflammatories COX-2 Inhibitors Opioids Gout Anaesthetics Inhaled anaesthetics General Anaesthetics

100 103 103 105 107 107 111 115 116 116

Gastroenterology, Vitamins and Minerals, Bone Metabolism Medications that affect acid secretion and balance Gastrointestinal mobility Diarrhoea and spams Bone Metabolism

121 121 128 135 137

Medicines in the Endocrine Diabetes Overview Oral Hypoglycemics Insulin Sex hormones and contraception Erectile dysfunction Oxytocin

144 144 149 154 157 159 160

Cardiovascular System Part 1 Antihypertensive medicines Medicines that manage cardiac dysrhythmia and heart failure

161 167 170

Cardiovascular System 2 lipid -regulating medication Part 2: Antianginal medications: Nitrates Part 3: Medicines affecting haemostasis

172 172 177 182

Medicin Managemen LECTURE NOTES Medicine managemen

Dru developmen - fro concep t registratio Dru Developmen

☆ Preclinica testin - usin animal ●

Mechanism of action ○

What receptors is the medicine acting on? I.E does the BP drop? If so how?

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Ecacy

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Toxicity studies (LD50)

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LD50 = Lethal dose of 50% population

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Looking for the maximum dose that kills animals and then determine what the safe dose is for humans

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Informs us what might be a safe dose for humans

Carcinogenicity ○

Does it cause cancer?

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High dose for as long as possible to see if it can trigger breaks in their chromosomes, as that is what will cause cancer

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Teratogenicity (incl. non-rodent tests) ○ IS this medicine that we create going to aect the next generation? ○

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How safe is it going to be with the o spring

Q.Describe the purpose of using fruit flies and rodents in preclinical drug development studies. ○

Rodents we are able to investigate into their organs to see if the medicine has caused damage to there organs or caused cancer

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Fruit flies are used as they breed fast, so you can see if there are any

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chromosomal abnormalities Similar DNA

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Two dierent species for safety

Clinica trial ●

Phase 1 & Phase 2 - is it safe in humans? ○

Healthy volunteers, then few patients

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Single-blinding

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Exclusion criteria ■

older people ●

Usually on other medicines and have existing medical conditions, it can be hard to determine what the adverse eects are a result of.

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Renal function diminishes, dementia starts to kick in, chromosomal abnormalities start

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child-bearing age women ●

■

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They are vulnerable

Children ●

Unethical to test on children - organs and systems aren’t fully developed

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Unable to give informed consent

PHASE 1 ○

Investigates the pharmacodynamics and pharmacokinetics of small healthy volunteers.

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The Maximum tolerated dose is determined, which is the lowest dose that

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cannot be tolerated before acute toxicity occurs. The first time in humans, designed to establish the safety of the treatment and the approximate dosing range. ■

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Purpose: determine safety and dosage ●

Safety

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Safe dose range

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Identify side eects

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Tolerability

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Pharmacokinetics Pharmacodynamics

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Route of administration

Phase 2 ○

Dose ranging studies to find the therapeutically eective and safe dose that can be administered.

○

Trial for people that have the disease. Studies how the treatment is absorbed, metabolised and eliminated. A range of doses are tried to look at dierences in

eect and any side eects. This helps researchers find the best dose and dosing interval for the desired eect. ■ Purpose: Ecacy and side eects ■

Specifically designed to assess dosing requirements (how much drug should be given)

■

Specifically designed to study ecacy (how well the drug works at the prescribed dose)

ƒ☆ Clinica trial (Phas 3) ●

Confirmatory phase as confirms the safety and ecacy of the drug

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Provides the long term safety data

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‘Gold standard’ ○

Randomised ■

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Reduces bias in the study

Double-blind ■ Both the participants and the researchers don’t know which intervention/treatment the participants are receiving until the clinical trial is over. ■

Patients can have a preconceived confidence in a treatment can influence the eectiveness of that treatment (implication for not double-blinding)

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Comparison (placebo, or standard practice) - not ethical to give people no medication (not fair), now we give the current medication and on top of that give the new medicine

○ ●

Not industry sponsored (publication bias)

Trial cessation ○

Evidence of harm (higher death rate!)

