Hazards of Geriatric Pharmacology

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Clinical Pharmacodynamics
Pathama Leewanich Department of Pharmacology
Faculty of Medicine Srinakharinwirot University
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Objectives
1. Describe relationship between drug dose and
clinical response 2. Describe mechanisms
of therapeutic and toxic effects of drugs
3. Describe
factors affecting drug response 4. Describe drug
therapy in breast-feeding, children and
elderly patients
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Contents

• Drug dose and clinical response
• Graded dose-response relation
• Quantal dose- response relation
• Clinical selectivity
• Beneficial vs toxic effects of drugs
  
• Factors affecting drug response
• Drug therapy in special population
• Drug therapy in pregnant
• Drug therapy in breast-feeding patients
• Drug therapy in children
• Drug therapy in elderly

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Drug Dose and Clinical Response
Graded dose-response relation
maximal effect
variability
Effect
slope
potency
Drug dose
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Potency
gt therapeutic dose
Effect
high potency lower dose, dose
adjustment low potency (opposite)
potency
Drug dose
depends on affinity
receptor-effector coupling
drug concentration at a receptor
(pharmacokinetics)
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Maximal effect
(efficacy / maximal efficacy)
maximal effect
Effect
Drug dose
depends on intrinsic activity
individual variation
side effect dose dependent
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Slope
gt mechanism of action - parallel
slope
Effect
Drug dose
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Slope
gt mechanism of action - parallel
slope
Effect
Drug dose
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Slope
gt mechanism of action - parallel same
receptor
slope
Effect
Drug dose
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Slope
gt mechanism of action - parallel same
receptor
slope
Effect
Drug dose
Steepness is relevant to dose range.
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Slope
gt mechanism of action - parallel same
receptor
slope
Effect
Drug dose
Steepness is relevant to dose range.
steep curve require threshold dose
synergistic effect
therapeutic and toxic doses are similar
difficult to adjust the dose
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Variability
Effect
population different person, same
conditions individual different conditions,
same person
variability
Drug dose
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Variability
Effect
population different person, same
conditions individual different conditions,
same person
variability
Drug dose
vertical variation same dose, different effect
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Variability
Effect
population different person, same
conditions individual different conditions,
same person
variability
Drug dose
horizontal variation different dose, same
effect
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Variability
Effect
population different person, same
conditions individual different conditions,
same person
variability
Drug dose
vertical variation same dose, different
effect horizontal variation different dose,
same effect
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Quantal Dose- Response Curve
Therapeutic Index
hypnosis
death
TD50/ED50
50/0.2 250
ED50
TD50

0.01 0.1 1 10 100
1000
Dose
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Therapeutic Index
hypnosis
death
TD50/ED50
10/0.3 30
ED50
TD50
0.001 0.01 0.1 1 10
100 1000
Dose
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hypnosis
death
Certain Safety Factor
TD1/ED99
ED50
TD50
0.3/10 0.03
ED99
TD1
0.001 0.01 0.1 1 10
100 1000
Dose
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Certain Safety Factor
1/1 1
TD1/ED99
hypnosis
death
100

80
60
of individual response

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ED99
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TD1
0

0.001 0.01 0.1 1
10 100 1000
Dose
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What are the Important Clinical Implication ?
GRADED DOSE/CONCENTRATION RELATIONSHIPS help to
understand how changing dose of drug will
effect the degree of response of an individual
patient.
QUANTAL DOSE/CONCENTRATION RELATIONSHIPS help to
understand how changing dose of drug will effect
the of your patients who will experience a
defined response.
The safety of a drug can be assessed by examining
the log dose-response curves for therapeutic
versus toxic effects.
The more separation between the therapeutic log
dose-response curves and the toxic log
dose-response curves, the safer the drug.
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Clinical Selectivity
1. Same receptor-effector mechanism
Toxic
D R DR Effector X
Beneficial
Direct pharmacologic extension of the therapeutic
actions of the drug
eg, bleeding caused by anticoagulant therapy
hypoglycemic coma due to insulin

• adjust the dose of drug

• not administering the drug at all

• add another drug

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Clinical Selectivity
2. Same receptors but different effector
Effector X
Toxic
D R DR
Effector Y
Beneficial
eg, digitalis glycosides, inhibits Na/K ATPase
methotrexate, inhibits dihydrofolate reductase
glucocorticoid hormones

• lowest dose
• adjunctive drugs with different receptor
• mechanisms and different toxicities
• selectivity of the drug's actions,
• - aerosol administration of glucocorticoid
  in asthma

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Clinical Selectivity
3. Different receptor
R1 DR Effector X
Toxic
D
R2 DR Effector Y
Beneficial
eg, ?- and ?-selective adrenoceptor agonists and
antagonists H1 and H2 antihistamines nicotinic
and muscarinic blocking agents receptor-selective
steroid hormones
More selective drugs
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Factors that influence drug responses
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Drug Therapy in Special Populations
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Drug Therapy in Breast-Feeding Patient

• Drug concentration in breast milk
• Effects of drugs ingested in breast milk

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Drug Therapy During Breast-Feeding

• Drug Concentration in Breast Milk

• Both water and lipid soluble drugs show up in
  breast milk
• a)  Water soluble drugs dissolved in free
• or bound to casein and/or lactalbumin.
• b) Lipid soluble drugs dissolve in milk fats
• Drug concentration in breast milk difficult to
  predict. However, effect on infant is usually
  lower than in mother.

