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Final PM > Last lecture > Flashcards

Last lecture Flashcards

1
Q

Parent:Metab ratio

A

Many drugs at steady state concentration parent to nor-metab. Ratio is unity or less than one
Carefully evaluated kinetics of particular drug

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2
Q

What can cause high parent :metab ratio

A

acute ingestion of the drug
Poor metabolizer 2D6
Consider the differing degree of PMR for parent or polar metab.

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3
Q

P:M ratio study

A

Looked at TCAs
The parent to metab. ratio in OD 1.3 therapeutic chronic .88 ratio
Various methods and incomplete histories
Did not check for poor metabolizer

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4
Q

Blood:plasma ratio

A

Clinical studies report plasma/serum concentration
Dose
Behavior/effects
Specimens most available in forensics, esp. Pm whole blood
Caution in direct comparison of whole blood values w/clinical studies reporting serum/plasma ratio
Important for drugs that are not evenly distribute between whole blood and plasma/serum

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5
Q

What should you know when applying blood:plasma ratio

A

Distribution ratio generally derived from in vitro partition experiment , may not match ration in authentic samples
blood to plasma ratios may not only vary among frugs, but also may vary between drug and its metabolite
Blood/plasma ratio in samples collected in living subjects may differ from those absorbed in pm samples

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6
Q

Clinical vs therapeutic doses

A

Large body of reports on PM conc. of drugs, some tissue distribution, found in fatal cases
serval will report therapeutic levels of the specific drugs
range of drug concentration in living subjects

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7
Q

Clincial vs therapeiutic doses study

A

In therapeutic dose was 5x higher in PM
Druid and Holmgram and Reis
Compilation of PM fatal and therapeutic drug concentration
9,000-16,000 FB samples in single lab

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8
Q

Alcohol and drug interaction

A

Pharmacokinetic
Enzyme induction or competition alteration of oral bioavailability
Pharmacodynamic
Additive effects ie CNS depression

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9
Q

Drug:Drug interaction pharmacokinetics

A

Antabuse
Inhibits metab of benzos leading to toxicity

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10
Q

Drug:drug interaction pharmacodynamics

A

Additives or potentiation
benzo/gaba and opioids
Meperidine and promethazine
Speedballs
Heroin and cocaine
Increase in meth as stimulant and fentanyl

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11
Q

Tolerance misconception

A

Drug tolerant person tolerant to ALL effects
Develops UNIFORMLY across all behaviors or effects at the same time/rate
Once gained remains WITHOUT change
Confers IMMUNITY to lethal intoxication

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12
Q

Tolerance History

A

Early chroniclers of drug effects noted responsiveness to drugs often decreased as a function of experience
Jean Moulin physician to the king of france wondered why individuals sometimes became progressively more sober while they were continuing to drink
Although the use of the term tolerance would wait for serval centuries
Two centuries later Benjamin RUsh recognized change in sensitivity to alcohol with chronic heavy drinking
More than 50 yrs late canadian Caniff wrote on the effect of alcohol on the human system and attribute these observations by others as tolerance
English physiologist Eh starling described all the main features of acquired tolerance including the relationship to heavy drinkers and to amounts that would cause death in individuals

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13
Q

Tolerance

A

ability to adapt or acclimated to effect of a drug

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14
Q

Tolerance types with time

A

Acute: decreaase in senstivity develops during a single exposure
Chronic: decreased sensitvity develops from repeated exposure

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15
Q

What is chronic tolerance influenced by

A

dose, frequency of dosing and duration of use

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16
Q

What kind of drugs could have tolerance

A

Alcohol, opiods, sedatives-hypnotic drugs

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17
Q

innate tolerance

A

Genetically determined sensitivity or lack of sensitivity

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18
Q

Types of acquired tolerance

A

physiological and adaptive

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19
Q

physiological tolerance

A

Metabolic pharmacokinetic
Self-induction of enzymes
Repeated use of phenobarbital induces lover P450 expression and thereby decreasing its own half-life
Increasing doses of phenobarbital may be required to achieve the same steady-state concentration
Genetic polymorphism may cause increased metabolism so that patient appears to be tolerant to standard dose
Co-ingestion of another drug may cause enhanced metabolism of target compounds so that the patient appears tp ne tolerant to standard dose

