PHAR 230 - TEST 2 - Modules 2 & 3

Break down the nervous system.

CNS & PNS

PNS: Nerves & Sensory receptors

Nerves: Afferent division (sensory) & Efferent division (motor)

Efferent division: autonomic & somatic

Autonomic: sympathetic & parasympathetic

Sympathetic: fight/fight

Parasympathetic: rest/digest

Describe the characteristics of the sympathetic and parasympathetic nervous systems.

Sympathetic: CNS neuron located in lateral gray horns of T1-L2; PNS ganglia near vertebral column; preganglionic fibers short - releasing acetylcholine; postganglionic fibers long - releasing norepinephrine

Parasympathetic: CNS neuron located in brain stem and S2-S4; PNS ganglia within vertebral column; preganglionic fibers long -releasing acetylcholine; postganglionic fibers short - releasing acetylcholine

What are the 3 types of synapses in the sympathetic nervous system and list their neurotransmitter, location, effect, and fate.

Cholinergic synapses:

• Release acetylcholine

• Located in sympathetic ganglion (where preganglionic neurons synapse with postganglionic neurons) or postganglionic fibers of sweat glands

• Effect: localized, always excitatory, persists for 20 msec

• Fate of neurotransmitter: broken down by enzymes:

  • acetylcholinesterase at synapses

  • pseudocholinesterase in surrounding tissue

Adrenergic synapses:

• Release norepinephrine

• Location: postganglionic fibers synapse with effectors (target muscle/gland, sometimes organ). This excludes sweat glands, which are cholinergic.

• Effect: localized; excitatory or inhibitory; persists for few seconds

• Fate of neurotransmitter:

  • Reuptake: 50-80% transported back to presynaptic neuron to be reused or broken down by monoamine oxidase (MAO) enzyme.

  • Broken down by catecholamine-O-methyltransferase (COMT) enzyme in synaptic cleft

Adrenal medulla transmitters:

• Release 80% epinephrine & 20% norepinephrine

• Location: whole body

• Effect: generalized; act as hormones; carried by bloodstream throughout body

• Fate: lasts longer as blood does not contain MAO or COMT

What are adrenergic receptors?

Protein molecules in target organs.

2 Classes: alpha receptors (a1 & a2); beta receptors (b1,b2,b3)

What adrenergic receptors do epinephrine and norepinephrine stimulate?

Epinephrine: all alpha & beta receptors

Norepinephrine: all alpha receptors, b1, and b3 (NOT b2)

Describe a1 receptors.

More abundant than a2

Excitatory effect on target cell:

• Vasoconstriction of blood vessel

• Closure of sphincters

• pupil dilation

Describe a2 receptors.

Inhibitory effect on target cell

Decreases release of norepinephrine

Help coordinate sympathetic and parasympathetic activities.

Describe the effects of all the beta receptors.

b1:

• Excitatory effects:

  • Inc smooth muscle contraction

  • Inc heart rate & contractility

  • Inc blood pressure

b2:

• Inhibitory effects:

  • Dec respiratory smooth muscle contraction → bronchodilation

  • Dec smooth muscle contraction → vasodilation & relaxation of walls

b3:

• In adipose tissue

• Stimulation → lipolysis

Where are a1,a2,b1, and b2 receptors located?

a1: smooth muscles (most tissues)

a2: CNS

b1: heart

b2: lungs, blood vessels, GI muscle, urinary muscles, uterus

What is the neurotransmitter of the parasympathetic nervous system?

Acetylcholine: broken down by acetylcholinesterase at synapse and pseudocholinesterase in surrounding tissue

Describe the 2 types of cholinergic receptors.

Nicotinic:

• Sensitive to nicotine

• Location:

  • Neuronal nicotinic receptors (Nn): autonomic ganglion cells

  • Neuromuscular nicotinic receptors (Nm): neuromuscular junctions of skeletal muscles

• Always excitatory

Muscarinic:

• Sensitive to muscarine

• Location: cholinergic neuromuscular or neuroglandular parasympathetic junctions; cholinergic sympathetic junctions (sweat glands)

• Effects are longer lasting than nicotinic receptors

• Excitatory or inhibitory

What two drugs act on the sympathetic nervous system?

Sympathomimetic agents: adrenergic drugs; stimulate SNS; agonists

Sympatholytic agents: antiadrenergic drugs; inhibit SNS; antagonists

What are the 3 classes of sympathomimetic agents? Describe them.

