Aug. 26: Pharmacokinetics Dynamics

Case Study: Ron Gold

Medications – General Concerns:

  • Apixaban: Significant bleeding risk, especially post-op. Avoid high-impact or aggressive manual therapy. Monitor for bruising or hematomas.

  • Celebrex & NSAIDs: Can increase cardiovascular risk, may affect renal function. Watch for swelling in lower extremities.

  • Atenolol & Ramipril: Could cause hypotension, fatigue, or dizziness during exercise. BP and HR should be monitored during PT sessions.

  • Statins (Pravastatin): Possible muscle aches or weakness that could affect rehab progress.

PT-Specific Concerns:

  • Bleeding risk: Avoid high-risk activities like aggressive joint mobilizations or balance exercises that could lead to falls.

  • Cardiovascular risk: SOB on exertion could be related to beta-blocker blunted HR response, hypertension, or deconditioning. Monitor vitals carefully.

  • Pain management: Pain is moderate (6/10); ensure pain is controlled enough for participation without over-reliance on acetaminophen or NSAIDs.

  • Function: Lives in a 2-story house; stair training is essential but should be approached cautiously due to pain, stiffness, and SOB.

Pharmacokinetics- Continued

Metabolism and Elimination (excretion)

  • effectively removes drug from body.

  • drug pass thru liver: metabolically changed to inactive form

  • drug is filtered into urine by the kidneys during the process of elimination.

  1. Amount of drug that enters bloodstream is determined by what process(s)?

    1. Absorption

  2. Amount of drug that arrives at site of action (plasma: inside and outside cells) is determined by what process?

    1. Distribution

  3. How rapidly drug is removed from the body is determined by:

    1. Metabolism and Excretion

Metabolism/Biotransformation

Two Effects

  1. Transformation to less active metabolite

  2. Enhancement of solubility

_LIVER_ is primary site for metabolism

  • also: intetstinal tract, kidney, lungs, circulating enzymes in plasma, skin

Many of our patients have liver and kidney disease!!!

Liver Disease:

- Slows metabolism of many drugs

- Prolongs effects of many drugs

- Dosage may need to be decreased

Metabolism:

Metabolism: total of all chemical reactions in body drug metabolism is chemical conversion of drugs into water soluble compounds that can be excreted by the body

Biotransformation: individual chemical reactions of metabolism

Chemical conversion of drugs from one form to another that results in increased or decreased activity

Prodrugs

  • drugs that require ,etabolism to make them active (anticipate drug going to liver and becoming active at that point)

  • designed to overcome pharmaceutical, pharmacokinetic, and/or pharmacodynamic challenges

  • drug is broken down by chemical reactions of metabolism and produces more intense response than original drug

Ex. Sulfasalazine used for ulcerative colitis: metabolized by bacteria in colon

Enzyme Induction- Metabolism

  • prolonged use of certain drugs “induces” body to enzymatically destroy drugs more rapidly than expected decreased therapeutic effect

  • cigarette smoking, alcohol, toxins in environment also cause enzyme induction

Tolerance: need for increased drug dosages to produce sam effect

Patient develops tolerance- person craves drug and takes more to get same effect→ addiction

First-Pass Effect-Metabolsim

Affects only drugs administered _Enteral_.

Drugs absorbed into hepatic portal circulation must pass through liver to reach systemic circulation.

Metabolism of drugs by liver occurs before drug reaches systemic circulation-** may reduce bioavailability of the drug significantly

Factors that Affect Metabolsim of Drugs

Patients differ in how effectively they metabolize enzymes.

  • Age

  • Kidney and liver disease-lose 1%/year from age 25 yo

  • Genetics

  • Gender

Some patients metabolize drugs very slowly; others, very quickly

Excretion

_Kidneys_is primary organ of drug elimination

Role: remove all non-natural and harmful agents in blood while maintaining a balance of other natural substances.

