(50 marks seminar) Presented by:

S.S.D.SreejaM.Pharmacy I/II

Pharmacology

Under the guidance of:

Dr. R. PadmavathiAssoc. Professor

M.Pharm, PhD.

• INTRODUCTION

• PHARMACOKINETICS AND DRUG THERAPY IN GERIATRICS

• PHARMACOKINETICS AND DRUG THERAPY IN PEDIATRICS

• PHARMACOKINETICS AND DRUG THERAPY IN PREGNANCY AND LACTATION

Pharmacokinetics deals with the description of concentration changes of drugs in the body as a function of time. It is best defined as what the body does to the drug.

it includes:

Absorption

Distribution across body compartments

Metabolism

Excretion

Pharmacokinetic Parameter Age related changes

Absorption Nil

Distribution ofLipid soluble drugsWater soluble drugsAcidic drugsBasic drugs

IncreasedDecreasedIncreasedDecreased

Metabolism Phase IPhase II

DecreasedNil

Excretion Decreased

System Age related Physiological changes Consequences

General Increased body fatDecreased total body water

Vd of lipid soluble drugs is increased requiring higher dose; eg. Diazepam.Vd of water soluble drugs is decreased requiring low dose; eg. Digoxin.

Gastrointestinal tract

Decreased gastric acidityDecreased gastrointestinal motilityDecreased hepatic blood flow

Absorption of basic drugs is enhanced; eg. Propranolol.Absorption of acidic drugs is decreased; eg. Barbiturates.Decreased metabolism of drugs.

Renal Decreased renal blood flow, GFR and tubular secretion

Renal clearance is decreased and hence drugs excreted through kidney should be used cautiously. Eg. Digoxin, aminoglycosides.

Musculoskeletal Decreased muscle massDecreased bone density

Resulting in functional impairment and fracture requiring treatment and hospitalization, etc.

Cardiovascular system

Increased blood pressure Cardiovascular complications requiring treatment, hospitalization, etc.

Central nervous system

Brain atrophyDecreased dopaminergic synthesisDecreased sleep (stage 4)

Results in forgetfulness, depression, Parkinson’s, insomnia etc. requiring therapy.

Genitourinary Vaginal/ urethral mucosal atrophyProstate enlargement

Bacteriuria, increased residual urine volume requiring hormonal or drug therapy.

Endocrine Decreased basal metabolic rateVulnerable to stressGlucose intolerance

Resulting in diabetes mellitus which needs life long treatment.

Class or Category Decreased Hepatic Metabolism Decreased Renal Elimination

Analgesics and anti-

inflammatory drugs

Ibuprofen

Meperidine

Morphine

Naproxen

Meperidine

Morphine

Providing safe, effective drug therapy for the elderly is challenging for many reasons:

They use more drugs than any other age group, increasing risk of adverse effects and drug interactions, and making adherence more difficult.

They are more likely to have chronic disorders that may be worsened by the drug or affect drug response.

Their physiologic reserves are generally reduced and can be further reduced by acute and chronic disorders.

Aging can alter pharmacodynamics and pharmacokinetics

They may be less able to obtain or afford drugs.

There are 2 main approaches to optimizing drug therapy in the elderly:

Using appropriate drugs as indicated to maximize cost-effectiveness

Avoiding adverse drug effects

Category Definition

Drug interactions Use of a drug results in a drug-drug, drug-food, drug-supplement, or drug-

disease interaction, leading to adverse effects or decreased efficacy.

Inadequate monitoring A medical problem is being treated with the correct drug, but the patient is

not adequately monitored for complications, effectiveness, or both.

Inappropriate drug selection A medical problem that requires drug therapy is being treated with a less-

than-optimal drug.

Inappropriate treatment A patient is taking a drug for no medically valid reason.

Lack of patient adherence The correct drug for a medical problem is prescribed, but the patient is not

taking it.

Overdosage A medical problem is being treated with too much of the correct drug.

Poor communication Drugs are inappropriately continued or stopped when care is transitioned

between providers and/or facilities.

Underprescribing A medical problem is being treated with too little of the correct drug.

Untreated medical problem A medical problem requires drug therapy, but no drug is being used to

treat that problem.

Some drug categories (eg, analgesics, anticoagulants, anti hypertensives, antiparkinsonian drugs, diuretics, hypoglycemic drugs, psychoactive drugs) pose special risks for elderly patients. Some drugs, although reasonable for use in younger adults, are so risky they should be considered inappropriate for the elderly.

