Post on 05-Apr-2018
7/31/2019 ANTIPARKINSONIAN DRUGS2
1/41
Block I Posting, Pharmacology
Lectures
antiparkisonian drugs
Dr. Aduragbenro Adedapo
7/31/2019 ANTIPARKINSONIAN DRUGS2
2/41
ANTIPARKINSONIAN DRUGS
Parkinsonism: - extrapyramidal motor disorder Xterisedby rigidity, tremor, hypokinesia = parkinsonian triad
10 IDIOPATHIC 20 CAUSES Drugs MPTP N-methyl-4phenyl-
1,2,3,6- tetrahydropyridine a chemical contaminant ofheroin, atherosclerosis, encephalitis, drugs which blockdopamine receptors e.g. neuroleptics for treatingschizophrenia phenothiazines eg chlorpromazine
Imbalance between dopaminergic (inhibitory ) &cholinergic (excitatory ) system in the striatum occursgiving rise to the motor defect.
NB cholinergic system is not primarily affected but itssuppression by anticholinergics tends to restore balance.
7/31/2019 ANTIPARKINSONIAN DRUGS2
3/41
Antiparkinsonism drugs
CLASSIFICATION Drugs affecting brain dopaminergic system i.e. increasing
dopaminergic activity Dopamine precursors - Levodopa (L-dopa)
Dopaminergic agonists e.g.
bromocriptine,pergolide,lisuride,apomorphine,ropinirole,piribedil Peripheral decarboxylase inhibitors-carbidopa, benserazide
Dopaminergic transmission facilitators - selegiline (MAOBinhibitor),
Stimulate dopaminergic release - Amantadine Drugs affecting brain cholinergic system Central anticholinergics:- Benzatropine, trihexyphenidyl (Benzhexol),
procyclidine, Biperiden
Antihistaminics :- Orphenadrine, Promethazine
7/31/2019 ANTIPARKINSONIAN DRUGS2
4/41
Levodopa
Levodopa
Inactive by itself.
Immediate precursor of DA
Greater than 95%of an oral dose is decarboxylated in the peripheral tissue(mainly gut & liver) high first pass metabolism
DA thus formed causes adverse effects e.g. on the heart, (tachycardia),acting on adrenergic receptors, blood vessels, other peripheral organsand CTZ (nausea & vomiting), though located in the brain i.e. floor of 4thventricle, not bound by BBB. Tolerance develop to the peripheral effect.
1-2% of admin. L-dopa crosses to the brain, is taken up by the survivingdopaminergic neurones, converted to Dopamine which is stored & releasedas transmitter.
Mech. of action L Dopa is decarboxylated to DA in the brain by dopa decarboxylase. Beneficial effects produced through the action of DA on D2 receptors.
DA itself is not used because it does not cross the BBB.
7/31/2019 ANTIPARKINSONIAN DRUGS2
5/41
Levodopa
Route of admin.OralPharmacokinetics -Peak plasma conc. reached in 1-2 hours, t 1-2 hours.
-Only about 1% reaches the brain a result of peripheral metabolism.
-Rapidly absorbed from the small intestines
-Utilize the active transport process meant for aromatic amino-acids.
-Bio-availability affected by:- i. Gastric emptying:- If slow, L-dopa is exposed for a long time to the degrading
enzymes in gut and liver, less will be available to penetrate BBB.
ii. Amino-acids present in food: will compete for the same carrier for absorptionhence blood levels are lower when taken with meals.
Ldopa undergoes high first pass metabolism in g.i mucousa and liver by thispathway.