20
Q

Adaptive tolerance

A

learned compensatory actions to accommodate effect of drug
Lack of visible signs of intoxication with high alcohol concentrations most common form of adaptive tolerance

21
Q

Drug/Disease interaction

A

Pharmacokinetic
Age and health
 Increasing age decrease in amount and efficacy of drug
metabolizing enzymes
 Neonates/infants immature metabolic systems
o Chronic liver diseases
 Associated with variable and non-uniform
reductions in P450s and lesser extent
glucuronidation
 Effect plasma protein binding – alteration in
distribution and elimination
 Associated with impaired renal function – drug
elimination
Pharmacodynamics
ASCVD and CoHb

22
Q

The general types of tolerance

A

Innate and Acquired

23
Q

What kind of change in receptor response after repeated exposure

A

Decrease number of receptor (down regulation)
Reduction of firing of receptor (desensitization)
Structural changes in receptor (receptor shift)

24
Q

Hammond case

A

woman w/ a high BAC of .780g% admitted to ER after MVC
3 hr later BAC was .520
11 hours later .190
fully coherent and normal neurological examination
demonstrated no signs of intoxication

25
Q

Mellanby effect

A

described development of acute tolerance to alochol
Greater effects when alochol concetration is rising when opposed to when they are declining
may apply to other sedative hypnotics

26
Q

Acute tolerance to methamphetamines

A

SHort term cuase by depletion of neurotransmitters
typically last 2-3 days until neurptransmitter levels restored
Prolonged overstim of dopamine recepotors cause downregulation to compensate for increase level of dopamine

27
Q

Acute tolerance mediated by

A

pharmacodynamic mechanism
Manifested as decrease response following single dose or during repeated dose over show period of time
pharmacodynamic tolerance secondary to receptor change
can occur quickly minutes to hour

28
Q

Examples of acute tolerance

A

Cocaine Intranasal euphoria decreases even when blood concentration increase
Ethyl Alcohol
Benzo

29
Q

Acute tolerance to cocaine

A

Evidence has suggested acute tolerance to the cardiovascular and subjective effects of cocaine
Independent of route of administration

30
Q

Acute tolerance Thiopental

A

rapid increasing of thiopental concentrations needed to produce a constant state of anesthesia

31
Q

Opiate Tolerance causes of adaptation

A

Span of blood concentrations of victims of methadone overdose overlaps that of methadone maintenance subjects
Difficult to distinguish between the two on blood concentrations alone
Similar issues with other opioids
Identified effect of opioid therapy is development of tolerance to analgesic effect
Dose escalation in chronic pain therapy is a consequence of increasing pain
Increased nociceptive input as disease progresses
Causes of adaption:
Desensitization
Reduced interaction with secondary messenger system [PGlyco-protein-extruder]
Deceased number of binding sites for opioid

32
Q

Selective Tolerance

A

Tolerance develops at different rates for various effects
Effects of opioids
Analgesia, nausea, vomiting, sedation, euphoria, and respiratory depression occur rapidly
Minimal development of tolerance to constipation and miosis
Effects of benzos:
Relatively quickly for sedative and anticonvulsant actions
Minimal if at all for anxiolytic and amnesic effects

33
Q

Cross tolerance

A

Long term exposure to one drug often results in development of tolerance to the effects of other structurally similar drugs in the same pharmacological class
Examples Benzo and Opioids
Pharmacological tolerance may develop to the opioid in use, tolerance may not be as marked relative to other opioids
Rarely complete

34
Q

Incomplete tolerance is due to subtle differences in

A

Molecular structure of each opioid
Interaction with opioid receptors

35
Q

Cross tolerance equianalgesic

A

Switching opioids, may be differences between published equianalgesic doses of different opioids and effective ratio for a given patient
Start with 50% to 75% of the published equianalgesic dose of the new opioid to compensate for the incomplete cross tolerance and individual variation, particulary if the patient hasz controlled pain