Direct acting: bind directly to receptors and elicit a response (e.g., epinephrine)

Indirect-acting: increase release of norepinephrine from presynaptic neuron (e.g., amphetamines)

Mixed: both direct & indirect effect (e.g., ephedrine)

What are the therapeutic indications for anaphylaxis, heart, asthma, nasal congestion and pupil dilation in relation to sympathomimetics?

Anaphylaxis - a & b agonists

Heart - b1 agonists

Asthma - B2 agonists

Nasal congestion - a1 agonists

Pupil dilation - a1 agonists

What are the 3 classes of sympatholytic agents?

a receptor antagonists: non-selective, a1 blockers, a2 blockers

b receptor antagonists: non-selective, b1 blockers, b2 blockers

a and b receptor antagonists

What are the therapeutic indications of hypertension, angina/CHF, dysrhythmias, and impaired peripheral circulation (raynaud’s) in relation to sympatholytic agents?

Hypertension - b blockers (preferably b1 blockers); a & b blockers during pregnancy

Angina/CHF - selective b1 blockers

Dysrhythmias: selective b1 blockers

Impaired peripheral circulation (Raynaud’s): a1 blockers

What are the therapeutic indications of pheochromocytoma in relation to sympatholytic agents?

a & b blockers

What are the therapeutic indications of benign prostatic hyperplasia, glaucoma, and neurological disorders in relation to sympatholytic agents?

BPH: a1 blockers

Glaucoma: b blockers

Neurological disorders: b blockers

What are the adverse effects of a-blockers?

Orthostatic hypotension

Nasal congestion

Headache, dizziness, weakness, fatigue

What are the adverse effects of b blockers?

Bronchoconstriction

Bradycardia, hypotension, exacerbation of heart failure, cold extremities

Depression, nightmares, hallucination, paresthesia

Masking the effects of hypoglycemia.

What are the adverse effects of a and b agonists?

Headache, restlessness, tremors, dizziness, anxiety, insomnia

Dysrhythmia, palpitation, vasoconstriction, hypertension, myocardial ischemia

Anorexia, nausea, vomiting, dry mouth, muscle cramps.

What 2 types of drugs act on the parasympathetic nervous system?

Parasympathomimetic agents:

• Cholinergics, cholinomimetics, cholinoreceptor activating drugs

• Stimulate PSNS

Parasympatholytic agents:

• Anticholinergics, antiparasympathomimetics

• Inhibit PSNS

How are parasympathomimetic agents used?

To stimulate muscarinic receptors or nicotinic receptors.

Not widely used as they can cause bradycardia and bronchoconstriction.

Used in treatment of:

• Glaucoma

  • Muscarinic receptor stimulants increase ciliary body contraction, increasing fluid drainage from eye, decreasing IOP

• Myasthenia gravis

• poor muscle tone in bladder

• Ileus

Used in diagnosis of asthma.

How is glaucoma treated?

Glaucoma, increased IOP due to fluid, is treated by increasing fluid outflow and reducing fluid secretion.

Increasing fluid outflow is done with:

• Prostaglandin analogues

• Cholinomimetics (a parasympathomimetic agent; Muscarinic agonists)

Reduced fluid secretion is done with:

• Beta blockers

• Carbonic anhydrase inhibitors

Alpha agonists are also used to simultaneously increase fluid outflow and reduce fluid secretion.

How are parasympathomimetic agents used to diagnose asthma?

Administering methacholine, a muscarinic agonist, causing bronchoconstriction. If there is a 20% drop of pulmonary function, person diagnosed with asthma.

What are the 2 classes of parasympatholytic agents?

Antinicotinic agents (ganglion blockers): block N receptors

Antimuscarinic agents (muscarinic blockers): block M receptors

Describe antinicotinic agents (ganglion blockers)

Block autonomic ganglia, inhibiting both SNS & PSNS

Limited therapeutic use due to wide range of adverse effects

Describe Atropine.

A muscarinic receptor blocker

Competitive antagonist of all M receptors

strong, long lasting anticholinergic effect

Causes dilated pupils, tachycardia, bronchodilation, inhibits secretions

Describe organophosphate compounds and poisoning.

Irreversibly inhibit acetylcholinesterase (ACHE) by phosphorylating serine residue on active site.