L-Dopa(Decarboxylase)Dopamine(MAO)DOPAC(COMT) HVA DopamineNoradrenaline
pyridoxine is a co factor for the enzyme decarboxylase N.B. DOPAC=3, 4 dihydroxyl phenylacetic acid, HVA=Homovanillic acid (3 methoxyl-
4-hydroxyl phenyl acetic acid)
7/31/2019 ANTIPARKINSONIAN DRUGS2
6/41
Levodopa (ctd)
-Metabolites are excreted in urine mostly after conjugation. INDICATIONS: L-Dopa is used to treat parkinsonism (except drug
induced extrapyramidal symptoms). CONTRAINDICATION: closed angle glaucoma. Caution: Elderly, Ischcemic Heart dx., Psychiatric dx., Hepatic dx., Renal
dx., Gout, Peptic ulcer.
ADVERSE EFFECTS: Nausea & Vomiting.
Psychiatric Side Effects. Schizophrenia like symptoms vivid dreams,confusion due to excess dopamine action in the limbic system (anti-dopaminergic drugs are anti-psychotic).
Cardiovascular effects- hypotension, cardiac arrythmias, exacerbation of
angina. Dyskinesia.
Alteration in taste sensation.
Fluctuation in motor performancegradually ranging from end of dosedeterioration, on-off effect, all or none response.
7/31/2019 ANTIPARKINSONIAN DRUGS2
7/41
STRATEGIES TO MANAGEMENT
Optimize L-dopa treatment, minimize its unwanted peripheral effects and maximizethe central effect with in the brain.
Carbidopa Peripheral inhibitor of dopa decarboxylese which cannot penetrate theBBB, prevents the extracerebral conversion of L-Dopa to dopamine.
Domperidone a dopamine antagonist, does not penetrate BBB, blocks peripheralstimulation of dopamine receptors.
Selegiline and entacapone, MAOB and COMT inhibitors, respectively inhibit
dopamine degradation centrally i.e. in the CNS. NOTE: Initial Rx with L-dopa is effective in 80% pts. with possible restoration of near
normal motor function.
L-dopa restores dopamine levels in the short term but has no effect on the underlyingdegenerative dx process, with progression in neuronal degeneration, corpus striatumis unable to convert L-dopa to dopamine sufficiently enough, i.e. capacity to convertreduce after 2-5 years of therapy, fluctuation in the level of symptoms control sets inand manifests as End of dose deterioration (wearing off ) which is initially (i.e. ashortening of the duration of each dose of L-dopa) gradual, develops into rapidfluctuations or switches in clinical state or the on-off effect. This varies fromincreased mobility and a general improvement to increased rigidity and hypokinesia.With time all or none response develops when the patient is alternately well anddisabled.
7/31/2019 ANTIPARKINSONIAN DRUGS2
8/41
Levodopa
INTERACTIONS: 1. Pyridoxine:- Abolishes therapeutic effect by enhancing peripheral
decarboxylation of L-dopa, less drug available to cross BBB.
2. Phenothiazines:- Butyrophenones, metoclopramide block DA receptors &prevent therapeutic effect.
Domperidone:- A peripheral DA receptor antagonist blocks Levodopainduced nausea & vomiting without affecting its anti-parkinsonian (since it does not
cross the BBB). Reserpine abolishes L-dopa action by preventing entry of DA into synaptic
vesicles.
3. Non selective MAOIs:- Prevents degradation of peripherallysynthesized DA and NAHypertensive crisis can occur.(MAO-A predominate inperipheral adrenergic neurones and intestines, while MAO-B occur in the brain andplatelets)
4. Anti-HT sive:- Postural hypotension more pronounced, therefore reducedose of anti HT if L-dopa is started.
5. Atropine and other anti-cholinergics:- additive effect with low dose L-dopa.
Atropine retards the absorption of L-dopa, giving more time for peripheral degradationto occur efficiency of L-dopa may be reduced.
7/31/2019 ANTIPARKINSONIAN DRUGS2
9/41
Carbidopa and Benserazide are peripheral (l-dopa)decarboxylase inhibitors. They do not penetrate theBBB. They do not inhibit conversion of L-dopa todopamine in the brain. Administered along with L-dopa.
Dopamine agonist e.g. bromocriptine, selective for the D2receptors, apomorphine also has agonist action at D1receptors.
