Introduction & Application of Clinical Pharmacology

(aka Bring the Pain)

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Dept of Family Medicine

Bruyere Academic Family Health Teamrhalil@bruyere.org

(On Twitter: @RolandHalil)

November, 2014

Objectives

• Review the basic parameters of pharmacology including:1. Mechanism of action2. Pharmacokinetics (PK)3. Pharmacodynamics (PD)

• Highlight various parameters that hold clinical utility in a primary care setting

• Outline a process for incorporating new pharmacology knowledge to guide therapeutic choices.

Clinical Utility of Pharmacology

• Is this an irrational drug combination?• Do I need a loading dose?• How long till this drug reaches steady state?• How do I manage drug interactions?• Will genetics affect my delivery of care?• How long till this drug is out of my system?• How do I manage this overdose?

Pharmacology & Therapeutics

• Therapeutics require a foundation of pharmacology.– Provides a mechanistic understanding of why

therapeutics work– Highlights most of the potential toxicities to your

patients.– Provides greater comfort in prescribing beyond first

line choices from guidelines– Avoids the trap of pattern recognition as a basis for

prescribing

Approach to Pharmacology

1. Learn the drug classes and mechanisms of action in your personal formulary

2. Learn (generally) if drugs are cleared via kidney or liver

– If hepatically cleared – ?Via P450 enzymes or not?• If so, use Lexi-Interact to check for drug interactions.• N.B. There are too many to know without software!

3. Learn (generally) if drugs have a lot of drug interactions or not

– Think of potential drug interactions via the 1 dynamic and 4 kinetic mechanisms

1) Efficacy 2) Toxicity

3) Cost & 4) Convenience(Affects compliance)

Prioritize: 1. Type of harm2. Quantity of harm3. Quality of evidence4. Time to harm

Prioritize: 1. Type of benefit2. Quantity of benefit 3. Quality of evidence4. Time to benefit

Approach to TherapeuticsFour Steps of Rational Prescribing

Pharmacology

• A science dealing with the fate of drugs in the body and their biological actions within the body

Drug

• Any substance that has the effect of altering normal body functions.

• The alteration can be beneficial or not!

• “Everything is a poison...the dose differentiates a poison from a remedy.” – Paracelsus

• Eg. Botulin toxin• Eg. Oxygen

Pharmacology

Pharmacokinetics

• What the body does to the drug

Pharmacodynamics

• What the drug does to the body

Pharmacodynamics

What the drug does to the body

1 – lipid-soluble drug crosses the membrane and acts on an intracellular receptor

2 – the drug binds a transmembrane protein, activating an enzymatic activity of its cytoplasmic domain

3 – the drug binds a transmembrane receptor bound to a protein TK, which it activates

4 – the drug binds to, and directly regulates the opening of, an ion channel

5 – the drug binds to a cell-surface receptor linked to an effector enzyme by a G protein

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Receptors

Receptors• With few exceptions, drugs act on target proteins:

– Receptors– Enzymes– Carriers– Ion channels.

• Specificity is reciprocal: – Drugs bind only certain targets– Targets recognize only certain drugs

• N.B. No drugs are completely specific in their actions.– Often, increasing the dose will cause it to lose specificity,

affecting other targets, sometimes leading to side effects.

Drug-Receptor Interaction• Receptor binding is only one step• Receptor activation must also occur

– Agonists – strongly activate receptors with high efficacy– Partial agonists – weakly activate receptors in isolation

• They can also block (antagonize) full agonists by competition in their presence

– Antagonists – bind, but do not activate receptors• This blocks agonists from activating receptors• Reversible (competitive) or • Irreversible (non-competititive)

Dose response curve

A rectangular hyperbola on a linear

scale

Dose response curve (log scale)

A sigmoid curve on a logarithmic

scale

Competitive Antagonist (= Reversible)

• Right shift of the D-R curve.

• Association & dissociation of antagonists with the receptors occurs quickly

• A new equilibrium is found at a higher concentration

Eg. Beta-agonists and beta-blockers

Non-Competitive Antagonist(= Irreversible)

• The antagonist dissociates slowly, (or not at all), from the receptors

• Less than maximal effect is achieved.

