Anticoagulants

INDICATIONS

1. Treatment and prophylaxis of venous

:thromboembolism (VTE)
      - Pulmonary embolus (PE)
      - Deep venous thrombosis (DVT)
2. Acute coronary syndromes (ACS)
3. Atrial fibrillation
4. Prosthetic heart valves
5. Post-surgical prophylactic use

Anticoagulants

THERAPEUTIC GOALS

What are the two main goals?

1. The goal is to prevent the formation or further progression of an intravascular thrombus

2. or to prevent a formed thrombus from becoming dislodged and forming an embolus.

(Main drugs are heparin and lovonox)

Anticoagulants

THERAPEUTIC GOALS

What drug is more suitable for out patient therapy and why?

for acute conditions, patients are started on unfractionated heparin (UFH) because of its fast onset of action. Some studies have shown long term benefits with enoxaparin for ACS. Low molecular weight heparins (LMWHs) may also be appropriate for intial therapy in patients with PE or VTE. When long-term therapy is anticipated, warfarin is begun shortly after UFH, LMWH (low molecular weight), fondaparniux or a DTI is started. The injectable anticoagulant is then continued until warfarin has achieved a therapeutic effect, which will take 4 to 5 days. After this, the patient may be maintained on warfarin alone. Warfarin, unlike IV or SQ anticoagulants, is orally absorbed making it more suitable for prolonged outpatient therapy.

Anticoagulants

THERAPEUTIC GOALS

If you want something to work quickly?

Anticoagulants

THERAPEUTIC GOALS

What lab value do you use when measuring lab values for warfarin therapy?

Dosage is guided by in vitro blood coagulation indices that have been found in studies to provide a desired therapeutic outcome with minimal risk of toxicity.
a. Warfarin - PT (prothrombin time, need a rearangent, can get a different number each time) or INR (International Normalized Ratio, factors in activity of reangent, get the same, USE INR) are used to guide dosage of warfarin. An INR was established to adjust for the variability found amoung the various reagents used to measure PT. Each laboratory can provide the PT range necessary to achieve the desired INR intensity. The target INR intensity varies with the condition being treated. The following are examples:... DONT memorise

Therapeutic Goals

Heparin

What do you measure?

If used post operatively, do you we watch aPTT?

- Activated PTT (partial thromboplastin time) is used to measure the effect of heparin. The dose is adjusted until the aPTT is between 2 and 3 (at JH hospital right now, can change, part of the problem, changes per institution, in seconds or ratio) times longer than control values. Note: aPTT is not used to monitor low molecular weight heparins (LMWH). Generally LMWH are not monitored for therapeutic effect. If measuring for therapeutic effect anti-factor Xa is sometimes used – desired peak value is 0.6-1.0 units/ml). Anti-Xa levels can also be used to monitor UFH (goal range 0.3-0.7 units/ml)

-If heparin is being used prophylactically in post-operative patients, a dose is used which has been found to be effective in clinical trials 5,000 units every 8 to 12 hours given deep subcutaneously (Not IM; will cause bleeding into muscle).

Therapeutic Goals

Bleeding

What are signs and symptoms of bleeding?

Monitor for signs and symptoms of bleeding such as hematuria (microscopic or overt), blood in stool (occult or melanotic), vaginal bleeding, wound bleeding, epistaxis, ecchymosis, sudden development of pain (e.g. joint pain or headache), orthostatic hypotension or decreased hematocrit. For other toxicities, see discussion of individual drugs below. (may be subtle)

Therapeutic

What symptoms and conditions and how long therapy should be established?

When a thrombus has already been formed, the initial goal of therapy (from time of diagnosis to 6 months) is to prevent extension of the clot, embolization or death. Long-term goals include prevention of post thrombotic syndrome, pulmonary HTN and recurrent VTE.

- 1st provoked VTE: 3 months
-1st unprovoked VTE  at least 3 months, re-evaluate for longer treatment

-1st unprovoked proximal DVT: life long
st
-2nd VTE & cancer at least 6 months (LMWH preferred)
-2nd episode of VTE  life long

Anticoagulation

Therapuetic

How long in mechacical heart valve?

Patients with prosthetic (mechanical) heart valves are treated for life. Goal INR 2.5-3.5 in the mitral position; 2-3 in the aortic position. Bioprosthetic (tissue) valves in the mitral position are treated for 3 months without other thromboembolic risk factors.

Anticoagulation

Therapuetic

How long for a patient with A.FIB?

Patients with atrial fibrillation are treated as long as atrial fibrillation is present. Can cardiovert AF without anticoagulation if cardioverted within 48 hours of onset. If >48 hours after onset, anticoagulate (INR 2-3) for 4 weeks before cardioversion. Treat with warfarin for four weeks following successful cardioversion. In cases of chronic paroxysmal atrial fibrillation, patients are placed on lifelong anticoagulation.

Therapeutic

Post-Surgical

How long should a patient with a knee or hip repair be placed on anticoagulant therapy?

Post-surgical patients treated prophylactically with low dose UFH/LMWH will continue receiving UFH/LMWH until they are fully ambulatory. Patients s/p total hip or knee replacement or hip fracture repair should receive at least 4 weeks of prophyaxis.

HEPARIN

PHARMOCOLOGY

What does heparin combine with?

Does heparin have a long half life?

1. Heparin  combines with and intensifies the activity of Antithrombin. (Anti-coagulant, make all by ouself, naturally occuring substance, heparin combines with and makes it more active)
2. Antithrombin is a naturally occurring inhibitor of coagulation which neutralizes the active forms of factors XII, XI, IX, X and II.
3. Onset of heparin is fast; Duration is relatively short

HEPARIN

ADMINISTRATION

What should I keep when I am administering heparin?

1. Heparin combines with and intensifies the activity of Antithrombin.
2. Antithrombin is a naturally occurring inhibitor of coagulation which neutralizes the active forms of factors XII, XI, IX, X and II.
3. Onset of heparin is fast

4. Keep a therapeutic flow chart: Date and Time

Heparin Dose

Anti-Xa (aptt)

Coumadin Dose

INR

S/S of bleeding

platelets

5. HEPARIN LOCK - Normal saline has been shown to be just as effective in preventing clots when used to flush a "Heparin Lock" catheter. (Don't call saline lock a Hep Lock)

Heparin

Toxicity

What can reverse HEPARIN toxicity?***

How long is is heparins half life?

What is a side effect of too much PS?

Bleeding - PROTAMINE SULFATE (PS)(if you inject too quickly, BP goes down) will reverse the effect of heparin and is used as an antidote in a patient who has been given too much heparin and has developed significant bleeding. If significant bleeding is not present, first try stopping the heparin and wait. (DO NO HARM!) One mg of PS will reverse 100 units of heparin. When calculating the dose of PS, remember the fast half-life of heparin. PS administered too rapidly may cause hypotension and an excessive PS dose may cause an anticoagulant effect of its own. Transfusions with whole blood or fresh frozen plasma may also be used to reverse the effect of heparin.

Heparin

What are the most common sites of bleeding?

Site of trauma
GI track
Urinary track
Oropharynx

Heparin

Can heparin achieve full anticoagulantion in patients?

Heparin

What can heparin cause if administered for 6 months or more?

Heparin

THROMBOCYTOPENIA

HAT

HAT (heparin associated thrombocytopenia) (common – 10%); non-immune mechanism, occurs within several days of heparin therapy, platelets are activated by heparin causing aggregation and a mild decrease in number (remain >100,000). Platelet count often returns to baseline with continued therapy. (NOT A PROBLEM OR WORRISOME)

HEPARIN

HIT***

THROMBOCYTOPENIA

What complex is important for bleeding and clotting?

HIT (heparin induced thrombocytopenia) (1-3%); Requires 4 - 14 days to develop (can happen more quickly in a patient who has had Heparin Induced Thrombocytopenia (HIT) in the past), mechanism is immune-based and can decrease platelet count to below <100,000. Patients with Type II HIT are at risk for developing Heparin Induced thrombocytopenia with thrombosis HIT(T) which is life threatening. Heparin complexes with normally occurring platelet factor 4 (PF4) (body generates antibodies against it). In some people, an antibody is formed against the heparin: PF4 complex. The antibody: heparin: PF4 complex is a potent stimulus for platelet adhesion resulting in thrombosis. (CLOTTING AND BLEEDING)

HEPARIN

WHAT IS THE TREATMENT FOR HIT?