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rarely if there is evidence of benefit ■

Purpose: Ecacy and monitoring adverse reactions

☆ Randomisatio ●

Random allocation ensures no systematic dierences between intervention groups in factors, known and unknown, that may aect the outcome. ○

prevents selection bias

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eliminates bias in treatment assignments

○ ○

produces comparable groups allows probability theory to explain chance as a source for the dierence of end outcome

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Participants are randomly assigned to a group, the intervention or treatment they

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receive depends on the group they are in No one can predict or control the result

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Using randomisation in clinical trials helps to get reliable answers for the drug that they are studying

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The implication of not using randomisation is bias, researchers or clinicians may give those that are the sickest the new experimental drug as they may believe that the new drug works better, alternatively they may give the current drug because they have more

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experience with it and know that it works, Characteristics in the group are similar; the only dierence is the drug each group is receiving, which further eliminates bias. ■

https://www.bmj.com/content/316/7126/201

☆ Doubl-blinde ●

minimises bias

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placebo eect

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measurement bias

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Ensures that no one can intentionally or unintentionally influence the results ○

Q. Explain what “double blinded-randomised” means in clinical drug trials, and why these are important ■

It is when both the researchers and participants don’t know who is receiving the studied medicine and the placebo. As a result of the this trial method, it minimises the placebo eect and measurement of bias

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It Produces an unbiased result of the study and allows the researchers to determine whether the medicine works or not.

Placeb effec – hidde v ope injection ●

the dose to reduce pain was much higher with hidden infusions vs. open

○ ●

relapse of pain faster and pain intensity greater when patients were told morphine was being stopped vs. hidden

○ Placeb effec – wh doe i matter? ●

In studies of treatment-resistant focal epilepsy, using cannabinoids: ○

seizures were reduced in 75% of drug-treated patients ■

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and seizures also reduced in 63% of placebo-treated patients

placebo response in children (19.9 %) was significantly higher than in adults (9.9 %)

☆ Name ●

One internationally recognised name ○

No confusion

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No mistakes

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No overdose

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No commercial endorsement

New Zealan Formular ☆ erapeuti classe ●

Learn one member of a class! ○ And then anything special about the others

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Similar core chemical structure, work on the same receptors, same function, slightly dierent adverse eects

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All a part of a family “same, same but dierent” ○

same core

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slight var chem structure

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same receptor same MoA

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slight var adr kinetics

Sal form ● morphine salts

and so..? e.g. fluconazole in NZ Formulary

“Dat shee” ☆ MEDSAFE - NZ Regulator Bod ●

Role is to make sure that the medicines that the doctors prescribe and the pharmacist dispense is safe for the patient and meet acceptable standards of safety, quality and ecacy

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Risk-benefit analysis ✓demonstrated ecacy in the target population ✓significantly better than placebo & alternative treatments х incidence of adverse reactions х severity of reaction (withdrew from trial) х likelihood of interactions

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Quality assurance ○

Manufacturer certification

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Medicine recall ■ They will look for trial drop out ●

What was the dropout rate from that clinical trial?

How the safety of a medicine established before it is approved for use in New Zealand ●

The pharmaceutical company responsible for that medicine provides Medsafe with safety information from clinical studies performed using that medicine. If the medicine has also been supplied elsewhere the company will also provide data from use in that country. The extent of the clinical studies varies depending on the type of medicine application.

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Medsafe evaluates the results from these clinical studies to determine if the safety profile is acceptable.

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Medsafe reviews the risks and benefits for each specific medicine to ensure that the safety profile is acceptable (ie, the benefits of the medicine outweigh the risks).

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The following factors are taken into consideration. ○

Benefits ■ Has ecacy been demonstrated in the target population (ie, those who will use the medicine)? ■

Is the medicine significantly better than a placebo?

■

How does the medicine compare to any alternative treatments?

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How many people have the condition that this medicine will treat or prevent?

■ ■ ○

What is the natural history of the disease? Is it self-limiting, chronic or fatal?

Risks ■

What proportion of people taking the medicine experience an adverse reaction?

■

How many of these adverse reactions are considered to be serious?

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How many people stopped treatment because of an adverse reaction?

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Are the adverse reactions reversible, treatable or avoidable (eg, interactions with other medicines)?