Route of admin oral.
With bromocriptine, improvement in symptoms occurwithin -1 hour, lasts 6-10 hours
Adverse effects: nausea, vomiting, constipation,headache, hallucinations, hypotension, xs daytimesleepiness, nasal stuffiness, conjuctival injection,dyskinesia may occur but less than with l-dopa.
7/31/2019 ANTIPARKINSONIAN DRUGS2
10/41
Amantadine:-
Stimulates the release of dopamine.
Developed as an anti-viral drug for prophylaxis of influenza A2 but was found tobenefit Parkinsonism.
Acts rapidly but less efficient than if L-dopa. More efficient than anti-cholinergics.
Mechanism of action Facilities presynaptic dopamine synthesis & release in the brain.
Inhibits its uptake in Ns. Also possible action on glutamate receptors. Additional muscarinic blocking actions.
Synergistic effect when used in conjunction with L-dopa to Rx Parkinsonism
has short term benefit because most of its effectiveness is lost within 3/12 of initiatingRx
Adverse Effects
Anorexia, nausea.
Hallucinations, insomnia, dizziness, confusion, nightmares. Livedo reticularisdue to local release of catecholamines resulting in
vasoconstriction.
Ankle oedema.
SE more marked when combined with anti-cholinergics.
7/31/2019 ANTIPARKINSONIAN DRUGS2
11/41
MAOBI,
Selegiline (Deprenyl)
Selectively inhibits MAOB enzyme in the brain (theenzyme is responsible for the degradation of dopamine).
Route of admin.: oral
Indication: used on its own to Rx Parkinsonism, and inconjuction with L-dopa to reduce end of dosedeterioration.
Adv. Effect
Postural hypotension, nausea, confusion, accentuates L-
dopa induced involuntary movements & psychosisContra-indication: Convulsions
Interaction: Pethidine excitement, hyperthermia, respdepression
7/31/2019 ANTIPARKINSONIAN DRUGS2
12/41
Anti-cholinergics
Antagonize muscarinic receptors
Reduce excess striated cholinergic activity
Oral administration
Adverse Effects dry mouth, Blurred vision, mildmemory loss, acute confusional state
Antihistamines less efficacious thananticholinergic, have antimuscarinic effect and
are better tolerated by some adults. Thesedative effect is also helpful. Orphenadrine hasmild euphoriant effect
7/31/2019 ANTIPARKINSONIAN DRUGS2
13/41
Myasthenia Gravis.
rare dx.
Autoimmune dx, antibodies directed to nicotinicreceptors in the skeletal muscle NMJ, affect 1 in
10,000 popn. Reduction in no of free Nm cholinoceptors.
Damage to NMJ weakness, easy fatigability onrepeated activity with recovery after rest.
Anticholinesterases are 1st line Rx for ocular dx,and adjunct to immunosuppressant therapy forgeneralised myasthenia gravis
7/31/2019 ANTIPARKINSONIAN DRUGS2
14/41
Myasthenia Gravis
Neostigmine
enhance neuromuscular transmission involuntary and involuntary muscle improvingcontraction
allow ACH released from prejunctional endingsto accumulate and act on receptor of a largearea.
Directly depolarizing the end plate.
Rx started with 15mg orally 6 hourly then adjustaccording to response.
Produces therapeutic effect for up to 4hours
7/31/2019 ANTIPARKINSONIAN DRUGS2
15/41
Pyridostigmine
an alternative, needs less frequent dosing
Longer acting, but less powerful and slower
in action than neostigmine.