E.g., nerve gases (sarin) and insecticides (malathion)

Poisoning manifests as DUMMBBLESS:

• Diarrhea

• Urination

• Miosis

• Muscle spasm

• Bradycardia

• Bronchoconstriction

• Lacrimation

• Emesis

• Salivation

• Sweating

Poisoning treated with atropine and oximes.

What groups of drugs have similar but not identical effects?

Sympathomimetic and parasympatholytic drugs: fight/flight

Sympatholytic and parasympathomimetic drugs: rest/digest

Where does somatic motor nervous system act?

Act at neuromuscular junction (NMJ):

• Synapse between a synapatic terminal of neuron & motor end plate of skeletal muscle fiber

• Neurotransmitter is acetylcholine which acts on nicotinic (Nm) receptors to produce muscle contraction

What are the 2 classes of neuromuscular blocking drugs?

Non-depolarizing:

• Competitive antagonists to acetylcholine

• Block nicotinic Nm receptors at neuromuscular junction

• This prevents muscle depolarization and action potential

• This prevents muscle contraction, causing muscle paralysis

• Can be overcome by using acetylcholinesterase inhibitors

Depolarizing:

• Acetylcholine agonists

• Activate nicotinic Nm receptors at neuromuscular junction

• This causes muscle contraction

• Not inhibited by acetylcholinesterase enzyme

• This causes continuous and prolonged activation of Nm receptors

• This causes persistent muscle depolarization

• This results in no time allowed for repolarization and relaxation

• This causes muscle exhaustion and paralysis

What are the 2 phases of depolarizing neuromuscular blockers?

• Depolarizing phase:

  • Disorganized depolarization of muscle fibers

  • Twitching

  • unable to repolarize

• Desensitizing phase:

  • After prolonged exposure to drug

  • Causes muscle repolarization and no longer responsive to acetylcholine

  • This causes muscle to become desensitized

  • Results in flaccid paralysis

  • Paralysis prolonged by using acetylcholinesterase inhibitors  

What are the adverse effects of neuromuscular blockers?

Paralysis of diaphragm and respiratory failure

Depolarizing blockers:

• Hyperkalemia

• Muscle pain

• Malignant hyperthermia

When do you increase and decrease neuromuscular blocker dose?

Increase dose for burns and upper motor neuron lesion.

Decrease dose for old age and myasthenia gravis.

How does botulinum toxin act on NMJ?

Blocks release of acetylcholine, stopping muscle contraction

What are the 5 major classes of diuretics?

Thiazide diuretics (K+ losing; calcium sparing)

Loop diuretics (K+ losing; calcium losing)

Potassium sparing diuretics (K+ sparing; Calcium sparing)

Carbonic anhydrase inhibitors (K+ losing)

Osmotic diuretics

Describe thiazide diuretics.

Site of action: distal convoluted tubule.

Decreases NaCl cotransporter, decreasing NaCl reabsorption, resulting in water staying in the urine (less reuptake) = more urine

Gentle diuresis = safe in elderly

Adverse effects:

• Hypokalemia (common)

• Hypomagnesemia

• Hyperglycemia, hypercalcemia, hypercholesterolemia, hyperuricemia

Describe loop diuretics.

Site of action: thick segment of ascending loop of Henle

Decreases Na-K-Cl cotransporter, decreasing NaCl reabsorption, resulting in water staying in urine and increased Ca & Mg excretion.

Strong diuretic

Adverse effects similar to thiazides except:

• Hypocalcemia → osteoporosis

• Ototoxicity → deafness

Describe potassium sparing diuretics

2 Classes:

• Aldosterone antagonists:

  • Competitive inhibition of aldosterone at receptor site, decreasing Na and water reabsorption while reabsorbing K.

• Sodium channel blockers:

  • Decreased Na reabsorption → water stays in urine

  • Weak diuretics 

Site of action: Distal convoluted tubule and collecting ducts

NaCl and water loss in urine; saves K+ (potassium sparing)

Adverse effects:

• Hyperkalemia (common)

• Spironolactone: androgen or estrogen like effects

Describe carbonic anhydrase inhibitors.

Site of action: proximal convoluted tubule

Decreases carbonic anhydrase enzyme, decreasing H+ excretion, increasing Na+ and K+ excretion.

Decreases intraocular pressure (treatment of glaucoma)

Adverse effects:

• Metabolic acidosis

• Hypokalemia

Describe osmotic diuretics.

