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1
Q

What needs to be considered during drug therapy?

A

Efficacy, Safety, Tolerability and Cost

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2
Q

What are some sources of individual variability in drug response?

A
  • genetics
  • adherence
  • age
  • weight/body comp
  • hormonal status
  • diet
  • disease states
  • lifestyles
  • other drugs
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3
Q

What are the differences in neonates and infants that result in a different drug response?

A
  • Absorption: higher gastric pH, longer gastric emptying, short intestinal transit time
  • increased Vd /kg
  • lower plasma protein binding
  • decreased clearance rate (increases in toddlers)
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4
Q

How is dosing calculated for children?

A
  • Formulation may need to be different
  • SA to mass ratio is higher

1) dose by SA: (1.5 x weight in kg) + 10 = % of adult dose
2) dosing by age: age/(age+12) = fraction of adult dose

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5
Q

What do you need to consider in older adults?

A
  • increased risk of adverse drug event
  • proportion of fat increases and water decreased
  • pharmacodynamic changes
  • more likely to have cognitive impairment
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6
Q

How does pharmacokinetics change for older adults and what are the consequences on the drug?

A
  • Vd increases for lipid soluble but decreases for water soluble drugs
  • decreased renal functions (fewer nephrons, lower cortical blood flow, decrease GFR, mayb change in drug transport)
  • 30% decrease in liver size, hepatic blood flow, and phase 1 metabolism
  • long half life
  • altered drug concentrationa
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7
Q

How do you calculate the adjustment for GFR?

A

Cockcroft-Gault Equation (serum creatinine)

Male: [1.2 x (140 - age) x weight in kg] / serum creatinine (umol/L)
Female: multiply by 0.85

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8
Q

How is drug variability seen in drug tolerance and physical dependence?

A
  • higher doses may be required to experience an equivalent effect
  • metabolic tolerance vs functional (target tissue)
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9
Q

What is the international normalized ratio (INR)?

A

how long it takes the blood to clot

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10
Q

What are the different classification of pharmacogenetic variants?

A

Monogenic - a single gene variation
- polymorphic vs rare

Polygenic - multiple genes

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11
Q

How was polymorphism of CYP2D6 first discovered?

A

Clinicians found unexpected clinical phenotypes (variable effectiveness and toxicity) to debrisoquine and sparteine

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12
Q

What drugs are affected by CYP2D6 polymorphism and what is the effect?

A

Codeine - PMs have poor analgesia
Dextromethorphan - a safe in vivo probe for CYP2D6 function
Tamoxifen - PMs have reduced relapse-free survival of breast cancer patients treated w tamoxifen

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13
Q

What are the consequences of defective CYP2C9?

A

CYP2C9 metabolizes warfarin

- those with defective enzymes may need dose reduction to avoid bleeding side effects

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14
Q

What drug does variable CYP2C19 effect and how?

A

Omeprazole

- PMs have better reduction of stomach acidity

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15
Q

What effect does variable thiopurine methyltransferase (TPMT) have?

A

deficiency results in increased toxicity in response to 6-MP in treatment of leukemia

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16
Q

What enzymes show genetic variability?

A

CYP2D6, CYP2C9, CYP2C19, and TPMT

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17
Q

What are some examples of pharmacogenomics of GPCR drug targets?

A
  1. beta2-adrenergic receptor response to isoproterenol increases with GLU at position 27
  2. response to salbutamol decreases with Gly at poisition 16 vs Arg
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18
Q

How is polymorphism seen in the mu-opioid receptor response to morphine-6-glucuronide

A

mutated A118G SNP which results in Asn -> Asp at AA 40

  • weaker response (shifted to right)
  • less of a decrease in pupil size
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19
Q

What is an example of pharmacogenetics of tumours and targeting cancer treatments?

A

Trastuzumab (Herceptin) - a monoclonal antibody against HER2 (growth factor receptor in some breast tumors)

expensive and only effective for those with genetic abnormality resulting in overexpression of HER2 (1/4 of patients)
test to assess HER2 expression before treatment

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20
Q

Why is there a need for the development and use of personalized medicines?

A
  • we often use trial and error for prescribing
  • prescribed drugs are generally effective in ~50% of patients
  • adverse reactions are the 4th leading cause of hospitalization and cost of treating is higher than medication
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21
Q

What is genetically-enabled personalized medicine?

A

The use of novel genetic technologies to develop better medications and predictive genetic tests to determine the right dose of the right drug in the right patient at the right time

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22
Q

What evidence supports the use of personalized medicines?

A

warfarin dose reduction to avoid bleeding side effect in individuals with genetic defects in CYP2C9

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23
Q

What are some limitations to warfarin and CYP2C9 testing and how can they be overcome?

