Last lecture

Question 1

Parent:Metab ratio

Answer 1

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

Question 2

What can cause high parent :metab ratio

Answer 2

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

Question 3

P:M ratio study

Answer 3

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

Question 4

Blood:plasma ratio

Answer 4

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

Question 5

What should you know when applying blood:plasma ratio

Answer 5

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

Question 6

Clinical vs therapeutic doses

Answer 6

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

Question 7

Clincial vs therapeiutic doses study

Answer 7

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

Question 8

Alcohol and drug interaction

Answer 8

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

Question 9

Drug:Drug interaction pharmacokinetics

Answer 9

Antabuse
Inhibits metab of benzos leading to toxicity

Question 10

Drug:drug interaction pharmacodynamics

Answer 10

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

Question 11

Tolerance misconception

Answer 11

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

Question 12

Tolerance History

Answer 12

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

Question 13

Tolerance

Answer 13

ability to adapt or acclimated to effect of a drug

Question 14

Tolerance types with time

Answer 14

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

Question 15

What is chronic tolerance influenced by

Answer 15

dose, frequency of dosing and duration of use

Question 16

What kind of drugs could have tolerance

Answer 16

Alcohol, opiods, sedatives-hypnotic drugs

Question 17

innate tolerance

Answer 17

Genetically determined sensitivity or lack of sensitivity

Question 18

Types of acquired tolerance

Answer 18

physiological and adaptive

Question 19

physiological tolerance

Answer 19

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

Question 20

Adaptive tolerance

Answer 20

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

Question 21

Drug/Disease interaction

Answer 21

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

Question 22

The general types of tolerance

Answer 22

Innate and Acquired

Question 23

What kind of change in receptor response after repeated exposure

Answer 23

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

Question 24

Hammond case

Answer 24

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

Question 25

Mellanby effect

Answer 25

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

Question 26

Acute tolerance to methamphetamines

Answer 26

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

Question 27

Acute tolerance mediated by

Answer 27

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

Question 28

Examples of acute tolerance

Answer 28

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

Question 29

Acute tolerance to cocaine

Answer 29

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

Question 30

Acute tolerance Thiopental

Answer 30

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

Question 31

Opiate Tolerance causes of adaptation

Answer 31

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

Question 32

Selective Tolerance

Answer 32

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

Question 33

Cross tolerance

Answer 33

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

Question 34

Incomplete tolerance is due to subtle differences in

Answer 34

Molecular structure of each opioid Interaction with opioid receptors

Question 35

Cross tolerance equianalgesic

Answer 35

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

Question 36

Cross tolerance exception

Answer 36

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

Question 37

Cross tolerance readily exist

Answer 37

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

Question 38

Tolerance with cross

Answer 38

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

Question 39

Ceiling effect

Answer 39

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

Question 40

Ceiling effect reflects the the limitations od some drug classes

Answer 40

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

Question 41

Ceiling effect - NSAIDs

Answer 41

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

Question 42

Buprenorphine

Answer 42

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

Question 43

Decrease in tolerance

Answer 43

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

Question 44

Determination of Tolerance

Answer 44

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

Question 45

Hair analysis

Answer 45

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

Question 46

Chronic use/tolerance does not immune you from death

Answer 46

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