Discontinue heparin (including heparin line flushes and heparin-coated indwelling catheters). Begin therapy with heparin like drugs that are not structurally related to heparin or to LMWH. (PUT HEPARIN IN THE ALLERGY FIELD AS WELL AS THE DIAGNOSIS)

HEPARIN

HIT

LEPIRUDIN (Redludan)

USED TO TREAT HIT

Monitor with aPTT (target 1.5-2.5x baseline)
May prolong INR
Avoid in patients with in renal dysfunction (drug accumulation)

HEPARIN

HIT

Argatroban

USED TO TREAT HIT

Monitor with aPTT (target 1.5-3x baseline)
No reduction in renal dysfunction is necessary
Will prolong INR

HIT

Biivalirudin

USED TO TREAT HIT

Monitor with aPTT (target 1.5-2.5x baseline)
Reduce dose in renal dysfunction
May also be used in pts undergoing percutaneous transluminal coronary angioplasty (PTCA) with aspirin (ACT is used to monitor)
Will prolong INR

HIT

****Dabigatran

What do you need to do when administering to a renal impaired patient?

No routine monitoring needed
Lower number of food and drug interactions
Studied for prevention of CVA in patients with A fib and for treatment and prevention of VTE
Given PO

(replacing warfarin, ****decrease dose in renal dysfunction)

Heparin

Patient Related Variables

1. Preexisting bleeding disorders.
2. Active peptic ulcer disease or ulcerative colitis
3. Head trauma
4. Liver disease - patients may require smaller doses
5. Drug interactions: NSAIDS, GP IIb/IIIa inhibitors

Low Molecular Weight Heparins (LMWH)

enoxaparin (Lovonox), dalteparin

***In what setting are these proven to be better?

***At what level do you need to decrease dose in renal impairment?

LMWH have been shown to be equivalent to UFH except for the following setting where LMWH appear to be more efficacious: (**Don't measure anything however member to decrease the dose in RENAL)
1. DVT prophylaxis following knee or hip replacement or hip repair
2. Treatment of patients with ischemic coronary syndrome.
3.DVT treatment in patients with cancer

LMWH are substantially more expensive than unfractionated heparin.
May be cost effective in the outpatient setting
Reduce dose in severe renal dysfunction (CCr < 30ml/min)

LMWH

Indwelling Spinal or Epidural cath

(DON'T memorize, BUT know that timing is crucial when it goes in or goes out)

Indwelling spinal or epidural catheters should not be removed in a patient who is anticoagulated (with LMWH, heparinoids or fondaparinux); as this appears to significantly increase the risk of spinal hematoma. Minimize risk by:
• Wait 24 hours after catheter placement before anticoagulation therapy is begun.
• Wait 12-24 hours after dose of LMWH before catheter is inserted
• Catheter removal should be done at least 10-12 hours after last dose of LMWH

Fondaparinux Sodium (arixtra)

(Fon da parin ux)

Does dose need to be reduced in renal failure?

WARFARIN

Pharmacology

What is the "Precursor Clotting Factors (CF)?*

Protein C&S
Vitamin K (activates precursor clotting factors) dependent carboxylase
Reduced vitamin K oxidized vitamin K
Vitamin K epoxide reductase(reduces it so its activated again, regenerates it so it reactivate more)
[warfarin Inhibits Vit K epoxide reductase]
Warfarin Creates a Vitamin K deficiency

WARFARIN

Pharmacology

The effect of warfarin is delayed...

II, VII, IXand X

Is a loading dose of warfarin a good idea?

The effect of warfarin is delayed because the active factors already made by the liver have to be used up before the effect of warfarin is seen.
Onset of anticoagulant effect: 12-24 hours (factor VII)      

– a loading dose is not a good idea. This early effect is deceptive, it causes INR to go up but since factor II has not had enough time to decrease, protection from clot propagation has not yet been achieved.
Onset of antithrombotic effect: 2-7 days (factor II, has the ongest half life)

WARFARIN

Pharmacology

What are the factor half lives?

WARFARIN

Pharmacology

What happens when it is first started?*

When warfarin is first started, the patient can actually be in a hyercoagulable state for about 36 hours(Rare, why start heparin first, have warfarin creep up). This is because protein C (a naturally occurring anticoagulant that is also vit K dependent) drops faster (half-life 9 hours) than factor II. Patients most at risk are patients with protein C deficiency(need Protein C to activate it, all activated by Vitamin K) . This is why warfarin therapy is begun with heparin until factor II has had a chance to decrease; 4-5 days. (Full affect need to wait a couple weeks)

Warfarin

ADMINISTRATION

where can confusion occur with medication names?

1. Warfarin is available under the brand name Coumadin and is also available as a generic brand. While these products are therapeutically equivalent, problems can arise if the patient has two prescription bottles, one labeled “warfarin” and the other labeled “Coumadin”.
2. Keep a therapeutic flow chart (see above)
3. Do not use loading doses of warfarin. A loading dose of warfarin will increase likelihood of bleeding without protecting the patient any faster.
3. Remember that the effect of a dose of warfarin is delayed (approx 3 days). Deciding that a particular dose of warfarin is inadequate after only one day is not rational. A dose of a drug should not be declared insufficient until enough time has been given to see the full effect of that dose. This requires an understanding of the time course of drug activity
4. Dose strategy – many factors at play. African Americans>Whites/Hispanics> Asian for warfarin dose requirements. Age >75 yo usually require lower doses and <30 yo require higher doses. Check INR more frequently until therapeutic then weekly then gradually

increase INR measuring interval to one month.
5. Generic warfarin is equivalent of coumadin – beware, however, of the patient with a bottle of coumadin and a bottle of warfarin. They may not know the drugs are the same!
6. If INR is too high, Check compliance and/or drug interactions
INR ACTION
3.5-5 hold 1-2 doses, decrease dose by 10-15%
5-9 hold 2 doses; restart when INR is therapeutic, decrease dose by 10-25%
>9 stop therapy, consider po vitamin K (2.5-5mg); if bleeding FFP or vitamin K given IV slowly. Reassess dose/compliance – restart when INR is therapeutic.
7. When heparin and warfarin are given concurrently, the INR will decrease by 0.3-0.8 when heparin is stopped. (NOT BY A WHOLE LOT)
8. Warfarin does not get into breast milk.

(DANGER NEEDS TO KNOW WARFARIN AND COUMADIN ARE THE SAME THING)

WARFARIN

TOXICITY

WHAT IS THE ANTIDOTE FOR WARFARIN?

***

1. Bleeding - Administration of PHYTONADIONE (Need to know this drug NOT vitamin K) will allow vitamin K to compete more successfully with warfarin and will allow the liver to complete the synthesis of the partially formed factors and begin making more completely formed factors from scratch. Administration of vitamin K will cause warfarin resistance. For this reason, transfusion with whole blood or fresh frozen plasma should be used if the patient needs to remain on anticoagulation therapy.
2. Skin necrosis is rare (0.01 - 0.1%), when it occurs it is usually within the first week of therapy. Patients with protein C or protein S deficiencies seem to be at highest risk.
3. In patients with antithrombin deficiency, it is important to cover them initially with UFH, LMWH, fondaparinux while INR is subtherapeutic.