• Less common than reversible type

• Eg. ASA & platelet COX enzymes

Therapeutic Drug Monitoring (TDM)

Drug excess (side effects)

therapeutic range

lack of effect

time

Dru

g C

on

cen

trati

on

On a concentration-time curve it looks sort of like this:

Pharmacodynamics

• Once you understand the molecular dynamics, you can better apply the physiological dynamics in practice!

Case example 1• 75 y.o. female patient presents to your office

with her son in an altered state of consciousness and PMHx of cognitive impairement.

• Her meds include:– Amitriptyline 100mg qhs for sleep– Oxybutynin 5mg qhs for urinary incontinence– Haloperidol 4mg qd for symptoms of dementia

• She recently started:– Chlorpheniramine 2mg qd for allergies

Case 1• Why is her consciousness altered?

– Additive anticholinergic side effects from all her meds = additive anticholinergic delirium

Pharmacodynamic Drug Interactions

N.B.• This is the most common type of drug

interaction!

• Additive, synergistic or antagonistic actions

Case example 2• 65y.o male patient with pneumonia was given

a Rx for Levofloxacin 500mg once daily for 10 days by his family doctor.

• You notice that his renal function is only 25mL/min.

• Should you give: – 500mg q48h OR– 250mg daily ?

Case 2

• Give 500mg q48hours.• Levofloxacin shows

“concentration-dependant killing” dynamics.– The higher the peak serum

concentration, the better the killing of bacteria

– A 500mg dose ensures the peak is kept high.

– A q48h frequency ensures it doesn’t over-accumulate.

24h 48h

Case example 3

• ID: 69 y.o. woman• CC: muscle cramps, red urine, fatigue• HPI: onset over the past 3 days, recently

started on new drug for cholesterol (fenofibrate)

• PMHx: MI, CHF, HTN, DM2, hypothyroidism, COPD, atrial fibrillation

• Meds:– Acetylsalicylic acid– Warfarin– Metoprolol– Amlodipine– Lisinopril– Furosemide– Nitroglycerin– Rosuvastatin– Metformin– Glyburide– Levothyroxine– Salbutamol– Tiatropium

Case 3• Exemplifies the importance of looking at temporal

correlations.– With ++ meds, the recent start of her fibrate is a red flag– Fibrate + statin = additive risk of rhabdomyolysis

• Consider ‘Challenge / Re-challenge’ tests to differentiate correlations from causations (on/off/on)– IF the consequences of the trial are small!

• Also exemplifies the risks of Prescribing Cascades– Unrecognized interactions result in new drugs to fix problems

that daisy-chain into a long lists of meds!– As many as 20 drugs can be seen over time!

Pharmacodynamics Summary

• On molecular level: – Drugs bind with receptors with a certain affinity– Once bound they might activate the receptor with a

certain efficacy• Maximal effect = full agonist• Sub-maxmial effect = partial agonist• No effect = antagonist

• On physiological level:– Drugs may interact additively, synergistically or

antagonistically each other or with body systems

Pharmacokinetics

What the body does to the drug

Pharmacokinetics

• Pharmacokinetics deals with the ADME of drugs:– Absorption– Distribution– Metabolism – Elimination

Pharmacokinetics

Absorption

Drug absorption and distributionRang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Pharmacokinetics

Oral Absorption• Dependent on many factors:

– Physicochemical factors • i.e. chelation (eg. Divalent cations (eg. Mg2+, Fe3+, Ca2+ etc) plus L-T4)

– Ionized and unionized states• Molecular pKa of weak acids and bases ~ dependent on pH• Strong acids and bases ~ poorly absorbed

– Gut motility• Slower GI usually = slower drug absorption • (extreme diarrhea can also reduce drug absorption)

– Particle size and formulation• Eg. 5-ASA and colonic site of action

– Passive vs Active absorption– Splanchnic blood flow

• Enhanced after a meal (Eg. propranolol, a lipophilic beta-blocker)

– Enterohepatic circulation

Pharmacokinetics

Absorption

Pharmacokinetics – Absorption

“F” = Bioavailability• Definition:

– “The Fraction of unchanged drug reaching the systemic circulation following administration by any route”

• F = 1.0 for IV drugs (100%) • Mathematically, the area under the blood

concentration-time curve (AUC) measures “F”– F is estimated as AUCoral /AUCintravenous

• F < 1 due to:– incomplete extent of absorption & – first pass elimination.