Drugs can be excreted in active or inactive form

Other minor systems: lungs (inhaled meds), skin, GI- bile (feces), breast milk (drugs may be dangerous for infants)

  • Kidney damage can:

    • significantly prolong drug action

    • a common cause of adverse reactions

Drug Elimination Rates

Affects dosage amount and duration of action.

  1. What will happen if drug is administered faster than it is eliminated?

    1. Accumulation of drug

  2. What if drug is eliminated faster than it is administered?

    1. Not enough of drug, WONT FEEL AFFECTS

Excretion

Drug Elimination can be described in 2 ways

  1. Clearance

  2. Half-life

Clearance (CL): volume of plasma that is completely cleared of the drug per unit of time (ml/min)

  • predicts rate of elimination of drug in relation to its blood serum concentration

Important to know time of clearance if person has allergic reaction- may need to medically manage

Half-Life (t1/2)

t1/2: time required for plasma concentration of drug to reduce 50% (EX: every 2 hrs, a drug decreases 50%, etc)

  • used to ensure max therapeutic dosages are administered

  • larger half live value, longer it takes for drug to be eliminated

With liver and kiidney disease- the expected t1/2 is prolonged

Steady State

When quantity of medication being administered at constant dose and constant dosing interval = amount being eliminated

  • takes 5x half-life to reach 100% of steady state

    • 5 x t1/2 = steady state

  • Long half-life allows longer dosing intervals as drug stays in system longer

  • LOWER t1/2 = more frequent dosing

** LESS FREQUENT DOSING tends to → imrpoved compliance

Factors influencing drug response and metabolism

• Concentration of administered dose

• Frequency of drug dosing

• Food-drug interactions- grapefruit juice- inhibits enzymes that would normally destroy a drug in GI track- drug will have increased response→ toxicity

• Drug-drug interactions

• Absorption rate

• Metabolic rate (lower in children and geriatrics)

• Genetics

• Excretion rate

• Half-life of administered drug

• Changing medical conditions (liver/kidney disease)

• Body composition- obesity can alter distribution and metabolism

• Gender

• Diet

• Exercise can alter distribution and metabolism

• Smoking and alcohol can influence metabolism

Drug-Drug Interaction

When 2 or more drugs are present in circulation at the same time, they may interact and alter each others' effects and metabolism. Most are insignificant but can be dangerous

1. Drugs combined can be beneficial and cumulative leading to better results: HTN, cancer drugs, HAART- highly active antiretroviral therapy

2. Adverse effects: ex. combine 2 drugs→ take 2 CNS depressants→ barbiturates and alcohol-→ toxic and possibly lethal

3. Can cancel each other out; negating benefits of one or both meds

DEFINITIONS:

Absorption: one drug may affect another’s absorption by binding with it in the stomach. Antacid may bind with tetracycline in stomach and decrease antibiotic effect

Distribution: one drug may displace another from a protein binding site Coumadin and aspirin

Metabolism: one drug may increase or decrease the metabolism of another drug

Excretion: one drug may inhibit the active transport site for tubular secretion in kidney

  • drug may stay in body too long and lead to a toxic event

Drug Side Effects

Statistics: 750 people in US age 65 and > are hospitalized everyday due to adverse drug events

80% of adults age 70 and > experience at least 1 drug side effect in a 6-month period

Side effects that PTs may notice: sudden cognition or behavioral changes, drowsiness, muscle weakness, dizziness, light-headedness (orthostasis), balance disturbance with increased falls (patients may not realize impairment is due to drugs- think it is old age.

Biggest culprits: blood thinners, diabetes medications, opioids

  • Responsible for 60% of ER visits

OTC Drugs: Side Effects

Long term use of NSAIDs (ibuprofen and naproxen → stomach ulcers (peptic ulcer disease), high BP, and increase risk of heart attacks

Dietary supplements can cause side effects alone or in combination with other medications

Aging increases risk: older people typically take more medications so increases risk for increased side effects

  • Also: liver and kidneys become less efficient or diseased→ decreased metabolism of drugs and decreased elimination from body

Recommendations

How does individual know if new sign or symptom is caused by 1 drug, drug interaction between 2 or more drugs, underlying health condition, or another new medical issue?