WARFARIN

PATIENT RELATED VARIABLES

What are the major drugs that interact with warfarin?**

1. Preexisting bleeding disorders
2. Active peptic ulcer disease or ulcerative colitis
3. Head trauma
4. Liver disease - patients may require smaller doses.
5. Poor compliance (NEED TO MAKE A CONTRACT, AND NOT GIVE THERAPY IF NOT COMPLIANT)
6. Malnutrition
7. Use during pregnancy - FDA PREGNANCY CATEGORY X
8. Drug interactions - THE LIST IS LONG - a good practice is to assume that all drugs interact with warfarin until you have had a change to look it up.
Inhibit platelets TEST
NSAIDS – (Celebrex and Trilisate do no interact)
Increase warfarin effect (not a complete list)
Acetaminophen (max 2 g/day) prolong INR
Bactrim
Metronidazole
Amiodarone
Steroids (dose-dependent) high dose*
Fluconazole (stabalized on warfarin, fungal infection, vaginal, 3 day course, patient sarted bleeding)
Multiple herbal products

Decrease warfarin effect (not a complete list)
Co-administration with Antacids
Phenytoin
Carbamazepine
Rifampin
9. Diet (Don't drastically change)
Vitamin K rich diets can antagonize the effect of warfarin: Liver, Broccoli, Brussels sprouts, cauliflower, chick peas, kale, spinach, turnip greens.
Be consistent in number of vitamin K rich servings patient has per week

Parkinson's Disease

Definition

Parkinson’s disease was first described in 1817 as “shaking palsy” by the English physician James Parkinson. It is a progressive neurologic disorder that afflicts approximately 1% of U.S. adults over 65 yo and generally presents in patients from 50 - 80 yo with about two-thirds of the cases presenting in the 6th decade of life (50-60yo). Patients gradually develop tremors, rigidity and bradykinesia which may eventually progress to an inability to take care of one's self. The classic signs and symptoms of Parkinson's disease are noted below:

Parkinson Disease

Early Symptoms

Constipation
Postprandial bloating
Orthostatic hypotension
Erectile dysfunction
Apathy
Anxiety

Resting tremor: Generally the least debilitating symptom, Often the sole presenting symptom
Often involved the hands (pill polling), but can involve the jaw or leg, Abates with purposeful movement and with sleep
Rigidity: Cogwheel rigidity, Contributes to postural instability,

Bradykinesia: Can be very debilitating,Facial masking
Slow handwriting,Decreased volume and clarity of speech
Postural instability: Most debilitating symptom
Occurs in later stages, Shuffling gate
Difficulty stating and terminating steps,Increased risk of falls

Parkinson Disease

How long can it take to progress despite treatment?

Parkinson's Disease

Goal of Pharmacology intervention

A. Goal of therapy
Maintain as much function as possible for as long as possible.
B. Therapy is generally begun at or soon after the diagnosis of PD is made.

(balance of Ach and dopamine)

What makes Parkinson's worse?

**KNOW 3**

Phenothiazines (e.g., chlorpromazine – Thorazine)
Butyrophenones (e.g., haloperidol – Haldol)
Thioxanthenes (e.g., thiothixene – Navane)
Reserpine
Methydopa
Metoclopramide (Reglan)

(can induce parkinson like symptoms)

Parkinson's

Stages of Disease

know there there

STAGE 0 : No clinical signs evident
STAGE I : Unilateral involvement
STAGE II : Bilateral involvement without impaired balance
STAGE III : Bilateral involvement with unsteady balance, patient walks unaided
STAGE IV : Bilateral involvement with marked postural instability but can still walk unaided
STAGE V : Confined to bed or wheelchair

Parkinson's Disease

Antcholinergic Agents

Anticholinergic agents : Cogentin (benztropine), Artane (trihexyphenidyl)

PHARMACOLOGY

What do they do?

Parkinson's Disease

Anticholinergic agents : Cogentin (benztropine), Artane (trihexyphenidyl

CLINICAL USE OF ANTICHOLINERGICS

NOT USED MUCH

These agents are avoided in patients > 70yo because of their anticholinergic side effects.
These agents are generally used early in the disease process so that response to l-dopa can be preserved (see below). They are often combined with l-dopa late in the course of the disease.
Anticholinergics are only effective in controlling tremors and excessive salivation..

Parkinson's Disease

Anticholinergic agents : Cogentin (benztropine), Artane (trihexyphenidyl

ADVERSE EFFECTS

Mental Confusion; Hallucinations
Dry mouth; Dry skin
Tachycardia; Blurry vision
Constipation; Urinary retention

DOPAMIERGIC AGENTS

L-dopa/carbidopa (Sinemet)

-L-dopa is a precursor of dopamine (DA). It is converted to DA by Dopa decarboxylase (DDC), an enzyme located both in the CNS and in the periphery.

SEE Diagram page 3

-Conversion of L-dopa to DA in the PERIPHERY results in an increased incidence of side effects such as nausea, vomiting and orthostatic hypotension. Carbidopa, a peripheral DDC inhibitor, is used to decrease the incidence of these side effects.

-Conversion of L-dopa to DA in the CNS results in increased CNS DA activity and a reduction in Parkinson symptoms.
-Increased DA activity in some areas of the brain causes side effects such as hallucinations, psychosis, insomnia and confusion.
-After DDC has been inhibited, Catechol O-methyltransferase (COMT) becomes the predominant enzyme that breaks down L-Dopa in the periphery. (N/V/hypotension)

DOPAMIERGIC AGENTS

L-dopa/carbidopa (Sinemet)

CLINICAL USE

-L-Dopa is more effective for akinesia (difficulty starting movement) and less effective for tremors.
-Since tolerance develops to the therapeutic effects of l-dopa, most patients will experience fluctuations in symptom severity after chronic L-dopa therapy. (reserve this drug when others don't work)

DOPAMIERGIC AGENTS

L-dopa/carbidopa (Sinemet)

ADVERSE EFFECTS/PROBLEMS

1. Poor Symptom Control (low dopamine in CNS)

HOW WOULD WE TREAT THIS SYMPTOM?

1. Poor Symptom Control (low dopamine in CNS)
-Increase carbidopa/levodopa dose
-Add or increase dose of dopamine agonist
-Add COMT inhibitor (to block reabsorption in brain) in patient on l-dopa

DOPAMIERGIC AGENTS

L-dopa/carbidopa (Sinemet)

ADVERSE EFFECTS/PROBLEMS...

Other administration issues**

a. Drug interactions -*KNOW* Phenothiazines, Butyrophenones, and Metoclopramide.
b. Protein will decrease or delay absorption of L-Dopa; give on an empty stomach
d. A combination of sustained release and prompt release formulations may be used together to achieve optimal control. (rapid and sustained to maintain level through the day)
e. Sustained release formulations are not absorbed as well as rapid release formulations so the dose of sustained release formulations needs to be 20-30% higher than with rapid release.
f. Sustained release tablets can be cut but not chewed or crushed. (get everything all at once)

Dopamine Agonists: Pramipexole (Mirapex); Ropinirole (Requip)

CLINICAL USES

a. These agents can delay the need for l-dopa and can also be used in conjunction with l-dopa or anticholinergic agents.
b. These agents are generally less effective than l-dopa; when added to l-dopa therapy, an increase in DA related side effects are seen.

Dopamine Agonists: Pramipexole (Mirapex); Ropinirole (Requip)

ADVERSE EFFECTS

a. Confusion, dizziness
b. Hallucinations
c. Nausea
d. Orthostatic hypotension
e. Somnolence
f. Impulse control disorders (e.g., gambling, excessive shopping, hyper-sexuality)

MAO-B Inhibitors: selegiline (Eldepryl); rasagiline (Azilec)

PHARMACOLOGY

Augments dopamine release from presynaptic nerve terminals and blocks DA reuptake. Also has some anticholinergic activity.
Also has antiviral activity.

MAO-B Inhibitors: selegiline (Eldepryl); rasagiline (Azilec)

CLINICAL USE

1. Used in combination with other anitparkinson drugs. 2. Loss of effectiveness occurs in 50% of patients after 30 to 60 days of therapy.
3. Provides modest improvement in bradykinesia, tremor, and rigidity.
4. Reduce dose with decreasing renal function.
5. Do not abruptly stop medication because it might precipitate Parkinson crisis.

MAO-B Inhibitors: selegiline (Eldepryl); rasagiline (Azilec)

ADVERSE EFFECTS

CNS - Dizziness, confusion, depression, irritability, hallucinations, insomnia, nightmares (Take last dose at noon to minimize insomnia and nightmares)
GI - Nausea, vomiting (minimize by taking with food)
Livedo Reticularis - Occurs in up to 80% of patients. Rose colored discoloration of skin usually involving the trunk and legs. Reversible when therapy is discontinued.