Pharmacokinetics – Absorption

1st Pass Elimination• Reduced bioavailability is caused by:

– liver metabolism (major)– gut metabolism (minor)

– liver excretion into the bile (minor)

• The effect of first-pass hepatic elimination on bioavailability is expressed as the Extraction Ratio (ER)– Drugs with high extraction ratios will show marked

variations in bioavailability between subjects because of differences in hepatic function and blood flow.

• Eg. isoniazid, morphine, propranolol, verapamil

Case example• 75 yo male with 4 days of new onset urinary

frequency and dysuria. Urine is cloudy and smelly. Patient has had hemodynamic instability and altered cognition for the past 1.5 days.

• Urine culture & sensitivity shows Pseudomonas aeruginosa sensitive only to ciprofloxacin.– Dx: Urinary Tract Infection (UTI), possible urosepsis– Rx: Cipro - IV or PO? Dose?

Case

• Hemodynamic instability, delirium, possible systemic infection, elderly patient – = intravenous (IV) dose to start– 400mg IV q12h

• 48h later, patient is feeling much better, stable, afebrile. – Step down to oral (PO) therapy– Bioavailability of Cipro?

• Where can I find it?• Dose = ?

Case

• F = 80%– 400mg IV is 80% of:– 500mg PO q12h

• complete 7-14 day course

• Pt returns 2 days later with the same symptoms and hemodynamic instability.

• Family states he has been taking his Cipro as directed every day with breakfast and supper.– Breakfast = Lucky Charms™– Lunch = steak & eggs, with salsa piquante

• Milk of Magnesia PRN– Supper = Grilled Cheese and yogurt cup

What happened?

Case

Absorption Interaction!• Chelation of ciprofloxacin by calcium ions

– Breakfast: milk– Supper: cheese and yogurt

• Any effect from lunchtime Milk of Magnesia?– No: antibiotic and Mg2+ are not in stomach at the same

time. – Chelation interaction is one of physical adsorption

• Solution: take on empty stomach or separate administration from interacting food/drugs by 2 hrs.

PK – Absorption InteractionsChelation

1. Fluoroquinolones or Tetracyclines plus minerals [Minerals = calcium (Ca2+) , magnesium (Mg2+) , iron (Fe3+) , aluminum (Al3+)] [Almost all buffering antacids (i.e. TUMS, Gaviscon, Milk of Magnesia, Rolaids, etc.), as well as multivitamins, iron tabs etc.]

– Risk of treatment failure!

2. Bisphosphonates plus minerals– Risk of osteoporotic fracture

3. Phenytoin plus minerals– Potential loss of seizure control

Separate administration by 2 hours

PK – Absorption Interactions

• Alteration of gastric pH– Increased pH

• Eg. Long term PPI use– Reduced absorption of B12, iron & Ca2+ = anemia & osteoporosis

• Eg. Iron / Ketoconazole / Vit B12 absorption is reduced– Administer with OJ or Coca-cola

• Alteration of GI motility– Decreased motility

• Eg. Decreased absorption of Levodopa– Increased metabolism at intestinal brush border

– Increased motility• Eg. Decreased absorption of Digoxin

PK – AbsorptionSummary

• Many factors involved in absorption• All can affect bioavailability

– None as much as first pass metabolism– N.B. Check bioavailability whenever changing

route of administration • (PO to IV or vice versa)

• Clinically important interactions often involve chelation.– Separate administration by 2 hours

• Rarely affected by changes in GI motility or gut pH

Pharmacokinetics

Distribution• To various body stores (reservoirs)• Volume of distribution (Vd)(in Litres)

– The measure of the apparent space in the body available to contain the drug

– Vd relates the amount of drug in the body to the concentration of drug in blood or plasma

– Not a physiological space (Abstract quantity)• Fat stores• Plasma proteins (eg. Albumin)• Tissue proteins• Bones etc etc

• Altered in geriatrics

Vd (L) = Amount in body (mg) . Concentration in blood (mg/L)

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Oral vs IV DosingThe effect of slow drug absorption on plasma drug concentration.