☆ 4t phas of  clinica tria ●

When medicines go out in to the 4th phase we are interested to see how safe it is for pregnant women and children and learn about rare adverse eects ○

Medsafe’s role to monitor new medicines for rare adverse eects ■

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Once it hits the market medsafe monitors the medicine for a great length

of time to see if any new side eects are becoming apparent A clinical trial continues once the new medicine is in widespread use ○

Fung et al (2001) – 121 products (’60s - ’90s) https://doi.org/10.1177/009286150103500134

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top 5 reasons for withdrawals from the market: ○

hepatic, hematologic, cardiovascular, dermatologic and carcinogenic

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median time on the market was 5.4 years before being withdrawn

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○ period of aggressive marketing Trials are conducted after the medicine has hit the market. Studies to identify rare side-eects that weren’t previously documented

Regulatio: th ‘birt’ of th FDA ●

thalidomide (1950s) ○

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“… can be given with complete safety to pregnant women and nursing mothers without adverse eect on mother or child...”

Most countries have a regulatory authority ○

Aotearoa NZ’: Medsafe

○

Australia: Therapeutic Goods Administration

☆ P-marketin surveillanc ●

Pharmacovigilance (Phase 4)

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The practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released in the market

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CARM ○

(advise the Minister of Health, via MEDSAFE)

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Prescriber Updates ■

Purpose: Long term safety and ecacy

■

Can further refine, confirm or deny the safety of a drug ot device after it is used in the general population

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Testing on new population, pregnancy, age groups

I i …? ●

a drug ○

Has the potential for misuse or abuse

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a medicine

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not a medicine

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‘chicken soup for the soul’

Medicine Ac ●

Describes: ○

what a medicine is ■

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Meaning of therapeutic purpose (section 4)

who can prescribe ○

authorised prescriber = a nurse practitioner; or an optometrist; or a practitioner; or a registered midwife; or a designated prescriber

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practitioner = medical practitioner (e.g. GP) or a dentist

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designated prescriber = registered health professionals, prescribe specified prescription medicines

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standing orders = written instruction, specific circumstances, any specified class of persons engaged in the delivery of health services

Medicine Regulation ●

Regulations provide the implementation/detail to the Act

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Schedules (lists) ○

Prescription ■

Codeine

○

restricted

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pharmacy-only medicines ■ Diclofolenuc

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general sale medicines (“OTC”)

Misus of Drug Ac ●

Classification of drugs (section 3a)

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..based on ○ the risk of harm ..to individuals, or to society.. ○

and place in therapy

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Class A: drugs that pose a very high risk of harm (cocaine, LSD)

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Class B: drugs that pose a high risk of harm; (pseudoephedrine, oxycodone)

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Class C: drugs that pose a moderate risk of harm (benzodiazepines, codeine)

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(see the Schedules)

Misus of Drug Regulation ●

Prescription requirements

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Record keeping

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Storage of controlled drugs ○

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Wards / hospitals

Schedules ○

lists of controlled drugs

Affordabilit

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Lisa ○

Rare chance to trial the medicine, may not get another chance to test the medicine

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Barney

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○ He can rejoin the workforce and pay for tax Grampa ○

Hip replacement has a high rate of success ■

Certainty with treatment

○

Has a wealth of knowledge

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Don’t treat may cause the health sector more money

Question on funding ●

Pose two dierent medicines or two dierent scenarios as PHARMAC which one will you fund? ○

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Think through ■

The condition

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The certainty

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The evidence

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Whole clinical picture

PHARMAC ○ ○

Decide on behalf of the DHB’s of the medicine They don’t evaluate life situations (that is DHB’s role)

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Decision making ■

What's the cost?

■

What is the benefit? ●

How much better a new medicine or related product is compared with those that are already funded

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Whether any benefit is worth the cost

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Whether funding a new medicine makes the best contribution to NZ’s health.

○

New Zealand’s Pharmac is unusual internationally in that it actively manages a list of publicly-subsidised pharmaceuticals on behalf of the government within a fixed annual budget

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Pharmac assesses the eectiveness of pharmaceutical products and negotiates prices with suppliers before agreeing to list and subsidise them

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Pharmac has been successful in keeping costs down but has been criticised for limiting access to some medicines, or delaying their availability

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If your spending more money on one thing your spending less on something else

☆ Factors for consideration of funding medicine ●

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