Pharm 2007 Lecture - Individual Variation In Drug Responses And Drug Addiction (student Handout Slides)

Variation is usually… INDIVIDUAL VARIATION IN DRUG RESPONSES

z Quantitative – Drug produces larger / smaller effect – Drug acts for longer / shorter time

(while still exerting qualitatively the same effect)

Carol Laic B.Sc., ND Qualitative differences in action of drug is called an ‘idiosyncratic’ reaction

Main causes of Drug Variability

Individual Variation Variation can be caused by:

z z

– PHARMACOKINETIC VARIATION z

Different concentrations at sites of drug action

z z

– PHARMACODYNAMIC VARIATION z

Different responses to the same drug concentration

– IDIOSYNCRATIC REACTIONS z

Often caused by genetic / immunological difference unique to the individual(s)

z z z z

Age Ethnicity Pregnancy Genetic factors Immunological factors Pathological states (KI / LV dz) Psycological state (placebo responder) Drug interactions

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Ethnicity

Age z Main

reason age affects drug action is that drug elimination is LESS efficient in newborns and elderly

z Chinese

vs. Caucasians in ethanol metabolism z Chinese vs. Caucasians vs. Afro-Caribbean in sensitivity to cardiovascular effects of propranolol z These

types of differences mostly genetic in origin but environmental factors may also contribute

z Physiologic

factors (drug metabolism) z Pathological factors z Body composition z

Age and Drug Metabolism

Age and Drug Metabolism z

z

Neonates (esp. premies) have low enzyme activity (conjugation enzymes) – i.e. chloramphenicol and grey baby syndrome – i.e. morphine during labour

Fat contributes larger proportion of body mass (therefore changes to drugs Vd)

Elderly sees very variable decline in these enzymes (and increased Vd for lipid soluable drugs) – Results in increasing t1/2 and drug accumulation – Insiduous effects are often misattributed to age-related

memory impairment vs. drug accumulation (i.e. Diazepam) – Increased variability of t1/2 between individuals with increasing age vs. younger adults

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Age and Renal excretion z Newborns: – Lower GFR and tubular function but increase to

Age and Renal excretion z Elderly: – GFR declines slowly after 20 years of age

adult levels in a week (can upto 2x at 6 mths) – Increase in renal function substantially slower in premies (therefore need to reduce / space out dosages)

– Falls 25% by 50 yrs old ; 50% by 75yrs old

Age and Sensitivity to drugs z Sensitivity

can be increased / decreased

with age: i.e. Benzodiazepines – more confusion and less sedation in elderly

Pregnancy z z z z z

i.e. Hypotensive drugs – postural hypotension more common with elderly

z

Maternal plasma albumin reduced Cardiac output is increased therefore increased renal blood flow and drug elimination Lipophilic molecules rapidly pass placenta Hydrophobic drugs slow to cross placenta Placenta is barrier to some drugs Fetus can only eliminate drugs slowly and will reswallow excreted drugs from amniotic fluid

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Genetic factors z z

Genetic varioationis an important source of phamacokinetic variability Examples where genetic variation influences drug response includes:

Idiosyncratic reactions z Is

a qualitatively abnormal and usually harmful drug effect that occurs in a small proportion of individuals: – Chloramphenicol and aplastic anemia

– Fast / slow acetylators (hydralazine, procainamide,

– G6PD deficiency is basis for the most common

isoniazid)

known form of genetically determined ADRs

– Plasma cholinesterase variants (suxamethonium)

z

– Hydoxylase polymorphism (debrisoquine)

z Often

Pharmacokinetic effects of Disease

PharmacoDYNAMIC effects of Disease

Absorption: z z z

z

z

Altered plasma protein binding Impaired BBB

z

z

Metabolism: z z

z

Gastric stasis (migraine) Malabsorption (steatorrhea from pancreatic insuff.) Edema of ileal mucosa (heart failure)

Distribution: z

z

the cause is poorly understood (bone marrow suppression with chloramphenicol)

Chronic LV dz hypothermia

Excretion: z

Acute / chronic renal failure

z

Receptors (myasthenia gravis, nephrogenic diabetes insipidus, familial hypercholesterolemia) Signal transduction (pseudohypoparathyroidism, familial precocious puberty) Unknown mechanisms (increased sensitivity to pethidine in hypothyroidism)