Dose AccumulationRepeated IV Doses

Figure 10.1CRang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Time to Steady State

Basic & clinical pharmacology [electronic resource] / edited by Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor.

Time to Steady State & Time to elimination

IV Infusion

1 t ½ = 50%

2 t ½ = 75%

3 t ½ = 87.5%

4 t ½ = 93.75%

5 t ½ = 96.875%

Figure 10.1ARang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Figure 10.2Rang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

1 t ½ = 50%

2 t ½ = 75%

3 t ½ = 87.5%

4 t ½ = 93.75%

5 t ½ = 96.875%

Time to Steady State & Time to elimination

Loading DoseDL (mg) = Target Concentration (mg/L) x Vd (L)

• Sometimes needed if the time to steady state takes too long, due to:– Long half-life

• Eg. Amiodarone (anti-arrhythmic) – t½ ~ 50 days!

OR

– Risk from sub-therapeutic effect is high• Eg. Clopidogrel (anti-platelet) – immediately post-stent

How does this relate to missed doses?

Eg. A patient receives a drug every 12 hours. The drug has a half-life of ~5.7 hour

The patient misses a dose but remembers half way through the interval.

Should the patient:1) Take the next scheduled dose

(forget missed dose)or …

2) Take the missed dose immediately and

resume normal dosingor …

3) Take two doses at the next scheduled time?

Option 1: Take the next scheduled dose (forget missed dose)

Curve will resemble the accumulation after 1st or 2nd

dose.

Same accumulation up to steady

state

Option 2: Take the missed dose immediately (in the 6th hour) and resume normal dosing (q12h)

Some extra accumulation and then drifts back to steady

state.

N.B. More extra

accumulation vs option 2

Still drifts back down to steady state!

Option 3: Take both doses next time it is due

Loading Dose

• Time to steady state is NOT faster! – Still 3 to 5 half-lives!– Without loading dose:

• Serum concentration drifts up to steady state (accumulates)

– With loading dose: • Serum concentration drifts down to steady state

Drug excess (side effects)

therapeutic range

lack of effect

time

Dru

g C

on

cen

trati

on

• Clinical scenario will guide which is needed- Which is more dangerous to the patient?

- Risk of poor outcomes with sub-therapeutic initial concentration? OR

- Risk of side effects with supra-therapeutic initial concentration?

1st Order Kinetics

• Dose accumulation (and decay) is exponential– “1st order kinetics”– Almost all meds follow this process

1st order Kinetics

Exponential decay

Linear on log scaleSlope = t½

Figure 10.1 Rang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Zero order kineticsLinear decay (on linear scale)

(velocity but no acceleration!)

Figure 10.3 Rang, H P. et al.- Rang and Dale's Pharmacology . Copyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Alcohol and Phenytoin (anti-epileptic) are the most common examples of drugs with zero order elimination.

AKA:- Enzyme saturation

kinetics- Non-linear kinetics- Michaelis-Menten

kinetics- Capacity-limited kinetics

1st order & Zero order kinetics

With zero order drugs, “small changes in dose can result in large changes in serum concentrations.”

Case example

• 70 yo female patient with new, symptomatic atrial fibrillation, failed electrical cardioversion and cannot tolerate her palpitations despite good heart rate control with a beta-blocker. – Cardiology starts Amiodarone (anti-arrhythmic)– t½ of Amio ~ 50 days. – What to do?

Case

• Time to steady state will be 150 - 250 days away!• Loading dose is needed:

– 200-400mg daily till achieve 10g total• Then 100-200mg daily thereafter• (Higher doses result in too many toxicities)

Case example 2• 70yo male with new myocardial infarction –

underwent stent implantation: will need antiplatelet therapy to prevent restenosis of the coronary artery– ASA 81mg plus– Clopidogrel 75mg daily maintenance dose OR– Clopidogrel 300mg loading dose?