A

increased risk for bleeding is not solely related to genetic variation in CYP2C9

  • VKORC1
  • CYP4F2
  • Factor V Leiden
  • non genetic factors ie. dietary intake of vitamin K

Multifactorial model to predict optimal warfarin dose

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24
Q

What are the challenges to the use of personalized medicine?

A
  • Polygenic inheritance
  • Technology
  • Clinical
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25
What is an example of the challenge of polygenic inheritance?
Tropisetron response 1. CYP2D6 metabolism variability 2. Crossing the BBB 3. At synapse, many genes can effect including 5-HT3 receptor, SERT, enzymes breaking down serotonin and synthesis
26
What are the technical challenges to personalized medicine?
- data production is difficult and expensive - analyzing data - genetic test development - ethics/privacy
27
When would personalized medicine be best used clinically?
When: - disease is serious - highly predictive test - high treatment cost - alternatives are not available - medication is widely used clinically - drug has a narrow therapeutic index
28
Why was the COVID vaccine fast?
- high recruitment/volunteers - greater funding available - great effort to be efficient
29
What must occur before a drug is administered to humans and what is the purpose?
Preclinical testing - examination of structure-activity relationships, in vitro assays, animal studies, etc. - examines pharmacokinetic parameters, adverse effects, effects in pregnancy etc.
30
What is inclusion criteria vs exclusion criteria?
In - what you need to have/be to participate | Ex - what you can't have/be to participate
31
Describe Phase 1
- first administration to humans: exception anticancer agents and intro of HIV drugs - mostly healthy volunteers - small sample size - controlled inclusion/exclusion criteria - establishes pharmacokinetic parameter - some safety examination
32
Describe Phase 2
- first time in patients - proof of concept: does drug have desired therapeutic effect - controlled criteria - dosing adjustments in patients - some safety examination
33
Describe Phase 3
- usually thousands of patients - clinical trials utilizing comparisons w standard current drug therapy/ placebo (examination of safety and efficacy) - fairly controlled criteria - very expensive to conduct, multiple sites - can be separated into 3a and 3b
34
How are different designs used to control perspectives?
Cohort design: start today, don't know the outcome | Case-Control design: know the outcome, look back in time
35
Placebo effect vs nocebo effect
Placebo - "I will please" - improvement without medication Nocebo - anticipating side effects
36
What is an issue that arises with the placebo effect/group?
ethical issue of people not receiving any treatment
37
What is the new drug submission (NDS)?
contains scientific info about the safety, efficacy, and quality of the product; - preclinical results - clinical results - how the drug is produced - proposed packaging and labelling - info supporting therapeutic value - conditions for use - info about potential adverse effects
38
What is the abbreviated NDS?
generic drug companies aren't required as much info as manufacturer w patent - same quality standard as NDS - info about production, packaging, and labelling - same safety and efficacy - similar drug concentrations over time, specific endpoints
39
What is the supplemental NDS?
when the manufacturer wants to make changes to product that was already authorized
40
Who reviews and regulates pharmaceutical drugs in Canada?
Therapeutic Products Directorate, Health Products and food Branch (HPFB), Health Canada - looking for safety, efficacy, quality
41
What is a notice of compliance?
If the manufacturer receives a NOC and a drug information number the drug can be sold in Canada - assigned based on conclusion that benefits outweigh risks/harms and any risks can be mitigated/managed
42
What is the Patented Medicine Prices Review Board (PMPRB)?
regulates prices so they're not excessive - includes strength of each dosage form - no authority to regulate generic drugs
43
Descrive Pase 4
- postmarketing surveillance: more safety | - real-world: multiple and complex diseases, multiple medications, less adherence
44
What is the deadline to market?
According to Patent Act, brand-name manufactures have 17 years of patent protection from when patent is issued OR 20 years from filling date
45
What are the common reasons for drug withdrawal?
- safety issues - lack of efficacy evidence - loss of therapeutic interest - poor market performance
46
What is the Special Access Program?
allows practitioners to request access to drugs that are not available for sale in Canada - limited to serious conditions on a compassionate/emergency basis when conventional therapies fail
47
What is the reward system?
Normal physiological system that reugalates and controls behaviour by inducing pleasurable effects reward = reinforces behaviour, increases intensity ie. mesolimbic dopamine system
48
What is the spectrum of psychoactive substance use?
Beneficial use -> casual/nonproblematic use -> problematic use -> chronic dependence
49
How can problematic drug use?
Misuse - initially prescribed as a therapeutic agent - pain medications - assistance sleeping Exposure in recreational settings - alcohol, street drugs etc