Distigmine: longest action but danger ofcholinegic crisis makes it less useful
therapeutically
7/31/2019 ANTIPARKINSONIAN DRUGS2
16/41
Adverse effects
Nausea, vomiting, increased salivation,
diarrhoea, abd cramps
Bronchoconstriction, increased bronchial
secretion, lacrimation, sweating, involuntarymicturition and defeacation
Miosis, nystagmus
Bradycardia, heart block, arrhythmias,hypotension
Atropine is useful for the muscarinic side effects
7/31/2019 ANTIPARKINSONIAN DRUGS2
17/41
Myasthenia gravis Rx (ctd)
Corticosteroids: Immunosuppresant action,inhibits nicotinic receptor antibodies, mayenhance synthesis of receptor e.g. Prednisolone30-60 mg .day. Maintenance dose 10mg per day
Other immunosuppresants: Azathioprine andcyclosporine
Plasmapheresis: for removal of antibodies
Thymectomy
Short acting anticholinesterases for diagnosis Edrophonium for diagnosis of M.G.or cholinergic
crisis, duration of action 2-10 min.
7/31/2019 ANTIPARKINSONIAN DRUGS2
18/41
ANTI-COAGULANTS
Drugs used to reduce the coagulability of blood.
In vitro.
A - Heparin: 150 U to prevent clothing of 100ml blood.
B Calcium complexing agents: Na citrate, Na oxalate, Na edetate
In Vivo A. Parenteral B. oral
Heparin, LMW heparin dalteparin, enoxaparin Heparinoids Danaparoid, Heparin sulphate, Dextran sulphate,
Ancrod.
Hirudinslepirudin, bivalirudin
Epoprosterenol (prostacyclin)
Fondaparinux synthetic pentasaccharide that inhibits activatedfactor X
7/31/2019 ANTIPARKINSONIAN DRUGS2
19/41
B. Oral anticoagulants
Coumarin derivatives: Bishydroxycoumarin
(dicumarol), Warfarin sulphate,
Acenocoumarol
Indandione derivatives: Phenindione
7/31/2019 ANTIPARKINSONIAN DRUGS2
20/41
HEPARIN
Discovered by a medical student, McLean in 1916.
Non-uniform mixture of straight chains mucopolysaccharide
Reffered to as standard or unfractionated heparin
MW 10,000 20,000
Active both in-vitro and in-vivo
Initiates anticoagulation rapidly, but has a short duration of action Acts indirectly by activating plasma antithrombin III (AT III)
The complex binds to & inactivates the clotting factors (Xa, IIa, IXa,XIa, XIIa and XIIIa) in the intrinsic and common pathway, but notfactor VIIa in the extrinsic pathway
Low concentration prolong aPTT without significant PT prolongation
Low conc interfere mainly with intrinsic pathway while high concaffect the common pathway as well
Sudden withdrawal of treatment may cause rebound coagulation
May have antiplatelet effect and prolong bleeding time
7/31/2019 ANTIPARKINSONIAN DRUGS2
21/41
Heparin
Not absorbed orally, does not cross BBB or placenta
Metabolized in the liver by heparinase and excreted inthe urine.
Half-life abt 1-5hrs depending on the dose, it is
prolonged in cirrhotics and renal failure, shorter inpulmonary embolism
Dose i.v. bolus 5,000-10,000U 4-6hrly (50-100U/kg), orcontinuous infusion of 750-1000U/hr after an initial bolusdose. Subcutaneous injection 10,000-20,000U 8-12hrly.NO I.M. injection because of heamatoma formation. Lowdose s.c. 5000U 8-12hrly to prevent DVT
7/31/2019 ANTIPARKINSONIAN DRUGS2
22/41
Do not mix with penicillin, TCN, hydrocortisone or NA in the samesyringe or infusion bottle
Adverse effects Bleeding, Thrombocytopenia, Alopecia, Osteoporosis,
Hypersensitivity reaction urticaria, angioedema, anaphylaxis.
Contraindication Bleeding disorders - haemophilia, Severe HT, Subacute bacterialendocarditis, recent cerebral haemorrhage, Ocular andneurosurgery, lumbar puncture, severe liver disease, oesophagealvarices, cirrhosis,
UFH given to maintain a PTT at 2.0-2.5 times control.