Catechol O – Methyltranserase Inhibitors (Tolcapone (NOT USED) – Tasmar, Entacapone – Comtan)

PHARMACOLOGY

COMT becomes important in breaking down levodopa when DDC has been inhibited by carbidopa. Inhibiting COMT increases the amount of levodopa entering the CNS

Catechol O – Methyltranserase Inhibitors (Tolcapone – Tasmar, Entacapone – Comtan)

CLINICAL USE

Used as adjunct therapy in combination with levodopa/carbidopa.
Allows dose of levodopa to be reduced.
Reduces the wearing-off phenomenon of levodopa

Catechol O – Methyltranserase Inhibitors (Tolcapone – Tasmar, Entacapone – Comtan)

ADVERSE EFFECTS

General (reduce dose of levodopa to avoid or treat)
Hallucinations
Nausea and vomiting
Dyskinesias
Tolcapone
Associated with rare cases of fulminante hepatic failure. Monitor liver enzymes.
Severe diarrhea in 3-4%.
Entacapone
Liver damage not reported

ASTHMA

DEFINITION

What is the main cause?

is a lung disease with the following characteristics: (1) airway obstruction that is reversible (but not completely in some patients) either spontaneously or with treatment; (2) airway inflammation; and (3) increasing airway responsiveness to a variety of stimuli.

that are inhaled into the lungs create an inflammatory response. This causes the release of proinflammatory cytokines and chemokines which activate eosinophils, macrophages and neutrophils. Histamine, leukotriene and prostaglandins are released further down the pathway. Bronchoconstriction occurs as a result of activating mast cells and basophils during the early phase of an exacerbation. An increase in inflammatory cells occurs during the late phase reaction and usually occurs 4-6 hours after initial antigen exposure.

1. Decrease Impairment

a. Suppress Inflammation
b. Prevent symptoms
c. Maintain normal pulmonary function (PEF ≥80%predicted)
d. Maintain normal activity
no sleep disturbances
no missed school or work
e. Satisfy the patient and the family

2. Decrease Risk
a. Avoid adverse drug reactions
b. No (or minimal) ED visits or hospitalizations
c. Provide optimal therapy

ASTHMA

Step 1 (Intermittent asthma)

PREFFERED
PRN Short Acting Beta Agonist (SABA)

ASTHMA

Step 2 (Persistent asthma)

*******

ASTHMA

Beta2

Adrenergic Agonists

(albuterol)

LUNG=beta2
d. BOTTOM LINE
1). Relatively selective beta2
2). At a given level of bronchodilation, relatively selective beta agonists cause the same amount of bronchodilation as non-selective drugs.
3). Inhaled beta agonists cause less cardiac stimulation than non-selective beta agonists.
2 agonists cause less cardiac stimulation than oral or parenteral beta agonists.
e. Non-selective beta agonists
isoproterenol
epinephrine
f. Relatively selective beta2
See metered dose inhaler (MDI) products below

ASTHMA

Beta2

Adrenergic Agonists

Place in therapy (NOT including salmeterol or formoterol)

a. ACUTE ASTHMA: Beta2 agonists have generally been found to be more effective in the treatment of acute asthma than theophylline and anticholinergics during the first 2 hours of the acute episode. Longer duration studies suggest that theophylline adds benefit in patients unable to be controlled with Beta 2 agonists alone.

b. EXERCISE INDUCED ASTHMA: The fast onset of inhaled beta2 agonists makes them ideal agents for prophylactic therapy just before engaging in an activity that may induce bronchospasm.
c. The fast onset of inhaled beta2 agonist also makes these agents ideal for prn therapy of symptoms.
d. Inhaled epinephrine (a non-selective beta2 agonist) is available OTC and is less effective (small dose) and shorter acting than relatively selective beta2 agonists.
e. ORAL: When compared to aerosol, oral beta2 agonists have a slower onset of action, are less effective, and cause tremor more frequently. Oral forms are useful when other forms cannot be used (i.e., young children). Because of the slow onset, oral dosage forms are generally avoided for treatment of acute asthma.
f. NOCTURNAL ASTHMA: Sustained release oral beta2 agonists (i.e., albuterol) may be helpful for nocturnal asthma when given as an evening dose.
g. When the patient increases prn use of a beta2 agonist, this should be used as a marker for worsening asthma. Add an antiinflammatory drug if dose of beta2 agonist is >8 puffs/day (> one canister/month). If the patient is also on regular doses of salmeterol/formoterol, doses of the short acting beta agonist 4 or more puffs/day should be seen by a practitioner for re-evaluation of condition.

ASTHMA

Beta2

Adrenergic Agonists

Place in therapy for salmeterol/formoterol – long acting beta agonists (LABA)

******

1) do not use LABAs in a patient controlled on other therapy, 2) Do not use a LABA as sole therapy, 3) Do not use an LABA as initial therapy and 4) as with all asthma medications – tell patient to seek medical treatment immediately if asthma worsens. (Excess death rate was in the subgroup of African Americans on monotherapy)

ASTHMA

Beta2

Adrenergic Agonists

ADMINISTRATION

a. Properly administered inhaled beta2 agonists (excluding LABAs) by metered dose inhaler (MDI), are as effective and less toxic than beta2 agonists administered by the parenteral or nebulized route. These latter routes may be necessary if proper MDI technique is difficult or not possible.
b. A relatively selective beta2 agonist is preferred over a non-selective agent.

SINEMET

What you do to treat the adverse effect of N/V/D?

(too much dopamine in the periphery)

-This problem can be minimized or prevented by slowly increasing the dose of L-dopa (i.e. 100 mg/week) or by d/c anticholinergic, amantidine or selegiline

SINEMET

Adverse Effect

"End of dose" wearing off effect

As blood level decrease at the end of a dosing interval, symptoms may worsen

How can you improve these symptoms?

-Minimized dividing the same total daily dose into more frequent doses during the day

-ADD COMT inhibitor

-Add selegiline if not already taking

SINEMENT

On/Off phenomenon

Not related to blood levels of levodopa. Patient can stop as if being turned off. Patient can then resume activity minutes to hours later. Mechanism is not known.

-Add dopamine agonist to l-dopa

-Add COMT inhibitor

- modify distribution of dietary protein.

Parkinsons

Amantadine (Symmetrel)

What are the problems and why isn't it used very often?

What is the rare side effect it causes?

-PROBLEM: doesn't work for very long, stops after about a month

-Livedo Reticularis: Occurs in up to 80% of patients. Rose colored discoloration of skin usually involving the trunk and the legs. Reversible with therapy.

h. Levalbuterol nebulization solution (Xpenex –R-isomer of albuterol)

More Expensive, They think it is more potent.

MAY CAUSE LESS TACHYh. Levalbuterol nebulization solution (Xpenex –R-isomer of albuterol) costs more than albuterol (approx 6x). Is more potent than racemic albuterol. Although some claim that this drug is more effective and less toxic than albuterol - neither of these claims are well supporting in the literature and levalbuterol appears to not have a clinically significant advantage over albuterol.

(controversal)

Salmeterol/foromterol

What are they not a substitute for?

salmeterol/formoterol

are they used for acute asthma?

NO! onset of action is 15-20 minutes. Using multiple doses during acute symptoms may lead to acute excacerbations.

*BE CAREFUL THAT THE PATIENT DOES NOT MIX UP THE CANESTER. Don't use as a quick reliever.

salmeterol/formoterol

Are they used for Nocturnal asthma treatment?

salmeterol/formoterol

Are they helpful for exercise induced asthma?

have FDA approval for exercise induced asthma as PRN

PRN

salmeterol and formoterol can also be used PRN for exercise induced asthma

What is the concentration of SQ we give to treat asthma?

What do we not want to confuse this with?

*******

(1:1,000 - this refers to a concentration of 1 gm in 1,000 ml which is the same as 1 mg/ml; the other concentration is 1:10,000 or 0.1 mg/ml).

The 1:1,000 concentration is generally used SQ when treating asthma and it should NOT be given intravenously. Typical Dose: Use 1mg/ml, dose is o.o1mg/kg (max 0.5mg) SQ every 20 min x3 doses. WHEN GIVING SQ EPINEPHRINE, TAKE CARE NOT TO INADVERTENTLY ADMINISTER IV.

- Shake the canister thoroughly
- Breathe out steadily
- Place the mouthpiece between the lips
- Tilt head back slightly
- Fire the inhaler while taking a slow, deep inhalation PROBLEM SPOT; PATIENTS ACTUATE INHALER AT WRONG TIME & PATIENTS TEND TO HAVE REFLEX GLOTTIS CLOSURE (fast or slow inhalation may not matter with beta2)
- Hold the breath at full inspiration while counting to 10 agonists)
- Repeat process after 1-5 minutes if second puff is prescribed
- Clean mouthpiece

-DONT PUT 2 PUFFS IN RESEVOIR AT A TIME.