50
What is addiction?
chronic relapsing disorder characterized by persistent drug-seeking behaviours - physical or psychological dependence - physical/social harm - route of administration and physiological effects play a role
51
What are the possible factors in substance misuse disorder?
Activation of brain reward system, physical dependence, genetic, behavioural/environmental cues
52
What is dopamine?
A signalling molecule that plays a role in motor control, compulsion, reward/motivation, euphoria/pleasure - increases inappropriately with addictive drugs leads to reinforcement
53
What is dependence?
Development of tolerance to drug may lead to physiologic dependent state (homeostatic balance)
54
What may result from acquired tolerance?
- increased dose requirement - additional therapy - physiologic dependence - withdrawal symptoms
55
How does metabolic tolerance differ?
repeated exposure may induce drug metabolizing enzyme activity - larger dose required to maintain therapeutic concentrations for same length of time - not physical dependence - equivalent to taking less drug doesn't alter dose-response curve at site of action but after repeated administration more drug is required at targer
56
What causes withdrawal syndrome?
Changes in cellular signalling/expression/pathway
57
NICOTINE | What is the mechanism of action?
nicotinic acetylcholine receptors dopamine released Na+Ca2+ enters the cell
58
NICOTINE | What is the mechanism of misuse?
- lipid soluble - tolerance and withdrawal - direct activation of acetylcholine receptors on neurons in reward pathway
59
NICOTINE | What SNPs or enzymes play a role?
CYP2D6, CYP2A6, and slow metabolizers
60
MARIJUANA | What are the pharmacodynamics?
THC binds to CB1 and CB2 receptors - in CNS, activation of CB1 inhibits release of specific neurotransmitters mimics endogenous ligands - anandamide and 2-arachidonylglycerol - retrograde synaptic messengers (memory, cognition and pain perception)
61
MARIJUANA | What are the pharmacokinetics?
dependent on route of transmission - 20 min onset - 3-6hrs duration - peaks at 1-2hr bioavailability: takes longer to peak orally lipid soluble binary exertion of metabolites - extended half life w chronic users
62
COCAINE | What is the mechanism of action?
Blocks the reuptake of DA from synaptic cleft | Blocks voltage gated sodium channels
63
COCAINE | What is the mechanism of misuse?
prolongs DA in synaptic cleft so it is around longer to activate DA R on neurons chronically depletes intracellular DA stores (craving) - withdrawal not as strong but tolerance and sensitization may occur
64
COCAINE | What are the intranasal pharmacokinetics?
enters CNS readily 3 mins fast onset short duration onset within minutes, half life 1 hour metabolized via hydrolysis and CYPS
65
COCAINE Effects
secondary: similar to amphetamines (sympathetic activation, extends duration of action) acute: increased mental awareness, euphoria, feeling of wellbeing, hallucination, paranoia - fight or flight high doses: paranoid psychosis, erratic behaviour, tactile hallucinations, convulsions - overdose: hyperthermia, cardiac arrythmias, convulsions, coma, death chronic use: loss of appetite, hyperactivity, insomnia
66
OPIOIDS | What are they?
natural or synthetic compounds: - prescription medications ie morphine, perfect, fentanyl - heroin
67
OPIOIDS | What is the mechanism of action?
mimics endogenous peptides and bind to opioid receptors - reduce neuronal excitability via G-proteins - acts in brain and peripherally
68
OPIOIDS | What is the mechanism of misuse?
tolerance and withdrawal | activate opiate receptors in reward pathway - stimulating DA release via disinhibition
69
What is HEROIN?
semi-synthetic opioid that's 3x more potent than morphine - rapidly converted to morphine by DME - highly addictive - short acting, more rewarding - initially more euphoric - similar secondary effects to morphine
70
What are the effects of heroin?
- euphoria - sedation, respiratory depression - pupil constriction - GI: nausea, constipation - dependence and reward pathway activated (severe withdrawal, misuse treated w pharmacotherapy, replacement with another opioid)
71
What are synthetic opioids?
prescription medications: - initially treatment of chronic pain - oxycontin - fentanyl: patches, 100x more potent than morphine Man-made illicit high potency opioids - carfentanil: 10 000x more potent
72
What causes additive drug-drug interactions?
Pharmacologically: targeting the same receptor Physiologically: target the same system
73
Why are overdose related deaths increasing?
- increasing potency of drug taken - inappropriate or unknown dose - tolerance to euphoric occurs more rapidly than drugs respiratory effects
74
What is the Narcan kit (Naloxone)?
free at pharmacies uOR competitive antagonist (reverses receptor binding-withdrawal) not orally available may req multiple doses - potency of opioid against: repeat doe 2-3min - half life is 30-45 min vs half-life of fentanyl is 7 hrs
75
What interventions are there for substance use disorders?
changes in prescribing practices - better educating physicians - alternatives to opioids for SOME types of pain safe injection/supervised consumption sites safer supply: diacetylmorphine hydrochlorine (heroin)

PCL201 (3 decks)

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