36
Q

Cross tolerance exception

A

Methadone Appears to have higher than expected potency during chronic dosing (compared with published equianalgesic doses for acute dosing)
Start with 10% to 25% of the published equianalgesic dose
Titrate appropriately to achieve pain control

37
Q

Cross tolerance readily exist

A

Benzo
Chronic use of benzos not only decreases the activity of the benzo site on the GABA receptor but also decreases the binding affinity of the barbiturate site
Diazepam tolerant mice are tolerant to the sedative effects of isoflurane

38
Q

Tolerance with cross

A

Tolerance and cross-tolerance is variable within drug classes
Tolerance not seen to all effects of drug
Tolerance to different effects develop at different rates
May see “Ceiling Effect” with some drugs

39
Q

Ceiling effect

A

Eventually max response [of a drug] is obtained; further increases in dose does not produce any greater effect

40
Q

Ceiling effect reflects the the limitations od some drug classes

A

Above a certain dosage no further increase in effect is observed
Doses above those needed to produce the ceiling effect usually cause other undesired, often toxic, drug effects
Drugs within a drug class that are more potent than other drugs in the same class will produce the ceiling effect at the lower dosage, but will not raise the ceiling

41
Q

Ceiling effect - NSAIDs

A

Ibuprofen- Laska et al (1986) reports analgesic ceiling is 400 mg/dose [1200 mg/day]
2400 mg/day effective for inflammation, with no additional benefit for pain
Acetaminophen
Skoglund et al (1991) compared doses:
APAP [1000 mg] with codeine [60 mg]
1000 mg APAP
2000 mg APAP
Single dose double blind study, placebo controlled
Dental and/or post-procedural pain
6 hr time frame
APAP ceiling for analgesia at 1000 mg

42
Q

Buprenorphine

A

Buprenorphine is a partial agonist, as such will have a ceiling effect
Safety factor
Carries a lower risk of abuse, addiction, and side effects compared to full opioid agonists
Dahan et al (2006) compared doses in 20 subjects
Analgesic effect increased significantly with higher doses
On-set and magnitude of respiratory depression same across doses
Concluded “ceiling effect” for respiratory depression but not analgesia
however, can block effect of full opioid agonist
thus can precipitate opiod withdrawal symptoms if admin with full agonist

43
Q

Decrease in tolerance

A

fter drug exposure is terminated, tolerance lost as desensitized receptors and enzymes return to original level of function
Due to incarceration or hospitalization
Voluntary cessation of use
Following period of abstinence
Heroin users who administer their “usual” dose end with fatal results
Dumas and Pollack reported in fully-tolerance animals
Drug holiday of nearly 6 days would be required in order to regeneratre 50% of inrtrinsic responsivity

44
Q

Determination of Tolerance

A

No biochemical or histological markers that can be used to predict tolerance
Postmortem assessment must rely upon decedent’s
History of drug exposure
Pharmacodynamic characterizes of the drug
Anatomical findings at autopsy

45
Q

Hair analysis

A

asses tolerance in opioid populations
Kronstand et al (1998) investigated the use of hair analysis in heroin overdoses
Absence of opiate detection in hair suggested “first” or occasional intake of heroin
Lack of tolerance could be a factor in the cause of death
Kintz (2010) cautions against the use of hair analysis to demonstrate long-term exposure
Case studies (n=5) found target drug in hair of decedents who were not exposed to the drug chronically
Study included extensive “decontamination” procedure
Suggests that contamination from aqueous sources (blood and putrefactive fluids) more difficult to remove than external contamination from smoke or other environmental sources
Metabolite identification not useful as it would be in fluids as well

46
Q

Chronic use/tolerance does not immune you from death

A

Dose exceeds developed tolerance
Multi-drug ingestion
Cross-tolerance not par

Final PM (4 decks)

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