Site of action: throughout nephron, especially proximal convoluted tubule

Filtered in glomeruli and cannot be reabsorbed from renal tubules, remain in tubular lumen, increasing osmolarity of tubular fluid, retaining water in urine

Decreases intracranial and intraocular pressure

Adverse effects:

• Increases extracellular fluid volume

• May aggravate heart failure and pulmonary edema

Describe diuretic resistance.

• Decreased glomerular filtration rate due to low cardiac output (e.g., heart failure)

• Increased proximal reabsorption of Na+

• Decreased secretion into tubule lumen

• Non-compliance

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Activation of renin-angiotensin-aldosterone system (RAAS)

How does sympathetic nervous system activity effect blood pressure?

Increased SNS = increased noradrenaline = vasoconstriction = increased BP

Vise versa

How does the renin-angiotensin-aldosterone system (RAAS) effect blood pressure?

Blood pressure falls, renin released, triggers angiotensin, triggers antidiuretic hormon release, increases salt and water reabsorption, increasing BP

What are the 2 types of hypertension?

Primary hypertension:

• No identifiable cause

• Most common

Secondary hypertension:

• Caused by underlying disease:

  • Renal disorders

  • Endocrine disorders

  • Pregnancy

  • etc

What are the 5 types of antihypertensive drugs?

Diuretics

Sympatholytics

Calcium channel blockers

Drugs acting on RAAS

Vasodilators

What diuretic is most used to treat hypertension?

Thiazide diuretics

Describe sympatholytics in relation to hypertension

Includes a blockers, b blockers, a & b blockers, adrenergic neuron blockers, centrally acting drugs

a blockers:

• Black a receptors, decreasing constricting effect of norepinephrine on smooth muscle cells of blood vessels, causing vasodilation

b blockers:

• Widely used, cardioprotective

• Block b receptors, decreasing sympathetic nervous system effect on cardiovascular system

• Decreases HR, myocardial contractility, cardiac output, myocardial O2 demand, renin secretion

• Can cause bronchospasm (asthma), bradycardia (heart block), mask hypoglycemia

• Better avoid in elderly

• Two types:

  • Nonselective b antagonist

  • Selective b1 antagonist (cardioselective, preferred)

a & b blockers:

• Used in pregnancy, e.g., labetalol

Adrenergic neuron blockers:

• Used in pregnancy, e.g., methyldopa

What 3 types of drugs act on RAAS?

Angiotensin converting enzyme inhibitors (ACE inhibitors)

Angiotensin receptor blockers (ARB)

Renin inhibitors

Describe ACE inhibitors.

A drug acting on RAAS.

Inhibit angiotensin-converting enzyme (ACE), preventing the conversion of angiotensin I into II and preventing antidiuretic hormone production, resulting in lower BP

Safe in asthma

No impotence (erectile dysfunction)

Useful in diabetes

Causes dry cough, hyperkalemia, teratogenic

Describe angiotensin receptor blockers.

Block the action of angiotensin II at the angiotensin 1 receptors

Similar effect as ACE inhibitors

Lower incidence of cough

What type of antihypertensive is recommended for:

• Elderly & HF

• Diabetes

• Coronary artery disease

• Pregnancy

• Prostatic enlargement

• Elderly & HF: diuretics

• Diabetes: ACE inhibitors or angiotensin receptor blockers

• Coronary artery disease: selective b1 blockers

• Pregnancy: Methyldopa (Adrenergic neuron blocker) or labetalol (a & b blocker)

• Prostatic enlargement: a blockers

AVOID:

• b blockers in asthma and advanced HF

• ACE inhibitors and angiotensin receptor blockers in pregnancy

What are the 2 types of angina?

Typical (exertional):

• Chest pain due to exertion

• Due to coronary obstruction

Variant (Prinzmetal’s):

• Chest pain at rest

• Due to coronary vasospasm.

What are the 3 types of antianginal drugs?

Organic nitrates (used in prevention/termination of angina attacks)

b blockers (used in long-term prophylaxis of typical angina, not variant)

Calcium channel blockers (used in long-term prophylaxis of variant angina, not typical)

Describe organic nitrates for treatment of angina.

Esters of nitric oxide

Short acting: glyceryl trinitrate (nitroglycerin/GTN)

Long acting: isosorbide dinitrate, isosorbide mononitrate

Nitrates reduced into nitro oxide, increasing guanlyl cyclase activity, converting GTP → cGMP, increasing PKG, decreasing intracellular calcium, and causing relaxation of smooth muscles of blood vessels - resulting in vasodilation.

