Drugs and Aging

=Objectives=

Define

 * Anticholinergic: An anticholinergic agent is a substance that blocks acetylcholine in the central and peripheral nervous system. The classic example is atropine.  Anticholinergics are classified according to the receptors they affect: anti-muscarinic and anti-nicotinic.  Some effects are: ataxia, dry mucous membranes, cessation of perspiration, increased body temp, mydriasis, vision problems, tachycardia, urinary retention, decreased bowel movement, increased intraocular pressure and shaking.  Some side effects are: confusion, disorientation, agitation, euphoria/dysphoria, respiratory depression, memory problems, inability to concentrate, wandering thoughts, incoherent speech, myoclonic jerking, auditory sensitivity, photophobia, hallucinations, and rarely seizures, coma or death.
 * Compliance: the degree to which a patient correctly follows medical advice.
 * Polypharmacy:
 * the use of multiple medications (some say >4, some say >6) by a patient,
 * when more drugs are prescribed than clinically warranted, or even when all prescribed medications are clinically indicated but there are too many pills to take.
 * The most common results are increased drug reactions, drug-drug interactions, decreased compliance and higher costs.
 * Successful aging: according to the UCLA Center for Aging, the successful components are: high level of engagement in life, low risk of disease, and high physical and cognitive function levels. Example: George Olsen

Absorption

 * There is a decrease in the surface area and motility of the small bowel and an increase in stomach pH, but there is no significant change in absorption for most drugs.
 * One exception is propanolol for which absorption is increased. This is partially explained by a diminished first-pass effect (i.e. decreased hepatic extraction).

Distribution

 * There is a decrease in muscle mass and body water and an increase in fat.
 * Results in a slight decrease in VD (volume of distribution) for water soluble drugs and/or drugs that bind to proteins (digoxin) and an increase in VD for fat soluble drugs (diazepam)
 * Serum albumin is decreased which decreases protein binding of many drugs
 * Alpha-acid glycoprotein (AAG) is increased.
 * Binds many basic drugs and therefore binding in plasma may be increased (lidocaine)
 * Change in protein binding affects interpretation of plasma drug levels but usually not overall drug effects
 * May be a decrease in CO

Drug Metabolism
Decreased significantly for flow limited drugs like lidocaine, but not as much for capacity limited drugs
 * Decrease (40%) in hepatic blood flow in elderly
 * Decreased hepatic enzyme activity for some Phase I oxidative rxns for many, but not all drugs. Effect greater in men than women.
 * Phase I rxns primarily occur in the liver.
 * Most of these reduce toxicity.
 * Often they convert prodrugs into drugs
 * Dr. Olson refers to them as "Preparative", they make the first metabolite
 * No change in Phase II rxns such as glucuronidation
 * Phase II rxns are metabolic processes that attach polar and ionizable groups to Phase I metabolites to form water soluble products
 * The products are usually devoid of activity and can be easily excreted
 * Examples include: glucuronidation, sulfation, methylation, acetylation, glutathoine conjugation and amino acid conjugation.
 * Smoking increases hepatic clearance of many drugs in younger people, but not very much in elderly patients
 * Chronic ethanol ingestion in the absence of severe liver disease increases the hepatic clearance of many drugs, but alcohol consumption is decreased in the elderly

Renal Excretion

 * Decreased for most drugs studied.
 * This is the most important pharmacokinetic alteration with aging.
 * Digoxin and gentamicin are two examples of the importance of this change
 * There is a decreased GFR (153-0.96 x age) and RPF (840-6.44 x age)
 * Cockroft-Gault relating clearance to age (40 to 80), weight and serum creatinine. Remember this???
 * Men: (140-age) x (body weight in kg) / Serum creatinine x 72 = Endogenous creatinine clearance
 * Women: (140-age) x (body weight in kg) x .85 / Serum creatinine x 72 = Endogenous creatinine clearance

Other Changes

 * Body water as a percent of body weight decreases
 * Lean body mass as a percent of body weight decreases
 * Body fat as a percent of body weight increases
 * Serum albumin decreases
 * Kidney weight decreases
 * Hepatic blood flow decreases
 * Cardiac Index (CO:body surface area) decreases
 * Maximal breathing capacity decreases

List life-style factors that promote successful aging.
Heavy drinking, no physical activity, plenty of illicit drugs, engaging in unprotected sex, and smoking

List at least 5 drugs that produce CNS depression in the elderly.

 * Tri-cyclic antidepressants (amitriptyline and nortriptyline)
 * Barbituates
 * Benzodiazepines (clonazepam, diazepam, desmethyldiazepam, N-desalkylfluazepam, lorazepam, oxazepam and temazepam)
 * Digoxin
 * EtOH (Maker's Mark, Pabst Blue Ribbon, etc)

Discuss the reasons for noncompliance with medication regimens in the elderly.
Money, polypharmacy, mental status, adverse effects, etc.

Drug List

 * Aspirin: GI bleeding, salicylism may mimic dementia
 * Amitriptyline: tricyclic with lots of sedative, anticholinergic, orthostatic hypotension effects as well as some NE reuptake
 * Clonazepam: Benzo with half life of 23 hours
 * Desmethyldiazepam: active metabolite of diazepam; half life of 73 hours
 * Diazepam: Benzo with half life of 43 hours (longer in elderly)
 * Digoxin: Eliminated primarily by glomerular filtration, slows AV nodal conduction
 * Donepezil: Used in dementia of Alzheimer's disease; reversible inhibitor of acetylcholinesterase; elimination T 1/2 is long (70 hours); seizures; GI effect; atropine given for overdose.
 * Memantine: Binds N-methyl-D-aspartase (NMDA) receptors, NMDA antagonist, may slow CA++ influx and nerve damage in Alzheimer's dementia
 * Nortripyline: tricyclic with little sedation, anticholinergic, orthostatic (possibly none) side effects. Also has NE reuptake equal to amitriptyline.
 * Oxazepam: Benzo with half life of 7 hours (shortest one)
 * Prazosin: vasodilator and alpha-1 blocker which can cause orthostatic hypotension
 * Proxpoxyphene: a narcotic pain reliever, also known as Darvon. It does stimulate the opiod receptors.  Therefore its side effects are: constipation, fatigue, sedation, nausea, confusion, postural hypotension, respiratory depression, addiction and abuse.  There is decreased Cl/F and increased T 1/2 and AUC.
 * Propranolol: T 1/2 is 2-3 hours, high lipid solubility, longer duration than expected from T 1/2 because of active metabolite, bioavailability 36% (high first pass effect), depression, memory loss, problem in asthmatics, contraindicated in AV block, used in angina and HTN, it is a non-selective beta adrenergic blocker.
 * Quetiapine: Second generation antipsychotic, with low incidence of extrapyramidal effects
 * Terazosin: Antagonizes alpha-1 adrenergic receptors, used for hypertension and benign prostatic hypertrophy.
 * Warfarin: Increased risk of bleeding with dietary lack of vitamin K, decreased hepatic inactivation with aging, and/or drug interactions with polypharmacy (ASA, metronidazole and erythromycin).