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Drug interactions z These

are many and varied; the rule is if in doubt, look it up z Interactions may be : – Pharmacokinetic: z Absorption, distribution (competition for protein binding), hepatic metabolism (induction /inhibition), renal excretion – Pharmacodynamic: z Often predictable from the actions of the interacting drugs

Drug interactions: PK z ABSORPTION: z

z

Drug interactions : PK z DISTRIBUTION: – Toxicity from the transient increase of free drug

before new steady state is reached – Target therapeutic concentration range will be altered by co-administration of displacing drug – Chronic problems with toxicity arise if elimination is reduced as well as drug displacement

Gastric emptying –slowed by atropine / opiates -accelerated by metoclopramide Two drugs may bind together preventing absorption i.e. - Ca++ and tetracycline - colestyramine and other drugs (warfarin) - adrenaline with local anaesthetics

Drug interactions: PK z METABOLISM – Enzyme induction:

(important cause of drug interactions) z

z

z

Over 200 drugs cause induction and thereby decrease the drug actions in the body Can increase toxicity of a second drug it toxic effects medicated via a metabolite (paracetamol) Exploited therapeutically in some cases (phenobarbital and premies)

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Drug interactions: PK z METABOLISM

Drug interactions: PK z Hemodynamic

effects and ELIMINATION:

– Enzyme inhibition:

– Variation in LV blood flow influence rate of

(slows metabolism hence increasing action of other drugs metabolized by same enzyme)

inactivation of drugs subject to extensive first pass effect – Inhibition of tubular secretion (probenecid and penicillin secretion) – Alteration of urine flow and pH (loop and thiazide diuretics with lithium)

Grapefruit juice and many drugs (cyclosporine) Terfenadine and ketoconazole -therapeutic effect of some are direct consequence of inhibition (mercaptopurine and allopurinol; disulfiram and warfarin, metronidazole and alcohol)

z z

Psychological factors : Placebo z

Placebo effect: when effects of drug cannot be attributed to its chemical properties and are correlated with its administration – Influenced by impressions at time of administration – Modified by therapeutic environment

z z

Administration of placebo produces a variety of +ve responders in 30% of pop. No specific group of people can be classified as ‘placebo responders’

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Objectives DRUG DEPENDENCE and DRUG ABUSE

z General

aspects of drug dependence and abuse z Pharmacology of 3 most commonly used non-therapeutic drugs: nicotine, cannabis, ethanol

Carol Laic B.Sc., N.D.

Drug Dependence z Defined

as a compulsive craving that develops as a result of repeated administration of a drug

z All

drugs that engender dependence have major CNS effects (psychotropic drugs)

The main drugs of abuse z Very z z

strong dependence liability

Narcotic analgesics (morphine) Psychomotor stimulants (cocaine, nicotine)

z Strong z z

dependence liability

General CNS depressants (alcohol, barbiturates) Psychomotor stimulants (amphetamines)

z Moderate

dependence liability z Weak / absent dependence liability z

Caffeine, LSD, cannabis

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Characteristics of Addiction / Dependence

Nature of drug dependence z

z z

Drug dependence > the state when drug-taking becomes compulsive, taking precedence over other needs Drug addiction > implies a state of physical dependence Drug abuse > any recurrent use of substances that are illegal or that cause harm to the individual including drugs in sport

z

An overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means regardless of damage to self / society

z

A tendency to increase the dose

z

A psychological and/or a physical dependence on the effect of the drug

Historical look at societal use of psychoactive drugs z

z

Virtually every society has had at least one psychoactive drug that was approved and incorporated into its cultures and traditions With the development of trade and travel, drugs native to one part of the world became accepted and appreciated in other areas

Social functions of Psychoactive Drugs z z z z z

z

Earliest known was for religious / magical purposes (use of red wine) Secular ceremonies (peace pipe, kava bowl, toasting with alcohol) Conviviality in social gatherings (coffee, alcohol) Individual private pleasure (wine with meals) Utilitarian usage (take clients out for drinks)

Development of chemistry lead to more potent synthesis of derivatives and analogs

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Factors governing extent of drug use z Degree

of social acceptance / rejection z Social upheaval z Legal constraints z Price z Ease of availability z Travel and mass communication

Dependence z

Habituation Mechanism z

Opioids (morphine) and cocaine produce similar brain effects on chronic administration:

z

Both increase the activity of adenylate cyclase in brain to compensate for acute inhibition of cAMP formation

z

But when the drug is terminated, it produces a rebound increase in cAMP (affecting ion channels, making cells more excitable), resulting in withdrawal syndrome symptoms

Psychological factors involved in drug dependence

The overall state of dependence (compulsive drug taking) is often associated with: 1. 2. 3.