  • Reduce likelihood of side effects:

    • take fewer drugs (if possible)

    • Simplify drug regimen: pill boxes, timers, special locked pill machines

    • Review drugs reg. w/ MD, including OTC/supps

    • Avoid prescribing cascades- new medicine is prescribed to 'treat' an adverse reaction to another drug in mistaken belief that a new medical condition requiring treatment has developed

Person may need a DRUG HOLIDAY- gradual reentry of necessary drugs

Compliance w/ Medication Regimens

  • Taking wrong medication

  • Taking wrong dose (too much/too little)

  • Taking medication off schedule (two together)

  • Skipping for cost savings

  • Cutting pills in half

  • Taking out of date medications

  • Not taking medications according to directions: with food, with water, with milk, on an empty stomach, sitting up

  • Not finishing prescription

Pharmacodynamics (how body respionds to drug)

  • Drugs exert effect by reaching plasma (target cells/ tissues) in sufficient concentration to have a desired effect (change function of cell in some way) but not so much to cause toxic effect

    Goals:

    1. help restore cells’ normal functions

    2. prevent disease process from occurring

RECEPTORS

specific components of cell which drugs bind to and reacts to produce

specific change in cell function

agonist: drug that facilitates the pharmacological response; facilitators of cellular action

antagonist temporarily blocks or depresses pharmacological response

  • Receptors may be located on the plasma membrane, or in the cytoplasm or nucleus of the cell

Drug-Receptor Interactions

Ability of drug to bind to any receptor is dependent on:

  • drug size and shape relative to configuration of the receptor.

  • electrostatic attraction between the drug and receptor

Drug Selectivity

Degree to which a drug has a selective effect on target tissue but not

others.

• Receptors are responsible for selectivity of drug’s action.

• function of drugs ability to bind with specific receptors on target tissue but not others, and not with receptors on other tissues

• Answers how drug knows where to go

• Drug receptor interaction is analogous to key fitting into lock

• Key in lock activates the lock

• Unlocking opens the door analogous to cell permeability

• May activate intracellular event like key starting an engine

Affinity, Efficacy, Potency

Affinity: ability to bind to receptor

  • attraction between drug and receptor

Efficacy: strength of response that can be generated by drug (ceiling effect)

Potency: more potent drug requires lower dose to achieve the same response as an alternative drug

Agonists and Antagonists

Agonist drugs

  • activate or stimulate their receptors

  • agonist must have both affinity and efficacy

Antagonist drugs

  • block access or attachment of body's natural agonists to receptors

  • Antagonists have affinity but no efficacy

Exceptions:

  • Some drugs produce effects without altering cellular function and without binding to a receptor.

  • Medications that act on foreign organisms:

    • Ex: antibiotics, antivirals, anti-fungals, antacids

RON GOLD:

  • OP= outpatient

  • s/p= status post

  • CC= chief complaint

  • PMH= Past Medical History

  • Hyperlipidemia= High Cholestrerol

  • GERD= Gastrol Esophageal Reflux Disease

Acetaminophen: Pain reliever (PRN = as needed)

  • po= per oral Q6H (every 6 hrs)

Celebrex: NSAID cox2 inhibitor

Apixaban: Blood Thinner

Ramipril: ACE inhibitor for High blood pressure

Atenolol: Beta blocker (lowers HR) for high blood pressure

Pravastatin: statin (lowers cholesterol)

  • statins can cause muscle aches and pains

Famotidine: reduce stomach acid (decreases acid reflux) (GERD is a fancy word for acid reflux)

Any concerns (PT intervention?

  • Lives alone, make sure he is safe

  • Address lifestyle, talk about things he probably shouldn’t be doing

  • why he got knee replaced; lifestyle

DVT (Deep Vein Thrombosis)= helps prevent blod clots

*****FOWLER POSITION (semi and high)

cephalic: head

caudal: tail