Organ Systems Unit 2 Drugs

Front 1

DESMOPRESSIN (DDAVP®)

Back 1

Releases stores of vWF into blood from “Weibel-Palade bodies” in
endothelial cells
• vWF then leads to rapid elevation of factor VIII
− Used to treat bleeding episodes and prior to surgery for prophylaxis of
bleeding
− Stores become depleted → Not for chronic treatment

Front 2

ASPIRIN

Back 2

NSAIDs inhibit COX-1 and thromboxane synthesis by platelets and, hence,
inhibit platelet aggregation.
• Aspirin is unique in that it is an irreversible inhibitor of platelet COX-1 at
relatively low doses
Treatment of suspected acute MI
• Prophylaxis of primary (discussed above) and subsequent
MI and ischemic strokes in patients at high risk, e.g.
− those who have already suffered MI or stroke
− stable angina, TIAs (mini-strokes), but not helpful for IC
− those who have undergone bypass surgery or angioplasty
• Aspirin should be avoided in patients with
1) Active peptic ulcer
2) Hepatic or renal disease
3) Disorders of blood coagulation

Front 3

TICLOPIDINE (Ticlid®)

Back 3

Irreversibly block ADP-induced platelet aggregation.
• Ticlopidine and clopidogrel are taken orally
• There is 1-2 day lag in the onset of action
Due to bone marrow toxicity, drug label has a “Black Box Warning” and it is
recommended that use of ticlopidine should be limited to patients who cannot
tolerate aspirin. Problems are usually seen in first 3 months
− Neutropenia - incidence ~2%
− Thrombotic thrombocytopenic purpura (TTP) and aplastic anemia also
occur - Incidence ~0.02%
• USES
− Thrombosis prophylaxis patients who have had a stroke or are at risk
and those that have coronary artery stents inserted

Front 4

CLOPIDOGREL (Plavix®)

Back 4

Irreversibly block ADP-induced platelet aggregation.
• Clopidogrel is a newer closely related drug, which has less frequent side
effects than ticlopidine and appears to be slightly more effective than aspirin
− Clopidogrel long-term (1-2 yr) treatment seems O.K.
− Bone marrow toxicity (neutropenia), incidence 0.04%

Front 5

ABCIXIMAB (ReoPro®)

Back 5

Abciximab is a mouse/human chimeric Fab fragment of an antibody to the
fibrin receptor integrin GpIIb/IIIa.
− Blocks Irreversibly
− Decreases death + MI associated with angioplasty from 10% → 5%
• USES: Prophylaxis of thrombosis during percutaneous coronary interventions

Front 6

DIPYRIDAMOLE (Persantine®)

Back 6

Inhibition of endothelial and platelet cAMP phosphodiesterases promotes
vasodilation and inhibits platelet aggregation.
• ACTIONS
− Coronary vasodilator and antiplatelet, precise mechanism uncertain
− Blocks adenosine deaminase – elevates adenosine
− Blocks phosphodiesterase – elevates cAMP

Front 7

CILOSTAZOL (Pletal®)

Back 7

Inhibition of endothelial and platelet cAMP phosphodiesterases promotes
vasodilation and inhibits platelet aggregation.
• Oral inhibitor of PDE III – raises cAMP
• Femoral vascular beds particularly sensitive
− Approved for treatment of intermittent claudication
Antiplatelet Drugs
10/28/2008 17
• Side Effects
− Increases heart rate and contractility – via cAMP elevation
− Contraindicated in CHF patients (Chronic use of inotropic drugs, other
than digoxin, is associated with increased mortality)

Front 8

PROSTACYCLIN (PGI2, EPOPROSTENOL, Flolan®)

Back 8

PGI2 raises platelet cAMP and lowers platelet Ca2+ thereby inhibiting the release
reaction and platelet aggregation. Due to its short (2-3 min) half-life (see Eicosanoid
notes) and the requirement for parenteral administration by continuous IV infusion,
usefulness is limited.
• Primarily used for treatment of primary pulmonary hypertension and pulmonary
hypertension associated with scleroderma. Benefits arise from both dilation of
pulmonary blood vessels and its inhibition of platelet aggregation and thrombosis.
− Major side effect is a decrease in BP.
• Can be used as an anticoagulant in place of heparin during extracorporeal circulation
of blood, e.g. hemodialysis

Front 9

HEPARIN

Back 9

Heparin accelerates the inactivation of thrombin, factor Xa and other proteases by
the endogenous plasma protein antithrombin III. Thus, provided the blood contains
adequate antithrombin III heparin works in vitro and in vivo.

