Drug Induced Diseases+Geriatric Considerations

Agonist vs Partial Agonist vs Antagonist

agonist:
binds to receptor→activates it
has intrinsic activity

partial agonist:
doesn’t give maximum possible response

antagonist:
binds to receptor→doesn’t activate it
blocks off agonist
-competitive vs non-competitive

Competitive vs Non-Competitive Antagonist

competitive antagonist:
competes with agonist for receptor site

highest concentration gets receptor site

reversible: increased concentration of agonist→reverses antagonism

non-competitive:
antagonist binds to receptor→stays bound

blocked from exerting effect

not reversible

Mx Pharmacokinetics (ADME)

absorption:
acidity
adsorption
GI

distribution

metabolism:
inhibition
induction

excretion

p-glycoprotein interactions

Pharmacokinetics: Absorption (General)

movement of mx from site of administration into central compartment/target

mainly PO mx

Bioavailability

measurement of the effective dose which reaches systemic circulation (bloodstream) from site of administration

contributing factors:
route of administration
ionization
protein binding
metabolism
ability of mx to pass through membranes

Pharmacokinetics: Absorption→Acidity (pH)

acidity/pH of the GI tract affects absorption

works in both directions on pH scales

mx: omeprazole
antiacids
etc.

Adsorption

one element binds to another on its surface (interaction between two molecules)
-cations+binding resins (cholestyramine)→don’t want to bind

ex: fluoroquinolones need to be given 2 hours prior/6 hours after antacids

Absorption Considerations

GI motility+absorption:
motility affects rate of absorption
not necessarily amount of mx absorbed
ex: metoclopramide (Reglan) speeds rate of gastric emptying
opiates decrease rate of gastric emptying

GI flora:
bacterial in stomach responsible for metabolism
-abx
-ethinyl estradiol (birth control)

first pass effect:
some PO mx metabolized by liver before going into circulation

Pharmacokinetics: Distribution (General)+Plasma Proteins

distribution:
drug delivery to interstitial+intracellular fluids

plasma proteins (albumin+A1-acid glycoprotein):

• bind drugs in the circulation

• percentage of drug bound to protein affects amount unbound to interact freely

• higher affinity drug wins binding spot

• less affinity→more unbound fraction

• clinically important: 90%+ bound/unusable+narrow therapeutic index

Pharmacokinetics: Metabolism (General)

metabolism:
phase 1 (oxidations)/phase 2 reactions that change drugs into more hydrophilic metabolites

• more polar/inactive metabolites excreted from the body

• can promote drug activity/no change/production of toxic metabolites

main sites:
liver
small intestines

Cytochrome P450 (CYP450):

• protein in membranes of smooth ER

• mostly found in liver

• metabolizes most of mx

CYP3A4→40-45% mx metabolism
CYP2D6→20-30%
CYP2C9→10%

• mx can be metabolized by different isoenzymes

• genetic variations in some cultures

Enzymes+Potent Inducers+Inhibitors

CYP1A2:

inducers:

• carbamazepine

• phenobarbital

• rifampin

inhibitors:

• amiodarone

• ciprofloxacin

CYP2C9:

inducers:

• carbamazepine

• phenobarbital

• phenytoin

• rifampin

inhibitors:

• amiodarone

• fluconazole

• fluoxetine

• metronidazole

• ritonavir

• trimethoprim/sulfamethoxazole

CYP2C19:

inducers:

• carbamazepine

• phenytoin

• rifampin

inhibitors:

• isoniazid

• ritonavir

CYP2D6:

inducers:

none

inhibitors:

• amiodarone

• diphenhydramine

• fluoxetine

• ritonavir

• terbinafine

CYP3A4:

inducers:

• carbamazepine

• st. john’s wort

• phenobarbital

• phenytoin

• rifampin

inhibitors:

• clarithromycin

• diltiazem

• grapefruit juice

• ketoconazole

• ritonavir

• verapamil

Dangerous/Deadly Mx Combinations

clarithromycin+CCBs:

• hypotension

• acute renal fialure

• inhibits CYP3A4 metabolism→impairs nifedipine

theophylline+ciprofloxacin:

• toxic levels of theophylline

• ciprofloxacin inhibits CYP1A2

• theophylline metabolized by CYP1A2

sidenafil+isosorbide mononitrate

potassium chloride+spironolactone: hyperkalemia→HF

SSRIs+tramadol: serotonin syndrome

Enzyme Induction vs Inhibition

enzyme inhibition:

• stops enzyme from working→substrate builds up→increased mx amount→increased mx effect

• inhibiting mx→mx with greatest affinity

• decrease metabolism of mx

• -competitive inhibition
  -non-competitive inhibition

enzyme induction:

• increases number of enzymes for metabolization/increases hepatic blood flow→decreased mx amount→mx doesn’t work

• increases metabolism of mx

• ex: PO contraceptives+rifampin

autoinduction

• ex: carbamazepine

• induces hepatic enzymes→increases own metabolism

• requires increased doses to maintain therapeutic level

defining characteristics:

• affinity

• half-life

• concentration

Half-Life

determines duration of interaction

complete elimination→3-5 half lives

Concentration Threshold

threshold concentration must be reached/exceeded in order to inhibit an enzyme

Mx Interaction Considerations

toxic potential: check that other mx don’t have strong affinity to same isoenzyme

efficacy:
prodrugs→need to be metabolized into active form

induction:
phenobarbital
phenytoin
rifampin
carbamazepine

CYP450 enzyme production/degradation→1-6 days

Pharmacokinetics: Excretion/Elimination

-biliary excretion
-renal excretion

reabsorption from kidneys into the bloodstream can occur

excretion can be affected by the pH of urine+alterations of pathways
-ionized mx excreted via urine
-acidic drugs become ionized in alkaline urine+vise versa for basic drugs

mx alters the pH of urine→increases reabsorption/excretion of another mx

P-Glycoprotein Interactions

p-glycoprotein (PGP):

• efflux transporter

• found in:
  -intestines
  -liver
  -kidneys

• intestines→absorbed through intestinal wall into circulation→PGP carries back to intestinal lumen
  -prevents it from getting into bloodstream
  -“boomerang”

• inhibited→more mx absorbed

• induced→less mx absorbed

Pharmacodynamic Effects

synergistic effects:

• same effect

• causes more of action

• multiple mx can have same effect→increases effect

changes in body chemistry:

• synergistic effects

opposing effects:

• competition of mx

absorption:

• altered extent of absorption

• altered rate of absorption

adsorption:

• molecules interacting with other molecules

food:

• creates physical barrier→prevents absorption

• several mx need to be taken on empty stomach

metabolism:

• certain foods affect P450 enzymes
  -grapefruit juice

excretion:

• fruit juices alter urinary pH
  -orange
  -tomato
  -grapefruit

pharmacodynamics:

• warfarin inhibits vitamin K-dependent clotting factors→affects warfarin absorption

• leafy green vegetables→large amounts of vitamin K

• pt education on balanced diet+avoiding changes in vitamin K intake

Effects of Mx on Nutrients

mx can interact with foods→effect nutrient absorption+excretion

chronic laxatives→decreased absorption of fat-soluble vitamines

metformin→decreased vitamin B12→anemia

Drug Disease Interactions (ADME)

absorption:

• GI function affects

• vitamin B12 needs stomach acid to be absorbed

distribution:

• albumin levels can fluctuate

metabolism/excretion:

• dx affecting liver/kidney

• kidney dx pt→monitor CrCl

alcohol intake:

• DM pts→potential hypoglycemia

• metronidazole→inhibits enzymes responsible for metabolizing alcohol

Adverse Drug Event (ADE)

harm caused by an appropriate/inappropriate use of a drug (not direct cause by mx)

occur with increased number of mx given to pt

100,000 deaths/year

2 million injuries/year

healthcare cost→up to $4 billion

Adverse Drug Reaction (ADR)

harm is directly caused by a drug under appropriate use (direct cause by mx)

-provider error
-non-adherence
-incorrect dosages

Levels of Warnings+Precautions

post-marketing surveillance

adverse events:
-clinical trial recording+results

warnings+precautions

black box warning

Allergic Reactions

medication→stimulation of the immune system→adverse reaction

1. mx acts as antigen→elicits immune response

2. mx directly interacts with immune receptors→activation of specific immune cells

common sx:

• hives

• itching of skin/eyes

• skin rash

• swelling:
  -lips
  -tongue
  -face

• wheezing

anaphylaxis sx:

• difficulty breathing 

• confusion

• dizziness

• fainting

• lightheadedness

• hives over different parts of body

• nausea

• vomiting

• rapid pulse

• palpitations

Joint Commission Do Not Use Abbreviations List

Challenges of Prescribing for Older Adults+Causes of Non-Adherence

multiple medical dx:

• nearly 80% medicare users have 2+ chronic conditions

• more than 60%+ medicare users have at least 3 chronic conditions

multiple mx/”polypharmacy”:

• ADR→30% of hospital admissions 65+ y/o

multiple prescribers

different metabolisms+responses

cost:

• up to 40% of older adults take mx improperly

self-medication issues:

• supplements

• herbals

• OTC mx

• drugs

• alcohol

• caffeine

• etc.

physical+mental changes:

• contributing lifestyle factors

Changes in ADME

absorption:

• not affected by normal aging

• food/drug interactions:
  -antacids
  -iron

• disease:
  -lack of intrinsic factor (B12 absorption)
  -delayed gastric emptying
  -increase gastric pH

distribution:

• less water→decreased volume of distribution→high concentration of water-soluble mx

• more fat→increased volume of distribution→longer action of fat-soluble drugs (increased half-life)

• lower serum proteins (ex: albumin)→increases concentration of unbound (free/active) form of mx
  -ex: warfarin
  -phenytoin

metabolism:

