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1 - 1Copyright © 2000-2009 TIPS Inc. Unauthorized reproduction of this manual is strictly prohibited and it is
illegal to reproduce without permission. This manual is being used during review sessions conducted by
PharmacyPrep.
Functions of ANS
The functioning of the organs of the human body is controlled by the endocrine system and the ner-
vous system. The endocrine system is controlled by hormones that act as messengers. Circulating
hormones of the endocrine system exert a slowly developing and long lasting control compared to
the control exerted by the nervous system. The autonomic nervous system (ANS) controls involun-
tary body functions. The ANS is composed of two divisions, the sympathetic (adregenic) system and
the parasympathetic (cholinergic) system.
Central Nervous System (CNS)
Spinal cord and brainPeripheral Nervous System (PNS)
Autonomic Nervous System (ANS) Sensory somatic nervous System
12 pairs of cranial nerves
31 pairs of spinal nerves
Cholinergic Adrenergic
Nervous System
▼ ▼
▼ ▼
▼ ▼
1 Autonomic Nervous System Drugs
Types of Neurons in ANS
• Efferent neurons (motor neurons)à deliver message from brain to organs
• Afferent neuronsà Collects message from organs to the brain
Efferent neurons divided into the
• Sympathetic (Adrenergic) nervous system
• Parasympathetic (cholinergic) nervous system
Responsible for regulation of
• Internal metabolic activity
• Myocardium
• Smooth muscle of the viscera
• Glandular activity
• Hormonal activity
• Ensure that the body operates in optimum range
There are four types of adrenergic receptors. These are αlpha-1 and αlpha-2 and βeta-1 andβeta-2. Alpha-receptors are located mainly in the blood vessels and pupils. Βeta-1 receptors
are in the heart and βeta-2 receptors are mainly in the lungs, skeletal muscles and uterus.
Afferent
Efferent
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Sympathetic (adrenergic) Parasympathetic (Cholinergic)
• Originate in the thoracic and lumbar region • Originate in sacral and cranial region
• Post ganglionic nerve fbre very long • Post ganglionic nerve fbre very short
• Preganglionic nerve fbre very short • Preganglionic nerve fbre very long
• Ganglia is near spinal cord • Ganglia is near innervated organs Neurotransmitters
• Norepinephrine (NE)
• Epinephrine (epi)
• Dopamine (D)
• ACh
Neurotransmitters
• ACh
Receptors:
• Norepinephrine (NE)à α1,α
2, b
1 (Not on b
2)
• Epinephrine (epi)àα1, α
2, b
1, b
2
• DopamineàD1 > b > α
• AChà M1
Receptors
• AChàM1, M
2, M
3, M
4 and M5
Functions
• Increase heart rate
• Increase blood pressure
• Increase blood ow to skeletal muscle and heart• Dilation of pupil and bronchioles
• Adjust in response to stressful situation (trauma,
cold, fear, hypoglycemia, exercise)
• Changes in emergencies (Fight or ight response)
Functions
• Maintains essential body functions
(Digestive, waste elimination).
• Oppose or balance the action ofsympathetic.
• Dominant over sympathetic in rest and
digest situation
Receptor Site Effectα
1Vessels Strong vasoconstriction
α1 Brain (postsynaptic) NeurotransmissionContraction
α2
α2
Presynaptic
Membrane
Penis
Auto inhibition of norepinephrine
release
Ejaculationβ
1Heart Stimulation
β1
Kidney
Juxtamedullary apparatus
Renin release
β1
Cerebral vessels Dilation (?)β
2Bladder (including Longitudinal muscle) Relaxation
β1
Fat cells Lipolysisβ
2Bronchial muscles Bronchodilation
β2
Vessels (Venules) Weak vasodilationβ
2Pancreas Relaxation
Insulin releaseβ
2Liver, fat cells Gluconeogenesis,
Glycogenolysis,
LipolysisD
1,D
2 Nigrostriatal pathway Motor coordination
D1,
D2
Median eminence, anterior pituitary Inhibition of prolactin releaseD
1 Nucleus accumbens, limbic system Control of emotions
D1
Renal and mesenteric vessels DilationD
1Chemoreceptive trigger zone Nausea
D2 Ganglia presynaptic membrane Auto inhibition of dopamine release
Both the sympathetic and parasympathetic nerves innervate the same structures. Their actions are opposing
but not equal in scope.