Toxicity Bleeding: stop heparin, administer heparin antagonist -Protamine sulphate.
7/31/2019 ANTIPARKINSONIAN DRUGS2
23/41
Protamine Sulphate:
Heparin antagonist, strongly basic, LMW proteinobtained from certain fish sperm
Admin i.v., neutralizes heparin weight for weight1mg needed for 100U of heparin.
It exhibits weak anticoagulant effect even in theabsence of heparin
If used in excess, it has an anticoagulant effect
May release histamine being basic,
hypersensitivity may occur. Rapid i.v. injection causes flushing and
breathing difficulty.
7/31/2019 ANTIPARKINSONIAN DRUGS2
24/41
LMW Heparin
MW range 3,000-7,000.
Selectively inhibits activated factor X but has less effect on AT andon coagulation in general.
Less antiplatelet action
Lower incidence of bleeding as complication
Better s.c. bioavailability (79-90%) compared to UFH (20-30%) Longer half-life, longer duration of action, once daily dose
Laboratory monitoring is not mandatory for the standard prophylacticdose, since aPTT/clotting times are not prolonged. This may berequired in patients at increased risk of bleeding eg renalimpairment, and I the underweight and overweight
LMW Heparins- enoxaparin and dalteparin are effective inpreventing development of DVT post op. Effective in Rx of acutevenous thrombosis, acute coronary syndrome
Dextan sulphate: is a sulphated polymeric sugar, less potent thanheparin but has a longer duration of action.
7/31/2019 ANTIPARKINSONIAN DRUGS2
25/41
Heparinoids
Semi synthetic
Sulphated mucopolysaccharides
Potent anticoagulants E.g. Danaparoid sodium
indications: prevention of DVT, thrombo-
embolic disease in patients with heparininduced thrombocytopenia
7/31/2019 ANTIPARKINSONIAN DRUGS2
26/41
HIRUDIN.
Powerful & specific thrombin inhibitor
available in recombinant form as lepirudin,bivalirudin
its action, is independent of antithrombin III, itcan reach and activate fibrin bound thrombin inthrombi.
Route of admin S. C. ,I. V.
Lepirudin has little effect on platelet or the
bleeding time. administered like heparin, monitorby the aPTT, has a short half life
accumulates in renal in sufficiency, no antidote.
7/31/2019 ANTIPARKINSONIAN DRUGS2
27/41
Epoprostenol
Protacyclin
Given to inhibit platelet aggregation alone orwith heparin
Half life - 3min Admin by continuous intravenous infusion
Potent vasodilator
Indicatons during renal dialysis, pry pulm HT
Adverse effects headache, flushing,hypotension, bradycardia, tachycardia, pallor,sweating, agitation, dry mouth,chest pain
7/31/2019 ANTIPARKINSONIAN DRUGS2
28/41
Fondaparinux
Synthetic pentasaccharide
Inhibits acivated factor X
Indications: prophylaxis and treatment of DVT
and pulmonary embolism
Caution: bleeding disorders, etc as for heparin
CI: active bleeding, bacterial endocarditis
Adverse effects: Oedema, haemorrhage,anaemia, hypotension, thrombocytopenia,
purpura, GI disturbance, rashes, pruritus
WARFARIN AND THE COUMARIN
7/31/2019 ANTIPARKINSONIAN DRUGS2
29/41
WARFARIN AND THE COUMARIN
anticoagulant
Oral anticoagulants (also used as rodenticides) (discovered fromspoiled sweet clover hay deficiency of plasma prothrombin andhaemorrhage ensured).
act as anticoagulant in-vivoand not in-vitro, act indirectly byinterfering with the synthesis of Vit. K dependent clotting factors inthe liver. They block the reduction of Vit.K epoxide, which is
necessary for its action as a cofactor in the synthesis of factors VII,1X.