• slowed:
  -phase 1
  -CYP450 reactions
  -oxidation
  -reduction
  -dealkylation

• altered metabolism→increased warfarin+phenytoin levels

• unchanged phase 2 reactions
  -conjugation
  -acetylation
  -methylation

• increased number of mx→increased risk of drug-drug interactions

elimination:

hepatic:

• decreased size→slowed clearance of mx→reduced dosage required

• decreased hepatic blood flow→slowed clearance of mx→reduced dosage required

renal:

• reduced renal clearance

• decreased lean body mass→serum creatinine not reliable for renal clearance

active mx metabolites accumulation:

• prolonged tx action

• adverse effects

AGS Beers Criteria (General)

reduce exposure to inappropriate mx→improve care of older adults

“do not use” list

identifies mx that risks outweigh benefits

not to be used as definite tx guide

emphasizes importance of team approach to mx tx+NP tx

Beers Criteria: Anticholinergic Mx

AE: more pronounced in old people

• confusion

• drowsiness

• blurred vision

• difficulty urinating

• dry mouth

• constipation

decreased clearance with advanced age

tolerance develops when used as a hypnotic

severe allergic reaction tx→diphenhydramine

Beers Criteria: Cardiovascular Mx

alpha-1 blockers→orthostatic HTN+CNS effects

alpha antagonists

antiarrhythmic mx→replace with rate control

digoxin→decreased renal clearance

immediate release nifedipine

spironolactone→hyperkalemia risk

Beers Criteria: Benzodiazepenes

increased sensitivity:

• long-acting→slowed metabolism

• similar neurocognitive effects to alcohol

increased risk of adverse clinical events:

• falls+fractures

• cognitive impairment

• delirium

avoid if possible→use lowest dose possible if necessary

mx:

short/intermediate-acting:

• alprazolam

• estazolam

• lorazepam

• oxazepam

• temazepam

• triazolam

long-acting:

• chlordiazepoxide (alone/+amitryptiline/clidinium)

• clonazepam

• clorazepate

• diazepam

• flurazepam

• quazepam

Beers Criteria: Sedative-Hypnotics

non-benzodiazepene hypnotics:

• eszopiclone

• zolpidem

• zaleplon

adverse events similar to benzodiazepenes:

• increased risk of delirium/falls/fractures

• increased ED visits/hospitalizations

• minimal improvement in sleep latency+duration

Beers Criteria: Antipsychotic Mx

1st generation/conventional:

• haloperidol

• prochlorperazine

2nd generation/atypical:

• risperdone

• quetiapine

• olanzepine

• ziprasidone

• aripiprazole

avoid→associated with dementia behavioral problems

use NP tx

only use if threat to self/others

AE: arrhythmias→QT prolongation
abnormal movements:
-parkinson’s
-tardive dyskinesia

FDA black box warning:

• CV events (HF/sudden cardiac death syndrome)→increased risk of death

• infections (pneumonia)

Beers Criteria: Pain Mx

non-COX-selective NSAIDS:

• GI bleeding

• peptic ulcer dx

• avoid chronic use

indomethacin+ketorolac:

• higher risk of GI sx

• higher risk of renal sx

• higher risk of CNS sx

merperidine:

• neurotoxicity

• safer alternatives available

Prescribing in Elderly: Initiation of Therapy

review risks+benefits of adding a mx→explore NP tx first

choose one mx→tx 2 coexisting problems

choose mx with least daily required doses

start with lowest dose possible→titrate up slowly

cost considerations→may deter compliance

• brand name

• generic

Prescribing in Elderly: Ongoing Pharmacotherapy Assessment

multiple chronic dx+multiple mx→schedule routine follow up examinations

reduce dose/discontinue mxs→avoid polypharmacy

advise pts to→bring all mxs to each office visit→for review

doccx all current mx+doses accurately

review mx added by other practitioners/specialists→inform them of changes made primary provider

mx→schedule blood tests regularly

• diruetics

• ACE inhibitors

• antiseizure mx

• anticoagulants

• antiarrhythmics

• digitalis

Prescribing in Elderly: Pt Support

give written list+instructions to pt for mx to take→after each office visit

provide written mx instruction+changes in large print→easily understood

explain+document generic+brand name of mx→avoids pt confusion

explain+doccument reason for each mx

recommend/provide→mx planners or weekly/daily dosage containers

• improve compliance

• promote safe mx administration

Reporting+Response of Adverse Events

FDA Adverse Event Monitoring System (AEMS)
-formerly: FAERS

response to reported errors

• phase IV clinical trials

• educate health professionals+pts

• “dear doctor” letter→tells doctor risks/AEs

• revise package labeling

• black box warning→severe warning on rx label

require→Risk Evaluation and Mitigation Strategy (REMS)

• create/require pt mx guides

• restricted use/distribution programs
  -ex: isotretinoin/accutane→iPLEDGE Program

• most severe→withdraw mx from market