• After a single, 300 mg loading dose:– Platelet inhibition of 40% - 50% is observed 2 - 5 hours.

• After repeat dosing of 75mg daily:– Platelet inhibition of 40% - 50% is observed in 3 - 7 days

Savcic M, et al. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost. 1999;25 Suppl 2:15-9.

Case example 3

• You are a PGY1 on a general medicine ward. Your staff physician phones you to start an ACE inhibitor (Ramipril 5mg daily) for your patient’s BP and then hangs up. (so rude!) – You know it could cause acute renal failure and

hyperkalemia and requires monitoring of SCr and K+– When you do you perform the routine monitoring

blood work?• In 3 to 5 half-lives! ~ 3-5 days • In family practice: ~ 1 week

• Displacement Reaction – (from protein binding sites)– Rarely clinically significant – Often need:

• Highly bound drug – (98% bound to 96% bound = 100% increase in free

concentration)

• PLUS, inhibition of metabolism (or elimination) to allow enough time for these effects before redistribution to a new steady state.

Pharmacokinetics

Distribution – Drug Interactions

Pharmacokinetics

Distribution – Drug Interactions• Eg. Warfarin + SMX/TMP (Septra®)

– Displacement of warfarin off protein binding sites• (plus inhibition of metabolism and Vitamin K synthesis by gut flora)

• Eg. Phenytoin + Valproic acid– Displacement of phenytoin off binding sites

• (plus inhibition of metabolism and zero order kinetics (enzyme saturation kinetics) of

phenytoin)

Hogan M.J. et al. DNS Aug. 30, 1999 http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_55693815/pg_4 Accessed Apr 18/12

PK – Distribution - Summary• Volume of distribution reminds us that drugs can

concentrate in many body spaces– N.B. Drugs bound to proteins are not active!

• Repeated dosing will result in accumulation until a steady state is achieved (1st order kinetics)– In 3 to 5 half-lives – (same as 1st order elimination)

• This knowledge will help you monitor the efficacy and safety of meds you prescribe!

• A loading dose will not achieve steady state faster, only prevent sub-therapeutic concentrations while it is being achieved

• Few clinically relevant drug interactions here

Pharmacokinetics

Metabolism• Hepatic

– Also intestinal, plasma, pulmonary etc. (minor)• Phase I metabolism

– Catabolic – Oxidation, reduction, hydrolysis reactions

• Render molecules more polar – easier to eliminate• Eg. Cytochrome P450’s

• Phase II metabolism– Anabolic – conjugation reactions – (rendering inactive)

• Eg. Glucuronidation, acetylation• Some conjugated products are excreted via bile, are reactivated

in the intestine and then reabsorbed (‘enterohepatic circulation’).

Clearance• The measure of the ability of the body to eliminate a

drug• The factor that predicts the rate of elimination in

relation to the drug concentration– CL = rate of elimination ÷ concentration– CLTotal = CLLiver + CLRenal + CLOther

• Affected by: – physiologic processes

• (eg, maturation of organ function in infants)– pathologic processes

• (eg, heart failure, renal failure)• N.B. Also affects volume of distribution, (the measure of the

apparent space in the body available to contain the drug.)

Prodrug

• An inactive precursor chemical that is readily absorbed and distributed and then converted to the active drug by biologic processes.

• Eg. Clopidogrel – Loading dose = 300mg– Maintenance dose = 75mg daily– Prodrug to active form

Pharmacogenetics / Pharmacogenomics

PK – Metabolism Interactions

• Metabolism occurs in many places– Skin, lung, intestine, serum, kidney, liver– Most metabolism occurs in the liver

• Few interactions with non-oxidative metabolism – (ubiquitous enzymes)

– Not everything is P450• P-glycoprotein poorly understood so far

– Genetic variability becoming more important• Isoniazid, codeine

PK – Metabolism Interactions

• Cytochrome P450 isoforms – so many!• Family - Subfamily - Genotype (eg. 2-C-19) (18) (42) (60)

– Substrates, inhibitors, & inducers for each isoform!– 3A4 - most common

• Inducers:

• Ask: Time to effect?– ~ 2 weeks to kick in– ~ 2 weeks to fade out

• Substrates:

– Ask: Consequences of sub-therapeutic doses?