The Beers Criteria are most commonly used to identify such inappropriate drugs. The 2012 American Geriatrics Society updates to the Beers criteria further categorize potentially inappropriate drugs into 3 groups:

Inappropriate: Always to be avoided

Potentially inappropriate: To be avoided in certain diseases or syndromes

To be used with caution: Benefit may offset risk in some patients

Anticholinergics:

First-generation antihistamines, as single agents or in combination products (brompheniramine, carbinoxamine, chlorpheniramine, clemastine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine [oral], doxylamine, hydroxyzine, promethazine, triprolidine)

Antiparkinson drugs (benztropine [oral],trihexyphenidyl)

Antispasmodics (belladonna alkaloids, clidinium-chlordiazepoxide, dicyclomine, hyoscyamine, propantheline

Anti-infectives: Nitrofurantoin

Antithrombotics: Dipyridamole, Ticlopidine

Cardiovascular drugs: Alpha-1 blockers (doxazosin, prazosin,terazosin) Alpha agonists, central (clonidine,

guanabenz, guanfacine, methyldopa, reserpine Antiarrhythmic drugs, classes Ia, Ic, and III

(amiodarone, dofetilide, dronedarone,flecainide, ibutilide, procainamide,propafenone, quinidine, sotalol)

Disopyramide†

Dronedarone Digoxin (> 0.125 mg/day) Nifedipine Spironolactone (> 25 mg/day)

Drug Reason for Caution

Aspirin for primary prevention

of cardiac events

Use with caution in patients ≥ 80 yr.

Lack of evidence regarding benefit vs risk in patients > 80 yr

Dabigatran Use with caution in patients ≥ 75 yr or with creatinine clearance < 30 mL/min.

Greater risk of bleeding than warfarin in patients ≥ 75 yr

Lack of evidence regarding efficacy and safety in patients with creatinine clearance <

30 mL/min

Prasugrel Use with caution in patients ≥ 75 yr. Increased risk of bleeding; benefit may offset

risk in highest-risk elderly (eg, those with previous MI or diabetes mellitus)

Antipsychotics:

Carbamazepine, Carboplatin,

Cisplatin, Mirtazapine,

Serotonin–norepinephrine

reuptake inhibitors, SSRIs,

Tricyclic antidepressants,

Vincristine

May worsen or cause syndrome of inappropriate antidiuretic hormone secretion or

hyponatremia

Monitor Na level closely when starting or changing dosages.

Vasodilators May increase episodes of syncope in patients with history of syncope

Absorption: Absorption from the GI tract is affected by:

Gastric acid secretion: Reduced gastric acid secretion increases bioavailability of acid-labile drug and decreases bioavailability of weakly acidic drugs.

Bile salt formation: Reduced bile salt formation decreases bioavailability of lipophilic drugs (eg, diazepam).

Gastric emptying time and Intestinal motility: Reduced gastric emptying and intestinal motility increase the time it takes to reach therapeutic concentrations when enteral drugs are given to infants < 3 mo

Bowel length and effective absorptive surface: Infants with congenital atretic bowel or surgically removed bowel or who have jejunal feeding tubes may have specific absorptive defects depending on the length of bowel lost or bypassed and the location of the lost segment

Drug-metabolizing enzymes present in the intestines of young infants are another cause of reduced drug absorption.

• Injected drugs are often erratically absorbed because of: Variability in their chemical characteristics, Differences in absorption by site of injection (IM or sc), Variability in muscle mass among children, illness and Variability in depth of injection (too deep or too shallow)

• IM injections are generally avoided in children because of pain and the possibility of tissue damage, but, when needed, water-soluble drugs are best because they do not precipitate at the injection site.

• Transdermal absorption may be enhanced in neonates and young infants because the stratum corneum is thin and because the ratio of surface area to weight is much greater than for older children and adults. Skin disruptions (eg, abrasions, eczema, burns) increase absorption in children of any age.

• Transrectal drug therapy is generally appropriate only for emergencies when an IV route is not available

• Absorption of drugs from the lungs varies less by physiologic parameters and more by reliability of the delivery device and patient or caregiver technique.

The volume of distribution of drugs changes in children with aging. These age-related changes are due to changes in body composition (especially the extracellular and total body water spaces) and plasma protein binding.

Higher doses (per kg of body weight) of water-soluble drugs are required in younger children because a higher percentage of their body weight is water Conversely, lower doses are required to avoid toxicity as children grow older because of the decline in water as a percentage of body weight.