Anticoagulation develops over 1-3days, though the synthesis ofclotting factors is reduced within 2-4hrs of Warfarin admin. Factor VIIhas the shortest half-life (6hr), factor IX (24hr), factor X(40hr) andprothrombin (60hr),
therapeutic effect occurs when synthesis of clotting factors is reduceby 40-50%
Warfarin is the drug of choice, others acenocoumarol andphenindione are seldom needed
7/31/2019 ANTIPARKINSONIAN DRUGS2
30/41
DRUG
Half life
(T ) (hr)
Duration
of action
(days)
Loading
Dose (mg)
Maintenance
dose (mg)
Adverse effects
(non-haemorhagic)
1.
Bishydroxycou
marin
(Dicumarol)
25-100
(dose
dependent)
4-7 200 for
2/7
50-100 Freq. Git disturbance
2. Warfarin
sod.
36-44 3-6 10-15 2-10 (single
dose, same
time dly)
Alopecia, dermatitis,
diarrhea
3.
Acenocoumarol
18-24 2-3 8-12 2-8 Oral ulceration,
git distur,
dermatitis urticaria
4.Ethylbiscoumacetate
2 1-3 900 300-600 Alopecia, bad taste
5. Phenindione 5 1-3 200 50-100 Orange urine,
rashes, fever,
leukopenia, hepatitis,
nephropathy,
agranulocytosis
Pharmacokinetic and adverse
effects profile of oral anticoagulants
7/31/2019 ANTIPARKINSONIAN DRUGS2
31/41
Warfarin sodium
a racemic mixture of R (dextro-) and S (levo-) enantiomers, well absorbed from the intestine, 99% plasma protein bound,
crosses placenta and is secreted in milk.
Metabolized by ring oxidation (levorotatory) and side chain reduction(dextrorotatory),
both are partially conjugated by glucuronic acid, undergo someenterohepatic circulation,
excreted in urine.
Indications
Prophylaxis or the Rx of DVT and PE.
Prophylaxis of embolism in Atrial fibrillation, Rheumatic dx and in pts
with prosthetic heart valves.
7/31/2019 ANTIPARKINSONIAN DRUGS2
32/41
Warfarin
Contraindications: as for heparin, pregnancy
Adv. Effect Haemorrhage
NOTICE: onset of action of vit K antagonists takes
several hours, owing to the time needed for thedegradation of factors that have already been
decarboxylated (t VII= 6hrs.
IX =24hrs. X = 40hrs.
II=60hrs.).
7/31/2019 ANTIPARKINSONIAN DRUGS2
33/41
Antiplatelet Agents
Aspirin
Clopidogrel
DipyridamoleGlycorotein IIb/IIIa Inhibitors- Abciximab
Glycoprotein IIb/IIIa receptor inhibitors
Eptifibatide, tirofiban
7/31/2019 ANTIPARKINSONIAN DRUGS2
34/41
Aspirin
acetylsalicylic acid originally derived from the willow tree.
blocks the synthesis of Thromboxane A2 (TXA2) fromarachidonic acid in platelets.
it acetylates and thus inhibiting the enzymecycloxygenase and thromboxane synthetase.
TXA2 stimulates phospholipase C thus increasingcalcium levels and causing platelet aggregation
ASA also blocks the synthesis of prostacyclin from
endothelial cells (PGI2 is a strong inhibitor of plateletaggregation). This effect is short lived becauseendothelial cells unlike platelets, can synthesis newcycloxygenese.
7/31/2019 ANTIPARKINSONIAN DRUGS2
35/41
Admin. Orally
Indications- prevention and Rx of Myocardial Infarctionand ischaemic stoke also as an analgesic and anti-inflammatory agent (increased dose)
Contraindication: Children below 12 years (risk ofReyes syndrome), breastfeeding, haemophilia, pepticulcer, known hypersensitivity.