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism Interactions

• Inducers of 3A4:– Rifampin / Rifabutin– Efavirenz /

Nevirapine– Glucocorticoids– Phenytoin– Carbamazepine– Barbiturates– St. John's Wort– Pioglitazone

(Actos™)etc

• Substrates of 3A4:– Clarithro / Erythromycin– Alpraz / Diaz / Midazolam– CSA / Tacrolimus– Indinavir / Nelfinavir

Ritonavir / Saquinavir– Amlodipine / Felodipine

Nifedipine / Verap / Dilt– Atorva / Simvastatin– Estrogen– Carbamazepine

etc

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism Interactions

PK – Metabolism InteractionsClinical Scenarios

• 50 y.o. male - PMHx of HTN, MI x3, COPD on:– Ramipril 10mg daily– HCTZ 25mg qAM – Amlodipine 10mg daily

– BP control borderline/high

– COPD exacerbation• Rx: PREDNISONE 25mg

qAM for 7 days

• Issues?» NO!

• 50 y.o. female – PMHx of DM2, renal transplant on:– Ramipril 10mg daily– Amlodipine 10mg daily– Tacrolimus 10mg BID– Cyclosporine 15mg BID

– Endo Rx: ACTOS 30mg qd

– N.D.: St John’s Wort i qd

• Issues?» YES!

• Inducers of 1A2:

– Nicotine

– Smoking cessation…

• Substrates of 1A2:

– Caffeine

– Sweaty, anxious, nauseous, sleepless…

– Nicotine withdrawal?– No! Caffeine

overdose!

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism InteractionsPearl

• Inhibitors:

• Ask: Time to effect?– Immediate effect– Hours/days to fade

• Substrates:

– Ask: Consequences of supra-therapeutic doses?

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism Interactions

• Inhibitors of 3A4:– Clarithro / Erythro– Ciprofloxacin – Fluco / Itra /

Ketoconazole

– Grapefruit juice – Amiodarone – Indinavir / Nelfinavir

Ritonavir /Saquinavir Delaviridine

– Verapamil / Diltiazem – Cimetidine

• Substrates of 3A4:– Alpraz / Diaz / Midazolam– Cyclosporine / Tacrolimus– Amlodipine / Felodipine

Nifedipine / Verap / Dilt– Atorva / Simvastatin– Clarithro / Erythromycin– Indinavir / Nelfinavir

Ritonavir / Saquinavir– Estrogen– Carbamazepine

etc

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism Interactions

PK – Metabolism InteractionsClinical Scenarios

• 60 y.o. female – PMHx of HTN on: – Nifedipine XL 60mg qd– BP: 105/60

– Enjoys a fresh grapefruit when in season.

• Issues?» No!

• 60 y.o. male – PMHx of NSTEMI, CHF on:– Atorvastatin 80mg qd– Ramipril 10mg qd– ASA 81mg qd– Bisoprolol 5mg qd

– New onset Afib – Cardio Rx: Amiodarone 200mg daily

• Issues?» Yes, two!

• Inhibitor of 2C19:

– Omeprazole• ?All PPI’s

– Time to effect is immediate

• Substrates of 2C19:

– Clopidogrel

– Lack of metabolism from pro-drug to active form

– Sub-therapeutic effect!

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – Metabolism InteractionsPearl

PK – Metabolism InteractionsSummary

• Inducers– Remember: time to effect ~

2 weeks • Longer treatments will

result in more significant interactions

• Harder to see the temporal correlation

– Lower doses of affected substrate need to be clinically relevant

• Inhibitors– Remember: time to effect

is immediate• Shorter treatments will

result in more significant interactions

• N.B. Drugs with long half-lives will take longer to show their effect!