Front 10

FONDAPARINUX (Pentasaccharide, Arixtra®, 2001)

Back 10

• Synthetic pentasaccharide containing only the antithrombin III binding
sequence
• Stimulates inactivation of factors Xa (and IXa), but has no effect on thrombin
• Clinical trials suggest it may be more effective than enoxaparin in
prophylaxis of DVT associated with hip and knee replacement surgery
• Half-life 17-21 hours

Front 11

PROTAMINE SULFATE

Back 11

• Neutralizes heparin
• Protamine Sulfate (1 mg/100 u UH or 1mg/mg LMWH) is
administered by IV infusion over a 10 min period
• MECHANISM
− Protamine is a strongly basic (positively charged), low mol.
Wt. protein isolated from fish sperm, which combines with
negatively-charged heparin to form an inactive salt.
− Note that protamine is less effective in neutralizing LMWHs,
producing a maximum effect of 60%
− Protamine Sulfate itself has weak anticoagulant activity
(binds to thrombin) and has a longer half-life than heparin. It
should not, therefore be administered in excess.

Front 12

enoxaparin (Lovenox®)

Back 12

Low Molecular Weight
Heparins (LMWH),
LMWHs bind much less strongly to a variety of proteins. This leads to
• Greater SC bioavailability
• Longer and dose-independent half-life,
• Lower incidence of thrombocytopenia
• Less bleeding
• Lower risk of osteoporosis
• More effective in prevention and treatment of DVT and MI
Net result: LMWHs permit 1-2 dose per day SC with no lab (or little)
monitoring, but need to be careful in patients with renal problems or who are unusually
large or small. LMWHs can also be self-administered by patient at home.

Front 13

HIRUDINS

Back 13

Hirudin is a direct inhibitor thrombin obtained from the medicinal leech (Hirudo
medicinalis). Since thrombin is a powerful inducer of platelet aggregation, hirudin is
potentially useful as an antiplatelet drug.
• MECHANISM: It is a 65 amino acid protein, which binds to the “substrate”
binding site and active site of thrombin but not the fibrin binding site. Hence, it can
block fibrin-bound thrombin in the clot itself. (Remember, most of the proteases are
protected from inhibition by antithrombin while they are bound within the clot).
• Must be administered IV or SC

Front 14

LEPIRUDIN

Back 14

recombinant proteins almost identical to hirudin
Lepirudin, IV infusion for treatment of HIT type II
Administered by continuous IV infusion. Half-life 1.3 hr,
excreted by the kidneys. Antibodies generated against lepirudin are seen in
40% of patients and may increase the anticoagulant effect by delaying renal
excretion. Allergic and hypersensitivity reactions including anaphylactic
shock have been reported.

Front 15

WARFARIN

Back 15

NO EFFECT on coagulation factors or their precursors in vitro, i.e. indirect action
• Effects in vivo are only seen after a lag of 36-72 hrs. Note, however, that the t1/2 is
long (37 ±15hrs) therefore steady state plasma concentrations will not be achieved for
7-10 days
• Blocks γ-carboxylation of glutamate residues of newly synthesized factors II, VII,
IX, X as well as protein C and protein S.
• Normal levels of non-carboxylated factors are still found in the blood
• The lag results from the time required for the natural decay of the normal factors and,
thus, reflects the half-lives of factors
IMPORTANT: Since the desired anticoagulant/antithrombotic effects are associated with
depletion of factors II and X, loading doses should NOT be given, since this
could deplete protein C below a safe level before prothrombin levels are affected