-WASH it

Metered dose inhaler is as active as a neb or

-trying to get off nebs

-just as effective as pill/iv

TOXICITY OF BETA 2 AGONIST

*****

a. Beta1: Tachycardia (particularly a problem in the elderly and in patients with Ischemic Heart Disease)
Arrhythmias
b. Beta2
Tremor (tolerance may develop)
Decreased serum potassium (with high doses) WILL CAUSE K TO GO INTRACELLULAR

d. Hyperresponsiveness may increase with regular use of beta agonists.
e. Sudden paradoxical bronchospasm has been reported.

THEOPHYLINE

What do they cause?

SAME category of drug: theophyline, caffeine, & theobromine

1. CNS stimulation: AVOID tox because seizures have 50% of death and the rest have brain damage (needs to be really high)

2. Heart Stimulation

3. Diuretic effect

4.Increases diaphragmatic contractility and delays onset of diaphragmatic fatigue (not sure if matters clinically)

5.

NOT mild asthma

ONLY FOR SEVERE FORM OF ASTHMA WHEN LOOKING FOR THINGS TO ADD TO THE REGIMEN TO CONTROL THEM.

THEOPHYLINE

NOCTURNAL ASTHMA

1X sustained release over night

AMNOPHYLLINE

What is it made up of?

What do you need to do if you switch patient to just theophyline

800 mg theophyline (take 80%as the dose)

ethylenediamine 200 mg (make sure patient is not allergic)

aminophylline

Should it be used in acute asthma?

aminophylline

Should you stick to one brand?

aminophylline

toxicity

a. CNS stimulation: caffeine like symptoms; seizures - in an overdose situation, prevent seizures with phenobarbital (not phenytoin) and stop seizure with diazepam.
b. Nausea, vomiting and anorexia
c. Theophylline overdose
Removal from body
- hemo & peritoneal dialysis - not very effective
- oral charcoal - intermediately effective
Treat Arrhythmias
- verapamil (avoid beta blockers)
d. Allergy - Patients allergic to aminophylline are most probably allergic to ethylenediamine and not to theophylline.
e. Poor school performance - Although anecdotal reports suggest this effect, there are insufficient data to support this as a toxicity.

What conditions decrease the metabolism of theophylline?

********

- Liver disease (decreased metabolism of theophylline)
- Heart Failure (decreased metabolism of theophylline)
- Viral Infections (decreased metabolism of theophylline)

theophyline

DRUG INTERACTIONS

****

- Erythromycin (decreased metabolism of theophylline)
- Cimetidine (decreased metabolism of theophylline)
- Ciprofloxacin (decreased metabolism of theophylline)
- Smoking (increased metabolism of theophylline)

ANTICHOLINERGICS

atropine ; Ipratropium (Atrovent); Tiotropium (Spiriva); Glycopyrrolate

-Decrease the sense of breathlessness

-more for treatment COPD

ANTICHOLINERGICS

 Ipratropium (Atrovent)

What is a BIG contraindicated for a MDI for this?

*****

b. Ipratropium (Atrovent) is given by metered dose inhaler or by nebulization (DOES NOT HAVE THAT AFFECT).
Contains peanut oil – CONTRAINDICATED IN PATIENTS WITH PEANUT ALLERGY JUST MDI

ANTICHOLINERGICS

atropine ; Ipratropium (Atrovent); Tiotropium (Spiriva); Glycopyrrolate

TOXICITY

a. When administered by inhalation, side effects are minimal.
b. Excess cholinergic blockade:
• Mad as a hatter (delirium and seizures)
• Dry as a bone (secretions are decreased-dry mouth, dry skin)
• Blind as a bat (eye cannot accommodate - can't see close; Pupillary dilation - photophobia)
• Red as a beet (cutaneous blood vessels dilate)
• Hot as a hare (skin feels warm)
ALSO:
• Increased heart rate
• GI slowing (constipation, decreased bowel sounds)
• Urinary retention

CROMOLYN SODIUM

What is it used for?

-NOT for acute asthma

Only long term medication

Leukotriene Modifiers

Singulair

-Count as antinflammatory component

-ok to use in children

Steroids (glucorticoids)

INHALED

CHRONIC LONG TERM Control

weeks to see full affect

Steroids

When do you use in acute asthma?

SYSTEMIC STEROIDS.

PARENTERAL or ORAL - In acute asthma, the anti-inflammatory action is delayed for 6 to 8 hours. Enhancement of beta-2 agonists, however, occurs within several hours.

a. PARENTERAL or ORAL - Used to treat acute symptoms unresponsive to short acting beta-2 agonists. Onset of action is delayed

Inhaled Steroids and Beta Agonist

Steroids work at the alveolar

When used in combination with a beta2 agonist, inhaling the beta2 agonist 30 minutes prior to inhaling the steroid will increase the delivery of the steroid to small airways.

(NOT STUDY THAT DEMONSTRATES THAT MATTERS)

STEROIDS

TOXICITIES

******

a. Oral candidiasis. Using a spacer can minimize candidiasis. Rinsing out the mouth with tap water after each dose.
b. Dysphonia (difficulty in speaking; hoarseness) with inhalation. Can occur in 0-50% of patients; spacers may decrease the incidence.
c. Long term high dose has been associated with hypothalamic-pituitary-adrenal axis suppression.Your body shuts off the negative feedback system,  And ACTH levels goes down, BP 0, Addison Crisis(MINIMAL BECAUSE NO SYSTEMIC EFFECT)
d. Growth retardation - average reduction is 1/3 of an inch per year. It has not been determined whether patient’s growth will “catch up” if treatment is discontented. Risk benefit ratio strongly in favor of its use.
e. Increased intraocular pressure.

Hypothalmic- Pituitary-Adrenal Axis Suppression

What happens?

Inhaled steroids at doses < 1,500 mcg/day in adults and < 800 mcg/day of beclomethasone in children do not appear to cause clinically important adrenal suppression in the majority of patients. Long term use of higher doses can cause adrenal suppression.
If a patient has adrenal suppression from chronic administration of systemic steroids, abruptly switching the patient from systemic to inhaled steroids will lead to signs of adrenal insufficiency.
When giving systemic steroids, adrenal suppression can be minimized by giving the dose in the morning and by giving the drug every other day (if the disease allows this).
Requirements for steroids increase during the times of stress. Patients who are adrenally suppressed will require an increase in steroid dosage during acute illness.

Steroid Withdrawal Syndrome

-Abruptly stopping high dose thereapt (independant of adrenal suppression). They will feel good for three days. and then when you stop you feel...

-The symptoms include: myalgia, joint pain, anorexia, nausea, lethargy and fever.

-This is why you taper the steroids.

-Abruptly stopping or decreasing the steroid dose may also cause exacerbation of the underlying disease.

monoclonal anti-IgE antibody which binds to IgE thus inhibits free IgE from binding to the mast cell and prevents activation and subsequent mast cell release of cellular mediators. If released, these cellular mediators would cause signs and symptoms of asthma

-SQ

-Take IgE levels. Takes 20 minutes to reconstitute

-Cost $350

-Some insurance won't pay

-Concern for anyphylaxis, patient has to be in your office for 2 hours.

Magnesium Sulfate

When do you use this?

ED when you have tried everything else and nothiing seems to work. Bronchodilator.

Somatic is localized(bone and skin, localized)

Visceral is poorly localized (open hand, diffuse)

Primary nerve lesion or nerve dysfunction

1. Pathologic changes to the peripheral nervous system

2. Stabbing/Shooting - Use anticonvulsants (Gabapentin or Carbamazepine), methadone
3. Burning/Numbness - Use tricyclic antidepressants

Resolves in 3 days

Pain resolves

-protective

Not good Not protective

Indefinite duration

-good for nothing

-patient may no appear as if in pain

OPIODS

(Codeine, Morphine, Synthetic, mixed agonist-antagonist)

Pharmacology

a. Pain transmission is decreased at the level of the spinal cord and peripheral pain receptors.
b. Receptors located in the brain are stimulated leading to an altered perception of pain. The patient still "feels pain" but it doesn't hurt as much as before the opioid was administered.

Mixed agonist-Antagonisti.

Pentazocine (Talwin)
ii. Butorphanol (Stadol)
iii. Nalbuphine (Nubain)
iv. Buprenorphine (Buprenex)

What happens when you give this to an opiod naive person?

What happens when you give this to an opiod tolerant patient?

1. Naive: Opiod like effect

2. Tolerant: Will knock all the morphine off the receptors and will experience increased pain

YES. Oral dose much bigger than IV

Conversion charts are not beggining doses.