Adv. Effects bronchospasm
GIT haemorrhage Dose:- 75-150mg dly
7/31/2019 ANTIPARKINSONIAN DRUGS2
36/41
Membrane phospholipid
Phospholipase A (enzyme)
Arachidonic acid
yclooxygenase (enzyme)
I
Cyclic endoperoxides
PGG2, PGH2I
PGE2, PGD2, PGF2,; TXA2, PGI2
Lipooxgenase (enzyme)
LTA4
LTB4, LTC4 ->LTD4 ->LTE4->
SRS-A
7/31/2019 ANTIPARKINSONIAN DRUGS2
37/41
Dipyridamole. - inhibits phosphodiesterase enzy that hydrolyse
AMP.
cAMP levels result in decreased calcium levels
and inhibition of platelet aggregation. Admin orally.
Used in conjuction with warfarin and other oralanticoagulant in the prophylaxis against
thrombosis associated with prosthetic valve. Adv. Effect hypotension, nausea., diarrhea,
and h/ache.
7/31/2019 ANTIPARKINSONIAN DRUGS2
38/41
Clopidogrel.
inhibits activation of the glycoprotein II b / IIIa
receptor on platelets surface which is required
for aggregation to occur. Admininstered orally
Indications: prevention of cardiovascular &
cerebrovascular events
Can be used in place of aspirin, in asprin allergy
Ticlopidine similar action to clopidogrel.
7/31/2019 ANTIPARKINSONIAN DRUGS2
39/41
FIBRINOLYTIC AGENTS
Streptokinase 47k Da protein produced from hemolytic streptococci group C, inactivebut combines with circulating plasminogen to form an active complex degrading otherplasminogen into plasmin.
t 40-80 min.
Indication - life threatening venous thrombosis
pulm embolism
arterial thromboembolism.
Acute M. IC.I - recent haemorrhage, trauma, surgery within 10 dayorgan biopsy puncture to
non-compressible vessels, active bleeding, bleeding diathesis aortic dissection,coma, hx of CVD, (see BNF for more) serious GI bleeding within 3/12 or activeintracranial process Hx of HT DBP > 110mmHg, acute pericarditis.
Commonly used in conjuction with antiplatelet and anticoagulant drug .
Derived from haemolytic streptococci.. antigemic.
Repeated admin could result in anaphylaxis like rxn. If repeated admin required use non antigenic type tissue plasminogen activator
7/31/2019 ANTIPARKINSONIAN DRUGS2
40/41
Anistreplase.
(Anisoylated plasminogen streptokinase activatorcomplex APSAC)- consists of a complex of purifiedhuman plasminogen and bacteria streptokinase. used for
coronary thrombolysis. However, when it is given as abolus injection at the recommended dose for coronary of30U, marked systemic fibrinolysis occurs.
Tissue plasminogen activators (t-PA): this activatesplasminogen that is bound to fibrin, thus confining
fibrinolysis to formed thrombus. Avoids systemicactivation.
7/31/2019 ANTIPARKINSONIAN DRUGS2
41/41
ANTIFIBRINOLYTIC AGENTS.
Inhibits plasminogen activation and clot dissolutionEpsilon aminocaproic acid (EACA) A lysine analogue.
Binds to lysine bindingof plasmin to target fibrin.
Potent inhibitor of fibrinolysis.
Can reverse hyperplasminemic states associated with excessive intravascularfibrinolysis resulting in bleeding e.g overdose of streptokinase/urokinase/alteplase.
- rapidly absorbed after oral admin.
-50% excreted unchanged in the urine rapidly within 12hrs.
Indication: adjunctive treatment in haemophilia, anti dote for bleeding from fibrinolytictherapy, prophylaxis for bleeding from intracranial aneurysms.
Adverse Effect. Hypotension, bradycardia, arrythmias, myopathy, nasal stuffiness,abdominal discomfort, diarrhea
Contraindications: DIC, genitourinary bleeding of kidney and ureters because of thepossibility of forming excessive clots.
Thrombi that are formed during Rx with the drug are not lysed e.g. in patients withhaematuria, urethral obstruction by clots may lead to renal failure after Rx withaminocaproic acid.