Front 16

phytonadione

Back 16

VITAMIN K1
Administration of vitamin K increases active factors within 6-12 hours (oral)

Front 17

STREPTOKINASE

Back 17

SK is a nonenzymatic protein (MW 47,000) activator of plasminogen
produced by type C β-hemolytic streptococci.
• Mechanism: SK forms a complex with free Pg causing a conformational
change that exposes its proteolytic activity. This complex then activates free
Pg to plasmin (see Fig. 19). This therapy works because the streptokinaseplasminogen
complex is resistant to inhibition by α2-antiplasmin.

Front 18

ε-aminocaproic acid (EACA)

Back 18

Plasmin Inhibitor

Front 19

ALTEPLASE

Back 19

TISSUE PLASMINOGEN ACTIVATOR
This is the “natural” endothelial activator of Pg produced by recombinant
DNA techniques. It is cleaved by plasmin to a two chain form without change
in activity.
• Supposed Advantages: Activation of Pg is limited to the surface of fibrin on
the thrombus. No antibodies present/produced.
• Disadvantages: Cost = $2,800. Half-life 5 min and 8 min for single and twochain
forms respectively.
• Usage: continuous IV infusion e.g. For treatment of MI: 15mg bolus
followed by 0.75mg/kg (max 50mg) over 30 min then 0.5mg/kg over 60 min.
For stroke: 0.9mg/kg (max 90mg) 10% as bolus followed by remainder over
60 min.

Front 20

acetylcholine

Back 20

• Agonist at all muscarinic and nicotinic receptors, therefore not
selective - many effects
• Quaternary compound - limited CNS distribution
• Ester bond is hydrolyzed by esterases in gut and very rapidly by
AChE and BChE in the blood stream - very short half-life
• Virtually no therapeutic uses

Front 21

pilocarpine

Back 21

cholinergic agonist
topical use for glaucoma
selective for muscarinic actions.
NOT a quaternary ammonium compounds - permanent charge.

Front 22

bethanecol

Back 22

cholinergic agonist
selective for muscarinic actions
quaternary ammonium compounds - permanent charge.
Bethanechol is sometimes given orally or subcutaneously to treat urinary retention resulting from general anesthetic or diabetic neuropathy of the bladder, or to treat gastrointestinal atony (lack of muscular tone).

Front 23

nicotine

Back 23

uses: insecticides, psychoactive drug
Various preparations available (gum, patch, inhalant).
Use and abuse patterns related to time-action characteristics.
Tertiary ammonium, lipophilic drug easily crosses mucosal membranes,
blood-brain barrier, skin, etc.
Agonist at NMJ, autonomic ganglia/adrenal medulla, and in CNS.

Front 24

muscarine

Back 24

cholinergic agonist
of interest in relation to mushroom poisoning, and as prototype muscarinic
agonist

Front 25

edrophonium

Back 25

a simple
alcohol cholinesterase inhibitor
Readily reversible inhibition of
acetylcholine hydrolysis. Duration of
action typically 5 - 15 minutes.
Quaternary ammonium - no CNS actions
Uses
Diagnosis of myasthenia gravis
Assess effects of longer acting anticholinesterases:
If dose is too low, edrophonium will increase strength
If dose is too high, edrophonium will decrease strength [i.e., depolarization block had
occurred]

Front 26

pyridostigmine

Back 26

anticholinesterase
Treatment of myasthenia gravis
Duration of action largely determined by rate of enzyme regeneration. Pyridostigmine is the
slowest of these examples.

Front 27

physostigmine

Back 27

anticholinesterase
tertiary N
physostigmine can cross the bloodbrain
barrier, but the others do not.

Front 28

Malathion

Back 28

organophosphate
Hydrophobic, lipophilic drugs that
can be absorbed through skin.

Front 29

(diisopropylfluorophosphate, DFP)

Back 29

organophosphate
Hydrophobic, lipophilic drugs that
can be absorbed through skin.