Methadone

Can I prescribe it?

NO. Unless I know what I am doing. Call the dosing clinic when a patient comes in.

Opiods

ADMINISTRATON KEY POINTS

-Avoid intramuscular

-PRN administration when appropriate

-If pain is severe: around the clock administraton is important. If you stay on top of pain, it is easier to control

-Sleep: hard to get on top of.

-PCA watch for overdose

(replace every 3 days) - Not good for fast titration - not indicated with acute pain – not good for opioid-naïve patients.

-Titrate slowly using immediate release opioid for breakthrough pain.

-Blood levels increase slowly taking 12-18 hrs to get a constant effect. Patients on fentanyl patch should also have an order for PRN dose of short active opioid (e.g., oxycodone, hydromorphine, or rapid release morphine). If a patient develops a fever, absorption can increase by as much as 15%.

-CAN'T FIND PATCH, NARCOTIC DISCREPANCY. Very potent.

-When waste it, waste it with a witness. Real street value.

Meperidine (DEMEROL)

-PROdrug that is converted to morphine

Morphine

Standard for comparison for opioids. Available in both rapid and sustained release oral formulations Do not adjust dose too frequently – use supplemental short acting opioids PRN while awaiting steady state. Steady state in 2-3 days. NOTE: morphine comes in both rapid release and sustained release formulations: Avinza – once daily; Kadian & MS Contin – usually twice daily. You need to specifiy whether it is rapid release, long term release

Hydromorphone

DILAUDID

Tincture of Opium, Deodorized (DTO) and

Camphorated Tincture of Opium (Paregoric).

*****

Paragoric contains 0.4mg/ml of morphine equivalent and DTO contains 10mg/ml of morphine equivalent. A 25 fold difference!!

(1 is in drops and ther other is in liquid)

Dexmedetomidine (Precedex)

Where is this used?

-Analgesic and a sedative. Is used in the ICU on vent patients

-Can not be give by infusion for more than 24 hours

-Do not use more than 12 hours in a 24 hour period

-no more than 3 patches at one time

-out of reach of children

Epinephrine

What is the purpose of this use in the setting of pain?

Pain

Tricyclic antidepressants

What kind of pain are they used to treat?

Pain

Anticonvulsants

What kind of pain do they treat?

FAST ABRUPT NEUROPATHIC PAIN (e.g., gabapentin (neurontin), pregabalin (Lyrica), phenytoin, and carbamazepine) are also useful in relieving pain related to peripheral neuropathy, postherpetic neuralgia and fibromyalgia.

OPIOD TOXICITY

NARCAN

1. Using 0.4mg/10ml, give 0.5ml q2min to reverse toxicity.
2.  An excessive dose in a patient with underlying pain can unmask the pain and cause significant stress to the patient.
3.  Upwardly titrate dose slowly in a patient who is physically dependent so as not to precipitate acute withdrawal.
4.  Naloxone administration is also appropriate to reverse significant respiratory depression caused by excessive amounts of partial agonist-antagonists (PENTAZOCINE, BUTORPHANOL, and NALBUPHINE) and the partial agonist BUPRENORPHINE. Can cause death if you GIVE A TOO BIG OF DOSE, Give a little bit every 2 minutes. Narcotic may kick in again.

Narcan

A low dose will block what drug toxicity?

Opiod

toxicity

Constipation

What do you need to use with an opiod?

Laxative... SENNA most common

Do not just use colace

-Drugs of abuse or decided by society

-Mentally dependent: Chronic, impaired controlled, Compulsive, Continued despite harm, and craving

physical dependence

(not the same as mental addiction)

Will go through withdrawal when medication is stopped.

ETOH---> BENZO

HEROINE--->methadone

You can not prescribe medication to prevent withdrawal in and OUTPATIENT SETTING unless you are part of a methodone maintenance program or bupimorphine.

You can in an inpatient setting

Give them there dose and then treat them as a normal patient.

-Call maintenance program and get the dose. Validate dose before you prescribe it. Otherwise you will overdose people.

Patients with chronic pain can manifest symptoms of addiction: Hoarding, concern about supply, and going to multiple practitioners for drugs. The problem is NOT because they are an addict, but because they have been inadequately treated for their pain.
i. Phase 1 – Occurs at the onset of pain if analgesic use is inadequate. Patient is left with undertreated pain.
ii. Phase 2 – Patient attempts to secure effective pain treatment. May involve escalating pain behavior (moaning, grimacing, and crying). Healthcare worker could see this as a poly to get more narcotics.
iii. Phase 3 – Pain behavior becomes more severe. Patient becomes angry with providers. Patient may be labeled an Addict.
iv. AVOID by trusting that the patient’s reports of pain are real.

You know what your doing

3 times or more it is usually to treat pain

IF PATIENT IS WEAK ONE DAY AND SHOTS HEROINE, THE HEROINE WON'T WORK. If you have a patient on heroine and you start Buprenex they will withdrawal.

Being used in place of methadone to treat opioid addicts. Advantages over methadone are its long duration of effect (2-3days) and less potential for respiratory depression in overdose. Disadvantage is that it can causewithdrawal if dose is started too high.

-Oral formulation may be combined with naloxone in a 4:1 ratio (Bup/Nx). Naloxone has poor oral bioavailability. If the oral tablet is dissolved and injected by the addict, all of the naloxone will be available for action and immediate withdrawal will occur. IS THERE TO FOIL THE PATIENT TO ATTEMPT TO SHOOT THIS MEDICATION THROUGH AN IV

ASA and NSAIDS

Pharmocology

What do they inhibit?

Inhibits cyclooxygenase (Cox-1 & Cox2) which is an enzyme needed to form prostaglandins and thromboxanes from arachidonic acid.

(Prostaglandins are involved with many physiological functions including the production of pain, the formation of the inflammatory response and the function of platelets. Aspirin is the only NSAID that irreversibly inhibits this enzyme.)

-thromboxane (TXA2) which leads to platelet adhesion.

-Prostacycline which inhibits platelet adhesion, leads to vasodilation and protects the stomach against gastric acid

leads to the formation of inflammatory mediators.

Cox-1 and Cox-2 Inhibitors

NSAIDS

Clinical Uses

ANALGESIC

a. Mechanism - Blocking formation of prostaglandins that are responsible for causing hyperalgia. (prostaglandins increase perception of pain)
b. Dysmenorrhea
c. Pain – unlike narcotics, NASIDS and acetaminophen have a ceiling to their analgesia.
d. Additive (maybe synergistic) with narcotics.
e. Osteoarthritis

Cox-1 and Cox-2 Inhibitors

NSAIDS

Clinical Uses

ANTIPYRETIC

Cox-1 and Cox-2 Inhibitors

NSAIDS

Clinical Uses

ANTI-INFLAMMATORY

a. Mechanism - prostaglandins responsible for inflammation (vasodilation - erythema; increased vascular permeability - edema; chemotaxis - WBC migration) are prevented form forming.
b. Sun Burn
c. Gout
d. Rheumatoid Arthritis

Cox-1 and Cox-2 Inhibitors

NSAIDS

Clinical Uses

ANTI-PYRETICS

Mechanism - Aspirin permanently inhibits COX and therefore inhibits both thromboxane A2 mediated platelet aggregation and the anti-platelet aggregation effect of prostacyclin. Thromboxane A2 is inhibited for the life of the platelet because platelets cannot produce more COX. Prostacyclin (in endothelial cells) is inhibited for only several hours because endothelial cells replace the permanently inhibited COX. GIVE ASA: how long with there will be increased, asa gone after one day, but platelet inhibited so have to wait the until the life of platelet is over with. After 1 week half of the platelets are gone, to see them all gone you would have to wait longer than a week, want to flush out platelets)

 ASA

ADMINISTRATION

-All products on the market

-Take with a full glass of water

-GOOD data for post MI prevention of another MI

(need to exercise, eat well, need to take in to account other risk factors)

ASA

Toxicity

What do you need to ask?

***What are the 3 drugs that areNSAIDS but don't significantly inhibit platelet function?****

-HISTORY: patient may not know they are taking asa, (anacin and nyquil). Ask what they take for pain, or..

-GI/Upset/Bleed

**1. Choline Magnesium Trisalicylate (Trilisate ® )

2. Nabumetone (Relafen) and 3. Celecoxib (Celebrex®)

ASA/NSAIDS

HYPERSENSITIVITY

****

Bronchospasm, could be allergic, could mean they are suspectiible to another anti-prostaglandin.