Drug metabolism and elimination vary with age and depend on the substrate or drug, but most drugs, and most notably phenytoin, barbiturates, analgesics, and cardiac glycosides, have plasma half-lives 2 to 3 times longer in neonates than in adults.

Phase I activity is reduced in neonates, increases progressively during the first 6 months of life, exceeds adult rates by the first few years for some drugs, slows during adolescence, and usually attains adult rates by late puberty. Phase II metabolism varies considerably by substrate

Drug metabolites are eliminated primarily through bile or the kidneys. Renal elimination depends on

Plasma protein binding

Renal blood flow

GFR

Tubular secretion

All of these factors are altered in the first 2 yr of life. Renal plasma flow is low at birth (12 mL/min) and reaches adult levels of 140 mL/min by age 1 yr. Similarly, GFR is 2 to 4 mL/min at birth, increases to 8 to 20 mL/min by 2 to 3 days, and reaches adult levels of 120 mL/min by 3 to 5 mo.

Drug treatment in children differs from that in adults, most obviously because it is usually based on weight or surface area. Doses (and dosing intervals) differ because of age-related variations in drug absorption, distribution, metabolism, and elimination. A child cannot safely receive an adult drug dose, nor can it be assumed that a child’s dose is proportional to an adult’s dose (ie, that a 7-kg child requires 1/10 the dose of a 70-kg adult).

Children are generally subject to the same adverse effects as adults but they have increased risk with certain drugs because of differences in pharmacokinetics or because of drug effects on growth and development

Drug Clinical Syndrome Mechanism Comments

Anesthetics, topical

(eg, benzocaine, mixture

oflidocaine and prilocaine)

Cyanosis Formation of methemoglobin (ferrous iron

oxidized to ferric iron)

Incidence rare

Ceftriaxone Jaundice

Kernicterus

Bilirubin displaced from albumin Affects only neonates

Codeine Respiratory depression

Death

Ultrarapid metabolization

of codeine tomorphine

Genetic variant

Deaths have occurred after surgery and in a

breastfed infant whose mother tookcodeine

Diphenoxylate Respiratory depression

Death

CNS depression (in immature CNS) Overdose syndrome, usually in children < 2 yr

Fluoroquinolones Cartilage toxicity Unknown Suspected based on animal studies, but adverse

effects in humans unproved—short-term use

may be safe

Lindane (topical) Seizures

CNS toxicity

Probably enhanced absorption in children Should not be used in children < 50 kg

(alternative should be used)

Prochlorperazine Altered CNS function

Extrapyramidal effects

Opisthotonus

Bulging fontanelles

Actions via multiple CNS receptors Febrile and dehydrated infants especially at risk

SSRIs Suicidal ideation Unknown Increased incidence of suicidal ideation in

children and adolescents

Tetracycline Discoloration and pitting of

tooth enamel

Chelation with Ca in growing teeth Not given to children < 8 yr

In pregnancy and labour the body becomes a complex physiological unit which consists of mother, placenta and fetus.

This unit is complicated not only because of integrated parts of the system are interrelated but also because considerable changes occur as pregnancy advances.

These changes may lead to important variations in the pharmacokinetic processes of absorption, distribution and elimination of drugs

Alterations in pharmacokinetic parameters in pregnancyAbsorption GI absorption: reduced intestinal motility; increased gastric and

intestinal emptying time; reduction in gastric acid secretion; increased mucus secretion; total perfusion is increased

Pulmonary absorption: haemodynamic and ventilatory factors

Hyperventilation: increased alveolar drug uptake

Intramuscular absorption: increased peripheral tissue perfusion due to vasodilation. In late pregnancy blood flow is decreased to lower limbs

Drug distribution

increased blood volume and cardiac output

Drug elimination

Renal Drug elimination – creatinine clearance and drug elimination.

Hepatic Drug elimination - increased rate of metabolism

decreased rate of metabolism - ethylmorphine

It is an index of the fetus to the drug taken by the mother.

It is the ratio of the total area under the drug concentration time curve for the fetus to that of the mother-from the time of drug administration to the mother to the time when all drug has been eliminated

Drugs that are intended to reach the fetus should have a high index of relative exposure, while that should preferably not reach the fetus but are intended for the mother then it should have a low index of relative exposure to the fetus.

category A- careful tests in humans have shown no harm.