Adverse effects:

• Headache, flushing, hypotension, tachycardia, dizziness, methemoglobinemia, tolerance

Tolerance occurs due to continuous exposure; prevented with nitrate-free periods (overnight). Causes Monday disease.

Nitrates + PDE5 = severe hypotension (DDI)

What are the 3 forms of vasodilation?

Venous dilation:

• Dec venous return

• Dec cardiac output

• Dec myocardial work

• Dec myocardial O2 demand

Coronary dilation:

• Inc blood supply to heart

• Myocardial perfusion

• O2 supply to ischemic myocardium

Arterial dilation:

• Dec peripheral resitance

• Dec blood pressure

Describe calcium channel blockers in relation to angina treatment.

Block L-type voltage gated Ca channels, preventing Ca flow into vascular smooth muscles - causing vasodilation in arteries rather than veins. Also prevents Ca flow into cardiomyocytes, decreasing cardiac contractility, decreasing CO

3 Classes:

• Dihydropyridine: more vascular selective, e.g., nifedipine

• Phenylalkylamine: more myocardial selective, e.g., verapamil

• Benzothiazepine: more balanced, e.g., diltiazem

Adverse effects:

• Myocardial depression

• Hypotension

• Inc HR with nifedipine; dec HR with verapamil, diltiazem

• Flushing, ankle edema, headache

Therapeutic indications:

• Angina: diltiazem, verapamil

• Hypertension: nifedipine, diltiazem

• Supraventricular tachycardia: verapamil

What are the 3 types of heart failure?

Left ventricular failure

Right ventricular failure

biventricular failure

What are the manifestations of HF?

Exertional dyspnea, fatigue, cough

Dependent edema

Enlarged heart

What are the drugs used to treat HF?

Diuretics

Inhibitors of RAAS: ACEI, ARB, aldosterone antagonists

Beta blockers

Vasodilators

Positive inotropic agents: cardiac glycosides (digitalis)

Where are cardiac glycosides sourced?

From plants

What is the chemical structure of a cardiac glycoside?

A molecule in which a sugar is bound to a non-carbohydrate (aglycone steroid nucleus) via a glycosidic bond.

Sugar: determines solubility

Aglycone steroid nucleus/non-carb: determines pharmacological activity

What is the mechanism of action of cardiac glycosides?

• Digitalis directly inhibits Na+-K+-ATPase pump activity in cardiomyocytes

• This increases intracellular Na+

• This reverses the Na-Ca exchanger

• Instead of pumping Ca out, the reversed exchanger brings more Ca into cell

• This increases intracellular Ca

• This enhances myocardial contractility (positive inotropy)

• This increases vagal effect on the heart:

  • Decreased SA node firing rate (negative chronotropy)

  • Decreased conduction at AV node (negative dromotropy)

• This decreases heart rate

What are the effects of digitalis on myocardial contractility and heart rate?

Increased myocardial contractility:

• Dec heart size

• Dec venous congestion

• Dec edema

• Inc renal perfusion

Decreased heart rate

What are the pharmacokinetics of digoxin?

Absorption: 70%

Onset: 1-2h

Peak: 6-8h

Half life: 40h

Duration: 3 days

Metabolism: liver (14% metabolized in liver)

Elimination: kidney (mostly excreted unchanged through kidney)

Digoxin accumulates in the body due to long duration and low amount metabolized

What are the therapeutic indications of digitalis/digoxin?

Congestive heart failure

Tachyarrhythmia: especially atrial flutter or atrial fibrillation

What are the drug interactions digoxin has?

• K+:

  • Hyperkalemia decreases digitalis activity bc it competes for Na-K-ATPase

  • Hypokalemia increases digitalis activity

    • K losing diuretics increase digitalis activity and thus pose risk for toxicity

• Hypercalcemia: inc risk of toxicity and dysrhythmia

• Quinidine & Verapamil: decreased renal clearance & volume of distribution of digitalis increases digitalis level and toxicity

• Antibiotics: inhibit intestinal flora that inactivate digoxin, increasing digoxin level.

What are the adverse effects of digoxin?

GI: anorexia, nausea, vomiting, diarrhea

CVS: sinus bradycardia, AV block, ventricular dysrhythmia

CNS: headache, fatigue, mental depression, confusion, hallucination, convulsions

Visual disturbances

Gynecomastia

What is the therapeutic range and toxic level for digoxin?