-Be aware that patient may have a reaction with another drug EVEN ACETOMINOPHEN

ASA/NSAIDs

toxicities

Rye Syndrome

avoid use of aspirin in patients < 18 yo (primary target are children with viral infections, e.g., chickenpox)

-Tyelenol and NSAIDS ok

NSAIDS

What do they do to BP?

NSAIDS

What can they do to renal function?

Decrease Renal Function

(esp in CHF, sneaks by because they are used more than you believe)

NSAIDS

Patient Related Variables

What increased risk is there when given with warfarin?

Increased risk for bleeding

NSAIDS

Patient Related Variables

Ibuoprofen TID with low dose ASA daily

What happened^?

ACETOMINOPHEN

(NON-NSAID)

What is it uses?

ACETOMINOPHEN

(NON-NSAID)

What is the max daily dose?

ACETOMINOPHEN

COMBINATION DRUGS

PROBLEM

ACETOMINOPHEN

TOXICITY

What can it cause with chronic use?

1. Nephrotoxicity:"People who often take acetaminophen or NSAIDS [>1 pill/day or >1,000 pills/lifetime] have an increased risk [double] of end stage renal disease, but not those who often take aspirin.
2. Hepatotoxicity: Patients admitted to the U of Pittsburgh Hospital with acetaminophen hepatotoxicity between 1987 & 1993 were reviewed. 50% of the patients ingested only 4-10gms of acetaminophen over 24 hours. The important risk factor in these patients was that they were FASTING.

ACETOMINOPHEN

ACUTE TOXICITY

acetylcysteine (Mucomyst)

PO or IV

(prevents toxic acetaminophen metabolite from killing normal tissue - primarily the liver). To be most effective, the antidote has to be given as soon as possible; can still be considered up to 24 hours after acute ingestion.

What is the Maryland Poison Control #?

*****

ACETOMINOPHEN

What should you throw out if you have this at home?

Syrup of ipecac... Won't be able to use charcol

Call Maryland control center

NSAIDS

What is th difference between ASA and other NSAIDS?

other NSAIDS are generally as effective as ASA, but cost more money and cause less GI symptoms

When should NSAIDs be taken?

NSAIDS

ASA

What are the three things it can do that ASA has that no other NSAID does?

-only NSAID that irreversibly inhibits cyclooxygenase

-only NSAID that has indication for post MI prophylaxis

-The least expensive NSAID

Chronic NSAID

What happens if you coadminister with PPI?

INDOCIN (INDOMETHACIN)

What was it used to treat and what does it have a 50% chance of causing??

Ketorolac (Toradol)

****

What is the max amount of days that you should use this drug for?

Only NSAID available for parenteral use as an analgesic. IM, IV or PO – regardless of route, therapy should
not be more then 5 days. increased GI toxicities

Gout

What are the treatment Goals?

1. Terminate and prevent acute gouty attacks
2. Correct hyperuricemia - maintain serum urate <4-6 mg/dL
3. Prevent chronic complications

GOUT

What order do you go in picking drugs for?

1. NSAIDS (not ASA)

2. Colchicine

3. Corticosteroids

(Don't decrease uric acid level)

GOUT

What drugs decrease uric acid?

1. allopurinol

2. Probenecid

(can cause acute gout)

GOUT

COLCHICINE

When is it most effective?

What does it act as in the setting of GOUT?

1. When given within 12 hours of a gout attack is when it works best

2. it is not a NSAID, but functions as an anti-inflammatory in the setting of GOUT

3. blocks the formation of chemotactic factors, don't get WBC formation and stop the circulation

GOUT

Where is colchicine most useful?

GOUT

What are the main toxicities

GI; diarrhea in 80% of patients

GOUT

NSAIDS

What would we use it for in the setting of gout?

Why do we avoid using ASA?

FAVORED FOR ACUTE ATTACK

USE MAX DOSE OF RECOMENDED DOSE FOR 24 HOURS AND THEN TAPER THAT DOSE.

a. The NSAID are now the favored over colcicine for treatment of acute gout. They work by inhibiting cyclooxygenase which blocks arachidonic acid from forming mediators of inflammation.
b. Indomethacin: 50% really back ha.

c. Problem with ASA variable effect of excretion of uric acid

ALLOPURINOL

pharmacology

What does this drug inhibit?

What is the half life? What is it metabolized to?

-inhibits production of uric acid by inhibiting xanthine oxidase (XO).

-The half life of allopurinol is 2 hours. The half life of the active metabolite of allopurinol (oxipurinol) is 18 to 30 hours. How long would you wait to see the full effect of a given dose of allopurinol? (acts like a pro-drug)

ALLOPURINOL

Why can a medication that decreases uric acid level cause acute gout?

-rapid changes of uric acid levels UP OR DOWN can precipitate acute gout.

-Will start after things have cooled off and they have been on colchicine for a few weeks.

ALLOPURINOL

What can happen if the patient is given this drug and ampicillin?

ALLOPURINOL

Patient related variables

What is the drug interaction that can kill?

***

Mercaptopurine (anti neoplastic: causes bone marrow suppression, it is metabolized by XO, so it will stick around longer and cause more bone marrow suppresion); azathioprine: metabolized to mercaptopurine and same story

Urolic (Febuxostat)

It does everything the same as?

allopurinol

only use when person is allergic to allopurinol because it is more expensive

GOUT

Probenicid

Pharmacology

What can do?

Probenecid is a URICOSURIC (an agent that increases uric acid in urine) which is another drug that can precpitate an acute gout attack because there is a rapid change in uric acid level.

GOUT

Rasburicase (Elitek)

What is the only setting we use this for?

- it can decrease uric acid levels very quickly

ONLY TIME YOU would use this is in tumor lysis syndrome (very high uric acid levels), so strong that on only one dose is neccesary

-Do have epinephrine and benadryl available.

-ToX: Can cause hemolysis ion patients with glucose 6-phosphate dehydrogenase deficiency (G6PD deficiency). Profound around mediteranean. These deficiencies are all not created equally.

NO you must use combination therapy.

DUAL therapy with PPI, amoxicillin and clarithromycocin has poor effectivenes.

*Triples treatments are most effective.

H2 Blockers

What are they used to treat?

PUD and mild GERD

-Initial course is continued 6-8 weeks

-After a successful course of therapy, recurrence of peptic ulceration can occur in 60-80% of patients within the first six months following therapy. To decrease this relapse rate, low-doses of an H2 blocker are sometimes continued. The decision to continue therapy should be weighed against the potential for drug toxicity and expense to the patient.

H1 Blockers

What are some toxicities?

1. CNS (confusion, somnolence) - Particularly in the setting of "normal" doses being given to an older patient who is unable to eliminate the drug normally due to renal dysfunction.
2. Gynecomastia (anti-androgen effect) - cimetidine only
3. There is a long list of uncommon side effects.

H2 Blockers

 What are some patient related variables?

***

What is a big drug interaction?

1. Renal dysfunction
2. Drug Interactions
Warfarin (cimetidine will decrease the metabolism of warfarin leading to an increase of the effect of warfarin)
Theophylline's metabolism is decreased by cimetidine but not by the other H2 blockers.
Ketoconazole is an oral antifungal medication which requires an acid pH to be absorbed. All H2 blockers significantly decrease the absorption of ketoconazole.

PPI

Pharmacology

They turn off the ability to secrete acid in the stomach.

Effective in PUD and mild-severe GERD

PPI

Administration

-decrease Gi tox with NSAIDS

-IV administration improvesthe outcome in a setting of a GI bleed.

-long term therapy in setting of Zollinger-Ellison Syndrome (ZE)

PPI

Increased risk for 2 things?

-Well tolerated short term use

-ketoconazole effects decreased

- Pneumonia and rate of fractures (for long term use consider supplementation with calcium citrate which does not depend on gastric pH to be absorbed.

PPI's

What is a major drug interactions?

Clopidogrel is a pro drug that needs to be activated by this enzyme. There is data to suggest that coadministration of clopidogrel with omiprozole may decrease the effectiveness of clopidogrel (clinical significance is debated). Pantoprazole is a weak inhibitor of CYP2C19 and is preferred if a patient is on clopidogrel.

Misoprostol (cytotec)

When should this drug not be used?

Misoprostol (cytotec)

When should this drug be used?