Front 30

pralidoxime

Back 30

for organophosphate poisoning, to help regenerate
cholinesterase
Quaternary - Pralidoxime does not enter CNS
Must be injected - usually by IV infusion
High doses can block NMJ
NOT effective after “aging” of the enzyme-inhibitor
complex.

Front 31

neostigmine

Back 31

anticholinesterase
myasthenia gravis

Front 32

echothiophate

Back 32

anticholinesterase
topical for glaucoma

Front 33

atropine

Back 33

competitive antagonist at muscarinic cholinergic receptors.
No significant action at nicotinic receptors.
no fixed charge, distributes to CNS.
should
not be used in men with prostatic hypertrophy, or people with glaucoma.

Front 34

scopolamine

Back 34

MUSCARINIC ANTAGONIST
compared to atropine, relatively greater CNS effects.
Scopolamine distributes readily to CNS, some absorbed through skin.
CNS effects - sedation; amnesia; dreamless-sleep.
Especially with high doses or in presence of pain, restlessness, excitement,
hallucinations, delirium.
Effective for motion-induced nausea (motion sickness), some effectiveness against
post-operative nausea

Front 35

ipratropium

Back 35

MUSCARINIC ANTAGONIST
Quaternary compound - will not cross the blood-brain barrier.
Used for certain respiratory diseases such as COPD (chronic obstructive pulmonary disease),
asthma .
Used by inhalation - helps achieve some selectivity.
Desired effects - bronchodilation, inhibition of secretion.
Adverse effects - dry mouth, etc.

Front 36

tolterodine

Back 36

MUSCARINIC ANTAGONIST
Somewhat selective for M3 receptors.
Relaxes the detrusor muscle in bladder.
Relatively small effect on salivary and other glands.
Used for overactive bladder, urinary frequency, urgency, incontinence.

Front 37

Atropine poisoning

Back 37

All the effects previously noted are prominent -
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter”.
There is difficulty with thermoregulation. Especially with infants and younger children,
hyperthermia may be quite prominent, and may lead to death.
The elderly tend to be relatively more sensitive to the CNS effects - hallucinations, confusion.
Many drugs have, as adverse effects, atropine-like effects. For some, the prominent signs of
intoxication are the same as atropine.

Front 38

Tubocurarine (curare)

Back 38

Rapid onset after i.v. injection.
Weakness progressing to flaccid paralysis.
Small muscles involved in finely-controlled movements (such as eye muscles) are most
sensitive, large muscles are less sensitive. Intercostals and diaphragm are least sensitive.
Curare is partly excreted unchanged, and partly as metabolites.
Compared to many newer drugs, curare has a relatively long duration of action.
Curare is not 100% selective; it has some effect to inhibit transmission at autonomic ganglia.
Curare can cause release of histamine from mast cells.
competitive antagonists at the nicotinic receptor.
Produce a non-depolarizing block

Front 39

Mivacurium
Pancuronium
Atracurium

Back 39

Competitive antagonists at nicotinic receptors of the skeletal neuromuscular
junction
ALL of these are quaternary. Limited volume of distribution, and NO CNS EFFECTS.
Thus, another drug must be given to depress consciousness.
All the newer drugs are more selective than tubocurarine.
Several (like vecuronium) are biotransformed more than tubocurarine, and have shorter halflives.
Break-down products of some have neuromuscular blocking actions of their own.
Atracurium breaks down spontaneously. One product (laudanosine) can cause seizures.
Mivacurium is very short-acting – hydrolyzed by plasma esterase

Front 40

succinylcholine

Back 40

Succinylcholine acts as an agonist at the nicotinic receptors of the NMJ.
Unlike acetylcholine, it is not hydrolyzed by acetylcholinesterase.
It produces a depolarizing block - same as occurs with excess ACh or nicotine
Succinylcholine action is intensified by anticholinesterase drugs (in contrast to their effect on
non-depolarizing blockers).
K+ may be released and cause serious hyperkalemia.
Succinylcholine may produce malignant hyperthermia.