– Higher doses of affected substrate need to be clinically relevant

PK – Metabolism - Summary

• Usually hepatic – very complex– Phase I & II

• Affects bioavailability (F)– F affected by Clearance, which is affected by blood flow

• Many, many potential drug interactions– P450 3A4 most common– Both inducers & inhibitors of substrate metabolism are

possible• Timeline to effect is most important!

Pharmacokinetics

Elimination• Hepatic or Renal

– (Rarely pulmonary for anaesthetic gases)– (Rarely via milk or other secretions)

• Usually a logarithmic process – (exponential decay)

• Elimination Rate Constant: ke • Half-Life: t½

– Determined by clearance (CL) and volume of distribution (VD)

1st order Kinetics

Exponential decay

Linear on log scaleSlope = t½

Figure 10.1 Rang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

Elimination of drugs by the kidney • Most drugs, unless highly bound to plasma

protein, cross the glomerular filter freely.• Many drugs, especially weak acids and weak

bases, are actively secreted into the renal tubule and thus more rapidly excreted.• Lipid-soluble drugs are passively reabsorbed by

diffusion across the tubule, so are not efficiently excreted in the urine.

• Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa.

Rang, H P. et al.- Rang and Dale's PharmacologyCopyright © 2012, © 2012, Elsevier Inc. All rights reserved.

• Rarely significant, but…– Enterohepatic circulation:

• Bile acid sequestrants + Warfarin or L-T4 or Estrogen

– Alteration in urine pH• Ion trapping

– Eg. Management of ASA overdose with bicarb– Eg. Methamphetamine overdose with Vit C / NH4Cl

– Competition for tubular transporters• Anion: Probenecid + beta-lactams (osteomyelitis)• Cation: Itraconazole /cimetidine + digoxin / quinidine

PK – Excretion Interactions

Case example• 55 year old male patient is highly distraught

because his citalopram (SSRI antidepressant) caused him terrible side effects and he is changing to a new anti-depressant and wants to know when the citalopram will be out of his system.

• You reassure him that the offending substance will be out of his system in:– Half life (t½) ~ 35 hours– 3 - 5 half-lives = 105 – 175hrs = 4 - 7 days

Summary

Pharmacology & Therapeutics

• Therapeutics require a foundation of pharmacology.– Provides a mechanistic understanding of why

therapeutics work– Highlights most of the potential toxicities to your

patients.– Provides greater comfort in prescribing beyond first

line choices from guidelines– Avoids the trap of pattern recognition as a basis for

prescribing

Summary

Approach to Pharmacology

1. Learn the drug classes and mechanisms of action in your personal formulary

2. Learn (generally) if drugs are cleared via kidney or liver

– If hepatically cleared – ?Via P450 enzymes or not?• If so, use Lexi-Interact to check for drug interactions.• N.B. There are too many to know without software!

3. Learn (generally) if drugs have a lot of drug interactions or not

– Think of potential drug interactions via the 1 dynamic and 4 kinetic mechanisms

1) Efficacy 2) Toxicity

3) Cost & 4) Convenience(Affects compliance)

Prioritize: 1. Type of harm2. Quantity of harm3. Quality of evidence4. Time to harm

Prioritize: 1. Type of benefit2. Quantity of benefit 3. Quality of evidence4. Time to benefit

Approach to TherapeuticsFour Steps of Rational Prescribing

Questions?

Pharmacology• Pharmacokinetics

– A• 1st pass, F, pKa• Eg. Drug interactions, chelation, pH,

– D• Vd, SS, Ld, Md• Eg. Drug interactions: warfarin septra, PHE, • Eg. Time to ss – 3-5 t ½’s

– M• Prodrug, CL, phase I & II, pharmacogenetics, substrates, inhibitors, inducers• Eg. Drug interactions P450

– E• Half-life, ke, 1st order, zero order • Eg. Ion trapping in OD• Eg. Time to be out of the system 3-5 t ½ ‘s

• Pharmacodynamics– Dose response curves, rec theory, agonist, partial agonists, reversible and irreversible

antagonists• Eg. Asa irrev inh of COX in platelets• Eg. Drug interactions – additive, synergistic, antagonistic effects