Therapeutic range: 0.8-1.6 ng/ml

Toxic level: >2.4 ng/ml

How is digoxin administered?

Route: oral or IV

Dose:

• Rapid:

  • Loading dose: 1-1.5 mg over first day

  • Maintenance dose: 0.125-0.5 mg/day

• Slow:

  • Start with maintenance dose of 0.125-0.5 mg/day

How is HF managed?

ABCD:

• A: ACEI, ARB, Aldosterone antagonists, ARNI (angiontensin receptor-neprilysin inhibitor)

• B: bed rest, beta blockers, natriuretic peptide

• C: cardiac transplantation

• D: diet, digitalis, diuretics, dilators

What does quadruple medical therapy of HF involve?

A combination of:

• Angiontensin receptor-neprilysin inhibitors

• Beta blockers

• Aldosterone antagonists

• Sodium/glucose cotransporter 2 inhibitor

Define hemostasis and thrombosis.

Hemostasis: the process that retains blood within vascular system.

Thrombosis: formation of a thrombus (blood clot) within a blood vessel

What are the steps of hemostasis:

Injury of a blood vessel causing loss of vascular integrity resulting in a series of 4 events:

• Vasoconstriction

• Platelet activation

• Blood coagulation & clot formation

• Fibrinolysis

Describe the role of vasoconstriction in hemostasis.

Dec blood flow to injured vessel = dec blood loss

Describe the role of platelet activation in hemostasis.

Platelets adhere to collagen fibrils on injured vessel

Platelets aggregate to each other under the effect of thrombin and fibrinogen, creating a platelet plug

Once activated, platelets release chemical mediators as ADP and thromboxane A2 to activate more platelets

Describe the role of blood coagulation and clot formation in hemostasis.

Activation of coagulation factors → coagulation pathway

Platelet plug turns into more stable blood clot (fibrin network + blood cells)

Describe the role of fibrinolysis in hemostasis.

The enzymatic process that dissolves the fibrin clot

Occurs simultaneously with coagulation

Controls the size and spread of fibrin clot

Carried out by the enzyme plasmin.

What are the 3 causes of bleeding disorders?

Vascular defects: e.g., vasculitis

Platelet defects: thrombocytopenia

Coagulation factor defects: hemophilias

Describe hemophilias.

Bleeding disorder related to a coagulation factor deficiency.

What are the 3 antithrombotic agents?

• Antiplatelets: inhibit platelet function

• Anticoagulants: inhibit coagulation factors

• Thrombolytic agents: breakdown fibrin

List and describe the different kinds of antiplatelets.

• Cyclooxygenase inhibitors:

  • Decrease cyclooxygenase enzyme, decreasing thromboxane A2

  • These include asprin and NSAIDS like ibuprofen

• ADP receptor blockers:

  • Block ADP receptor, decreasing ADP-induced platelet aggregation

  • Safe when aspirin is contraindicated.

  • E.g., thienopyridines

• Phosphodiesterase inhibitors:

  • e.g., Cilostazol

  • Selective decrease in PDE3, inc cAMP in platelets, increasing active protein kinase A, dec platelet aggregation

  • Used for intermittent claudication in peripheral vascular disease

  • Avoid in HF

• Prostacyclin analogues:

  • inc activity of prostacyclin receptors, inc adenylyl cyclase enzyme, inc cAMP level in platelets

  • Inhaled or IV

  • E.g., iloprost, carbacyclin

• Adenosine reuptake inhibitors:

  • inhibit adenosine reuptake by RBCs, platelets, and endothelial cells

  • Inc extracellular adenosine concentration, acting on receptors

  • Inc platelet cAMP synthesis

  • cAMP inhibits platelet aggregation

  • e.g., dipyridamole

• Glycoprotein IIb/IIIa receptor blockers

  • Block glycoprotein IIb/IIIa receptors on platelets, dec platelet aggregation

  • Adverse: thrombocytopenia

  • Route: IV

  • e.g., a

What are the types of anticoagulants?

Heparin:

• Unfractionated heparin

• Low molecular weight heparin

Oral anticoagulants:

• Warfarin & Dicoumarol

• Direct thrombin inhibitors

• Direct FXa inhibitors

Describe unfractionated heparin.