Misoprostol is indicated for the prevention of gastric ulcers in patients on chronic NSAID therapy. It is not clear if misoprostol decreases serious ulcer complications and bleeding. Misoprostol does not reduce GI pain or discomfort associated with NSAID ingestion.

Misoprostol (cyototec)

In which patients should this drug be avoided?

What are other toxicicties?

NOT in Pregnant women, it is a abortifacient. (BLACK MARKET)

-it causes diarrhea

ANTACIDS

What are the combinations used for treatment?

-Antacids work by neutralizing acid in the stomach. The higher pH induced by antacids also decrease the activity of pepsin. The action of antacid is terminated primarily through gastric emptying; therefore, frequent dosing is important. Antacids also, increase lower esophageal sphincter tone. (can help with pain)

-Aluminum Hydroxide (constipating) and Magnesium Hydroxide (diarrhea). Decreases phosphate and increases Ca

ANTACIDS

Toxicities

1. Constipation: with Calcium or Aluminum containing
2. Diarrhea - with Magnesium containing
3. Phosphate depletion - Aluminum containing antacids will bind to phosphate in the GI tract. This is used therapeutically patients prone to develop hyperphosphotemia such as patients with renal failure. This action can also lead to hypophosphatemia if excessive doses are given. Antacids should be given with meals.
Calcium acetate and Calcium Carbonate can also bind to phosphate in the GI tract.
4. Hypermagnesemia - patients with renal dysfunction are unable to efficiently remove magnesium. In this setting enough magnesium may be absorbed from magnesium containing antacids to cause hypermagnesemia.
3. Hypercalcemia can be caused by excessive administration of calcium carbonate (TUMS).
6. Fluid overload can be caused by excessive use of Sodium Bicarbonate.

ANTACIDS

Patient related variables.

DRUG INTERACITONS

IF GIVEN AT THE SAME TIME AS THESE DRUGS WILL CAUSE DECREASED EFFECTS OF THE FOLLOWING:

digoxin
tetracyclines
ketoconazole
oral fluroquinolones:
ciprofloxacin
norfloxacin

SUCRALFATE (Carafate)

DIARRHEA

What can we use to replace fluids?

1. Remove cause

2. Fluid/Electrolyte replacement
a. Pedialyte (use unflavored with juice)
b. Flat soda
c. IV Therapy may be necessary
d. AVOID using bouillon (contains too much sodium) Broth
e. Children (not dehydrated) continue age specific diet
f. Gateraid lacks potassium

DIARRHEA

Treatment

NARCOTICS

When do you not use these, in what kind of diarrhea?

****

 a. Paregoric, diphenoxylate/atropine (Lomotil), loperamide (Imodium) - May be considered to treat acute diarrhea if patient is afebrile with no systemic symptoms.
b. Sometimes useful in chronic diarrheal states.
c. Loperamide has been found effective in treating travelers diarrhea.
d. Use in infants and young children should be avoided. Narcotics may decrease bowel movements without decreasing fluid and electrolyte loss into the bowel. Children can become dehydrated quickly and close monitoring of input and output is very important.
e. Avoid using these drugs when the diarrhea is caused by a bacterial infection.
f. Deodorized Tincture of Opium (DTO) is NOT the same as paregoric, DTO is more concentrated *** don't mix them up

Diarrhea

Yogurt and Lactinex

Does it work?

kaolin pectin (Kaopectate)

What do you need to watch for?

a. Results in a formed stool BUT DON'T BE DECEIVED - FLUID LOSS CONTINUES
b. May decrease the absorption of some drugs (Digoxin)

Bismuth subsalicylate (Bepto Bismol)

What can this treat in large doses?

CONSTIPATION

Therapy

for Opiod Induced Constipation

Methylnaltrexone (Relistor)

b. Methylnaltrexone (Relistor)
i. Quaternary amine opioid antagonist – does not cross the blood brain barrier so it decreases opioid induced constipation without antagonizing opioid analgesia.
ii. Given SQ once every other day, reduce dose in severe renal dysfunction
iii. Used when other laxatives are not effective
iv. Adverse effects – transient abdominal cramping and flatulence

(STAYS IN GI, used when laxatives don't work, senna works for opiod induced constipation)

CONSTIPATION

Emollients (Stool Softeners) - Colace

Dioctyl (Sodium or Calcium) Sulfosuccinate
Active ingredient in windex, its detergent action allows water to penetrate better into the stool. IT MAKES WATER WETTER. DECREASES WATER TENSION

CONSTIPATION

MINERAL OIL

What is it used for?

PREVENT constipation it will not treat it once it is there.

-For short term use; in debilitated or recumbent patients, mineral oil may be aspirated leading to lipoid pneumonia - do not use at bedtime, Decrease absorption of lipid soluble vitamins (DAKE), leakage through anus (anal puritis). NOT GOOD LONG term

CONSTIPATION

Bulk forming agents

a. Initial DOC (drug of choice) especially in elderly, during postpartum, and with poor diets
b. Hydrophilic compounds that hold water in the gut lumen
b. Methylcellulose
c. Psyllium preparations - Metamucil - (some of these preparations are 50% sugar ALSO preparations that fizz in water may have a very high sodium content)
d. These products should be taken with a full glass of water USE THE AMOUNT OF WATER IT SUGGESTS TO USE/ some have A LOT OF NA

CONSTIPATION

Saline Cathartics

HOW DO THEY WORK?

JUST LIKE MANITOL IN PULLING WATER OUT OF INTERSTITUAL SPACES

a. Magnesium salts are the most commonly used. These salts are poorly absorbed and hypertonic resulting in water being pulled into the colon and trapping it there. Use primarily as a bowel preparation.
b. Milk of magnesia
c. Magnesium citrate
d. Patients with renal dysfunction should not have repeated doses of magnesium containing preparation because of the possibility of systemic magnesium accumulation.

a. These compounds work by decreasing water reabsorption and colonic/ileal motility, and increasing water secretion into the colon. Should not be used daily. Can be used periodically to treat constipation.
b. Castor oil (ricinoleic acid)
c. Bisacodyl (Dulcolax)
Co-administration of bisacodyl tablet with an antacid will cause premature dissolution of the enteric coated tablet which will lead to gastric upset.
d. Anthraquinone derivatives (senna, cascara) – used in combination with colace to treat opioid induced constipation

Osmotic laxatives

Lactulose

Metabolized by colonic bacteria to osmotically active nonabsorbable substances resulting in water accumulation similar to the saline cathartics.

Constipation

Glycerin

Drugs

How they cause nausea?

A. Anticipatory nausea and vomiting: a response based on previous treatment
B. Acute emesis: occurs within less than 24 hours of chemotherapy administration
C. Delayed emesis: any emesis that occur after 24 hours of chemotherapy administration

Benzodiazepime (lorazepam)

What it will treat?

N/V

Anticholinergic

1. Mechanism
a) Block impulses from vestibular apparatus
2. Class side effects
a) Drowsiness
b) Dry mouth
c) Urinary retention (esp. in a pt. with BPH)
d) Mydriasis and loss of visual accommodation
3. Scopolamine
a) Most effective of this class for motion sickness
4. Diphenhydramine (Benadryl); Dimenhydrinate (Dramamine); Cyclizine

N/V

Antiserotonin (5HT3 blockers)

What do they not cause?

***

2. Ondansetron (Zofran) & Granisetron (Kytril) & Dolasetron (Anzemet) & palonosetron (Aloxi)
a) Chemotherapy related N&V
b) Postoperative N&V
c) Unlike metoclopramide, have no extrapyramidal side effects
d) May cause hypotension and headache
e) Onset of ondansetron is faster than with granisetron
f) If 5HT3 blockers fail – do not use this class of drug as rescue therapy

IF ONE OF THESE DRUGS DOES NOT WORK, DO NOT USE A DRUG FROM THE SAME CATEGORY

N/V

Antidopamine

Phenothiazines: Prochlorperazine (Compazine); Promethazine (Phenergan); Chlorpromazine (Thorazine)

****

a) General N&V
b) Chemotherapy related N&V
c) Postoperative N&V
d) Can cause extrapyramidal side effects (treat with Benadryl - diphenhydramine) example dystonia, IV benadryl treats those symtpoms
e) EPS more common in children

Neurokinin-1 (NK-1) receptor antagonist, aprepitant (Emend)

When do you use this?

Corticosteroids

Marinol