Category B- animal studies have shown an adverse effect, but adequate and well controlled studies in pregnant women have failed to demonstrate any risk to the fetus.

Category C- animal studies show some harm and there are no good studies in humans.

Category D- adequate well controlled studies in pregnant women have demonstrated a risk to the fetus.

Category X- adequate well controlled studies in animals or in pregnant women have shown that the drug causes fetal abnormalities.

Stage Gestation period Main cellularprocess

Altered by:

Blastocyst formation

0 – 16 days Cell division Cytotoxic drugs

Organogenesis 17 – 60 days DivisionMigrationDifferentiation

Teratogens

Histogenesis, functional maturation

60 days to term (same as above) MiscellaneousAlcholnicotine

• A substance, organism, physical agents or deficiency state capable of inducing abnormal structure or function such as: – Gross structural abnormalities

– Functional deficiencies

– Intrauterine growth restriction

– Behavioral aberrations

– Demise

• Timing of exposure

• Developmental stage during exposure

• Maternal dose and duration

• Maternal pharmacokinetics

• Genetic factors/phenotypes

• Interactions between agents

• Placental transfer may occur by:

– Passive diffusion

– Facilitated diffusion

– Active transport

• Placental surface area

• Placental metabolism

• Diffusion from maternal plasma into

milk

• Higher maternal plasma levels mean

higher breast milk concentrations

• Equilibrium will be established with

most drugs between milk and plasma

ANTIEPILEPTICS: Uncontrolled epilepsy in a pregnant woman is a serious and potentially life threatening condition for both mother and child. But they have adverse effects such as:• Fetal abnormalities• CHF,• Neural tube defects,• Neuro genital defects.

CARBAMAZEPINE

Structural birth defects.

Compatible with breastfeeding

VALPROATE

Should be avoided in reproductive women.

Major malformations including spina bifida.

Compatible with breastfeeding.

LAMOTRIGINE

Plasma concentrations of lamotrigine fall early in pregnancy,so dose increases may be necessary to control seizures

At the post partum lamotrigine concentration rises with in a few days and dose reduction may be required to prevent toxicity.

Excreted in considerable amounts into breast milk.

PHENYTOIN

Less frequently used because of increased malformations.

Increased clearance, decreased plasma concentrations lead to loss of seizure control.

Post partum monitoring of plasma concentrations helps in preventing phenytoin toxicity.

CLONAZEPAM

No particular pregnancy risks.

Causes drowsiness in breast feeded neonate.

Withdrawal effects

PHENOBARBITONE

Marked increase in plasma clearance.

Neonatal drowsiness and apathy.

ANTIDEPRESSANTS

Harmful effects:

In pregnancy –Shorter gestational length and lower birth weight in new born.

Raised cortisol levels with the increased vulnerability to psychopathology

In lactation-women who develop post natal depression are most likely to stop breastfeeding.

SSRIs during pregnancy: First trimester-no teratogenic effects.

Paroxetine - Cardiovascular abnormalities. Second trimester-significant risk of shorter gestational length and

lower birth weight in infants. Third trimester-increased respiratory distress,irritability and feeding

problems. Persistent pulmonary hypertension in new born and possibly

intraventricular haemorrhage.

SSRIs during lactation:

Compatible with breastfeeding.

Highly protein bound so less drug is transferred from mother to the infant during lactation.

Anticancer drugs

Radio pharmaceuticals

Ergot & its derivatives

Lithium

Chloramphenicol

Phenyl butazone

Atropine

Thiouracil

Iodide

Mercurials

sulphonamides

Drugs which inhibit/suppress lactation:

• Bromocriptine

• Bendroflumethazide

• Estradiol

• Oral contraceptives

• Levodopa

• Trazodone

Drugs which are hazardous to the infant:

Large doses of Alcohol, caffeine, theophylline.

Hand book of clinical pharmacokinetics Milo Gibaldi and Prescott

Applied biopharmaceutics and pharmacokinetics ;Leon shargel,Susanna wu-pong,AndrewB.C.YU

Clinical pharmacokinetics ; Rowland and Tozer

Clinical pharmacology and pharmacotherapeutics; Roser walker

Pharmacological basis of therapeutics; Goodmann and Gilmann

www.spingerlink.com

www.wikipedia.org

www.pubmed.gov

www.pharmainfo.net

Last full review/revision June 2014 by J. Mark Ruscin, PharmD; Sunny A. Linnebur, PharmD, FCCP, BCPS, CGP

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