• Augments the effect of antithrombin, inhibiting thrombin and factor Xa

• Side effects:

  • Bleeding

  • Thrombocytopenia

  • Allergy

  • Osteoporsis

• Route: IV or SC injection

Describe low molecular weight heparin.

• More selective inhibition of factor Xa while sparing thrombin

• Imrpoved pharmacokinetics

• Less side effects

• No need for coagulation monitoring

• Administered SC

• E.g., tinzaparin, enoxaparin

Describe warfarin.

• Vitamin K is required for activation of many factors in the liver by carboxylation

• To be effective, vitamin K has to be in reduced form under the effect of vitamin K epoxide reductase enzyme

• Vitamin K epoxide reductase enzyme is inhibited by warfarin

Describe the differences in plasminogen binding, potential allergic reactions, antigenicity, risk of bleeding, plasma clearance (mins), and relative cost of streptokinase (a thrombolytic agent) and tissue plasminogen activator (t-PA)

• Plasminogen binding:

  • Streptokinase = indirect

  • Tissue plasminogen activator = direct

• Potential allergic reaction:

  • Streptokinase = yes

  • Tissue plasminogen activator = no

• Antigenicity:

  • Streptokinase = high

  • Tissue plasminogen activator = low

• Risk of bleeding:

  • Streptokinase = more

  • Tissue plasminogen activator = less

• Plasma clearance:

  • Streptokinase: 15-25 mins

  • Tissue plasminogen activator = 4-8 mins

• Relative cost:

  • Streptokinase = +

  • Tissue plasminogen activator = +++

Describe bronchial asthma.

Inflammation of bronchial walls, causing narrowing of airways and increased resistance to airflow.

What are 3 factors the increase airway obstruction?

Bronchoconstriction: contraction of bronchial smooth muscles

Mucosal edema: resulting from inflammation

Bronchiolar secretions: inc mucus secretion due to inflammation

What are the 2 types of anti-asthma agents?

Bronchodilators and anti-inflammatories.

What are the 3 classes of bronchodilators?

B2 adrenoreceptor agonists:

• inc B2 adrenergic receptors on bronchial smooth muscles, resulting in bronchodilation

• Dec mediators released from mast cells

• Most effective bronchodilator

• Short acting: salbutamol (albuterol) and terbutaline

• Long acting: salmeterol and formoterol

Anticholinergics:

• dec muscarinic receptors, blocking cholinergically-mediated bronchoconstriction

• Usually adjunct therapy

Methylxanthines:

• 3 pharmacologically active compounds:

  • Caffeine

  • Theobromine

  • Theophylline:

    • Effect anti-asthma drug

    • dec phosphodiesterases, dec cAMP hydrolysis, resulting in accumulation of cAMP, relaxing bronchial smooth muscles, causing bronchodilation

    • Narrow therapeutic range with lots of CVS, CNS, and GI side effects

What are the 5 types of anti-inflammatory agents?

Glucocorticoids (steroids)

Mast cell stabilizers

Leukotriene inhibitors

Omalizumab

Methotrexate

Describe glucocorticoids

• Anti-inflammatory effect on bronchial mucosa

• dec macrophages, eosinophils, lymphocytes

• dec mucus secretion

• Mostly inhaled, also oral and IV

• e.g., beclomethasone

Describe mast cell stabilizers.

• Stabilize mast cells, dec release of chemical mediators (histamines) that cause bronchoconstriction, dec incidence of attacks

• Used for prophylaxis, not suitable during acute attacks

• Inhaled

Describe Leukotriene receptor antagonists.

Selective blocking of leukotrienes action on respiratory tract, resulting in dec mucus secretion and dec bronchoconstriction

Used as adjunct therapy and for prophylaxis (not suitable during acute attacks)

Orally administered

Describe leukotriene synthesis inhibitors.

dec 5-lipoxygenase enzyme, dec leukotrienes production

Used as adjunct therapy and for prophylaxis

Not good for liver

Administered orally

Describe omalizumab.

Recombinant anti-IgE antibody

Binds IgE, inhibiting the binding of IgE to the high-affinity IgE receptor

Used in severe, persistent allergic asthma uncontrollable with steroids

Administered via SC injection every 2-4 weeks.

Can cause anaphylaxis.

Describe methotrexate.

A cytotoxic drug mainly used for treatment of malignancies and autoimmune diseases

Significant side effects, so limit its use (liver toxicity, bone marrow failure)

Oral or parenteral injection