If nursing mother must take drugs, optimal time
is 30-60 min after feeding and 3-4 h before next
feeding.
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Drug Therapy During Breast-Feeding

• Effects of Drugs Ingested in Breast Milk

• Examples
• Tetracycline cause permanent tooth staining in
• infant.
• Diazepam cause sedation in infant
• - Alcohol one drink doesnt affect infant, but
  many.
• Cancer chemotherapy - 125I-tracers cause
• subsequent thyroid cancer in
  infant.
• Lithium same concentration in breast milk as
  in
• plasma, produce toxic effects
  in children
• - Heroin produce dependence in mother

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Drugs that are contraindicated during
breast-feeding
Drug Therapy During Breast-Feeding

• Controlled substances
• - amphetamine, cocaine, heroin, marijuana,
• Anticancer drugs / Immunosuppressants
• - cyclophosphamide, cyclosporine,
  methotrexate, doxorubicin
• Other drugs
• - bromocriptine, ergotamine, lithium, nicotine

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Drug Therapy in Children
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Drug Therapy in Children
Pediatric population is divided into 3 groups

• Neonates lt 1 month
• Infants lt 1 year
• Children 1 12 years
• Adolescents 12 16 years

different than adult
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Ontogeny of Body Composition
Drug Therapy in Children
Protein
Other
EC H2O
IC H2O
Fat
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult
of Total Body Weight
Kaufman, Pediatric Pharmacology (Yaffe Aranda,
eds) pp. 212-9, 1992
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Drug Therapy in Children
Pharmacokinetics
Neonates and Infants
Absorption

• Oral administration

- Gastric emptying time prolong until
6 8 months
stomach absorption intestinal absorption
- Gastric acidity very low
acid-labile drug absorption
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Drug Therapy in Children

• I.M. administration

• Low blood flow through muscle

absorption delay

• Percutaneous administration

• Thin skin

absorption greater than children
toxic from topical drug
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Drug Therapy in Children
Distribution

• Protein binding

• Albumin low until 10 12 mths

free drug
effect

• Blood-brain barrier

- Not fully developed
drug easy access to CNS
sensitive to drugs those can penetrate to CNS
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Drug Therapy in Children
Metabolism

• Hepatic metabolism

- Metabolism capacity decreased until 1 yr.
sensitive to drugs metabolized by liver
Excretion

• Renal excretion

- Renal function reduced until 1 yr.
drug half-life
drug accumulation
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Drug Therapy in Children
Pharmacokinetics
Children 1 yr - Older
Most pharmacokinetic are similar to adults
But metabolism

• Faster than adult until 2 yrs.

dose or dosing interval
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Drug Therapy in Children
Adverse Drug Reactions (ADRs)

• High drug level
• Organ immature
• Ongoing growth and development

ADRs
age-related effects - growth suppression from
glucocorticoids discoloration of teeth from
tetracycline kernicterus from sulfonamides
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Drug Therapy in Elderly
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Pharmacokinetic Changeswith Aging
Drug Therapy in Elderly

• Absorption Few alterations

Rate of absorption may be slow
Drug response may be delayed
Distribution Lean body mass
Total body water
Vd of water-soluble drugs
Drug concentration
Drug effect
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Drug Therapy in Elderly
Body fat
lipid-soluble drug storage
drug concentration
drug effect
Serum albumin
protein binding
free drug
drug effect
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Drug Therapy in Elderly
Metabolism hepatic enzyme
drug half-life
prolonging response
Elimination renal function
drug excretion
drug accumulation
adverse drug reactions
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Pharmacodynamic Changeswith Aging
Drug Therapy in Elderly
knowledge is restricted to a few drugs

• Receptor number

• Receptor number

• Receptor affinity

• Receptor affinity

effect
effect
i.e. ?-adrenergic blocking drugs
i.e. CNS depressant, warfarin
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Drug Therapy in Elderly
Adverse Drug Reactions (ADRs)
Factors predispose the older patient to ADRs

• Drug accumulation
• Polypharmacy
• Severity of illness
• Multiple pathologies
• Use of drugs with a low therapeutic index
• Altered pharmacokinetics / pharmacodynamics
• Inadequate supervision of long-term therapy
• Poor patient compliance

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Drug Therapy in Elderly
Patient Compliance
Factors that contribute to poor compliance in the
elderly

• Forgetfulness
• Failure to comprehend instruction
• Inability to pay for drugs
• Use of complex regimens
• Unpleasant side effects

Most are unintentional noncompliance
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The End
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Any Questions?