Psychological dependence (craving) Tolerance to the drug (via various mechanisms) Physical withdrawal syndrome (varies in type and intensity for different drug classes)

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Psychological factors involved in drug dependence z The

common feature of dependenceproducing drugs is that they have a positive reinforcing action (reward) associated with activation of the ‘reward pathway’ (mesolimbic dopaminergic pathway) z They either increase dopamine levels or inhibit its re-uptake

Mechanisms of psychological dependence z

Deletion of dopamine receptors showed dopamine responsible for the positive reward (psychological dependence) but not for the negative withdrawal effects

z

Increasing 5-HT activity showing to reduce drugseeking behaviour (Buspirone)

z

Glutamate receptor antagonists also show decreases positive reward effects (Acomprosate)

Habituation Mechanism z

Opioids (morphine) and cocaine produce similar brain effects on chronic administration:

z

Both increase the activity of adenylate cyclase in brain to compensate for acute inhibition of cAMP formation

z

But when the drug is terminated, it produces a rebound increase in cAMP (affecting ion channels, making cells more excitable), resulting in withdrawal syndrome symptoms

Genetic factors z Twin

studies suggest that genetic factors contribute up to 60% of an individual’s susceptibility to most forms of drug abuse

z As

of yet there is no specific genes identified that may account for this susceptibility

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Other characteristics influencing reinforcement

Tolerance Tolerance > a decreased pharmacological effect on repeated administration of drug

z Timing z Route

of administration z Genetics z Motivational forces z Environmental stimuli z Physical dependence z Intensity of behavioural dependence

Cross-tolerance z If

two drugs cause similar pharmacological effects via essentially the same mechanisms, one might anticipate that adaptive changes arising from the use of one drug will also confer tolerance to the other similarly acting drug

z

Metabolic tolerance > drug detoxification pathways may become induced leading to tolerance of regular dosages

z

Cross–tolerance > one drugs metabolic effects can influence the breakdown of other drugs

z

Adaptive Tolerance > tissue changes to offset effect of drug (self-protective mechanism)

Cross-tolerance and transfer of dependence z When

one drug in a cross-tolerance group is withdrawn, another drug from the same group can be used to decrease or abolish the withdrawal symptoms

z Example: – use benzodiazepines with alcohol withdrawal

(still necessary to gradually decrease dose so not just replacing one drug problem with another)

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Tolerance and physical dependence (withdrawal) z

z

Withdrawal z Severity

In withdrawal, the body becomes hyper excitable because it is no longer balanced by drug (cAMP)

z

Withdrawal syndrome can be very specific for a particular drug (i.e. morphine) or it can be general (sleepless, tremor, irritable, hallucinations, seizures)

z Intensity z

z

Physical dependence is confirmed if the withdrawal syndrome symptoms are abolished when the drug is re-dosed

Non-drug factors that influence tolerance z Sensitivity

of individual to drug effects type and level of ongoing activity at time drug is taken z Environment where the drug is taken z Individuals previous drug-taking history

depends on:

Degree of adaptive changes in nervous system while taking the drug (this depends on degree and duration of use of drug)

depends on:

Time coarse of action of drug (the slower acting drugs result in less intense withdrawal)

Treatment of drug dependence Pharmacological agents may help in many ways: 1.

z The

2.

3.

Substitution (in short-term to blunt withdrawal / long term): with less reinforcing and legal drug (methadone maintenance for heroin/ morphine addicts; benzodiazepines for alcoholics) Blocking response: Use of specific blockers to prevent drugs reinforcing effects (naltrexone to block heroin action) Aversive therapies: Agents that interact with drug to cause unpleasant effects (disulfiram (antabuse) with alcoholics)

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Treatment of drug dependence 4. Treat underlying emotional disturbances that may drive the abuse (lithium / antidepressants with alcoholism / barbituate abuse) 5. Direct reduction of reinforcement effects in the brain (SSRI to decrease reinforcing effects of alcohol)

Treatment of drug dependence z Physical

dependence (cause of withdrawal syndromes) is not the major factor in longterm drug dependence

z Psychological

dependence, outlasts the physical withdrawal syndrome, and is the major factor leading to relapse among treated addicts

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