Anatomic Distribution and Main Effects of Catecholamine Receptors
cAMP = cyclic adenosine monophosphate
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Effector Organ Sympathetic ParasympatheticAdipose ↑ Lipolysis (β3)
Metabolise fatty acidsArterioles Skin and mucosa Skeletal Muscle
Constriction (α1)
Usually relaxation (β2,
M) Some relaxation (M)
Some relaxation (M)
Bladder
Detrusor Sphincter
Relaxation (β2)Contraction (α
1)
Contraction (M)Relaxation (M)
Eye Radial Muscle, iris
Sphincter muscle, iris Ciliary muscle
Mydriasis (contraction, α1)
-
Accommodation(Relaxation, β
2)
-
Miosis (M)Contraction for nearvision (M)
Heart Sinoatrial node Atrioventricular node Atria
Ventricles
↑Heart rate (β1)àChronotropic
↑ Conduction (β1)àDromotropic
↑ Contractility (β1)àInotropic
?
↓ Heart rate (M)
↓ Conduction (M)
↓ Contractility (M)
?Kidney Renin secretion (β
1) -
Lacrimal glands - ↑ Tear secretion (M)Liver Glycogen breakdown (β2) Glycogen synthesis (M)Lung (bronchial muscle) Relaxation (β
2) Contraction (M)
Male sex organs Ejaculation (α2) Erection (M) Nasopharyngeal glands - Mucus secretionPancreas ↑ Insulin secretion (β
2) ↑ Fluid secretion (M)
Salivary Glands Viscous secretion (α1) Marked water secretion
(M)
Stomach & intestine
Motility Sphincters Secretion
Decrease (β2)à
PeristalisisContraction (α1)àSpincter
-
Increase (M)Relaxation (M)
Stimulation (M)
Sweat glands ↑ Secretion (M) ↑ Secretion (M)Uterus ↑ Contraction (α
1)à Relaxes detrusor
muscles
Relaxation (β2)
-
Veins (systemic) ↑ Dilation (β2) -Spleen Contraction (α1) -
(a=alpha, β =beta, M=cholinergic-muscarinic)
Abbrevation and Terminology
ANS Automic Nervous System
CNS Central Nervous System
EPI EpinephrineM Cholinergic-muscarinicACh AcetylcholineD DopaminecAMP Cyclic Adenosine Monophosphate
NE Norepinephrine
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Generic and Brand
Epinephrine Epipen, Anapen
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a1agonists
a1 agonists • Phenylephrine
• Pseudoephridine• Methoxamine
Pharmacologicalactions
• Bronchodilation• ↑ Blood Pressure• ↑ Peripheral Resistance
• ↑ Closure Sphincter bladder• Mydriasis• Vasoconstriction
Therapeutic use • Dimetapp Cold (Night time) extra strength containsà Phenylephrine + chlorpheniramine + acetaminophen
• Dimetapp Daytime Cold extra strength containsà Pseudoephedrine + Acetaminophen
a2 agonist – Centrally acting antihypertensive
a2agonists • Methyldopa• Clonidine• Guanabenz
Adrenergic agonists
Alpha agonist • Alpha 1 agonist
• Alpha 2 agonist
Beta agonist • Beta 1 agonist
• Beta 2 agonist
• Mixed alpha and beta agonist
Adrenergic antagonists
Alpha antagonists
(a-blockers)
• Alpha1 antagonists (a1-blockers)
• Alpha 2 antagonists (a2-
blockers)
• Alpha 1 and 2 antagonistBeta antagonists
(b-blockers)• Beta antagonists (b-blockers)• Non selective b-blockers• Cardioselective b-blockersPartial alpha and beta blockers
• Partial agonist and antagonist
2Adrenergic Drugs
(Sympathetic Drugs)
Adrenergic agonist (Sympathomimetics)
Epinephrine
(in blood)
Adrenergic
ReceptorAdrenergic
Receptor
Norepinephrine
Ach
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Mechanism • Decrease Central adrenergic outow• a
2 receptors located on perineuronal membrane
• a2 receptors have inhibitory action on epinephrine and NE
• Increase alpha2 receptors increase inhibitory action on epi and NE
• ↓ Blood Pressure• ↓ Release of insulin• ↓ NE• Bradycardia
Therapeutic use • Centrally acting antihypertensive• Hypertension with renal disease (no decrease blood ow to kidney)
Common side effects • Rebound hypertensionà clonidine
b-agonists pharmacological actions
b-agonists non selective • Dobutamine (b1>b
2)
• Isoproterenol (b1= b
2)
Mechanism • Tachycardia
• Increase lipolysis• +ve Inotropic effect (increase force of contraction of heart)• Increase Cardiac output (CO)• Increase Heart rate (HR)• Bronchodilation
Therapeutic use • Dobutamine (Dobutrex)à the treatment of adults with cardiacdecompensation due to depressed contractility resulting fromorganic heart disease or following cardiac surgical procedures inwhich parenteral therapy is necessary for inotropic support.
Contraindication Tachycardia and ventricular brillation
Beta 2 agonist
Beta2 agonist Short acting beta
2 agonist
• Albuterol (Salbutamol)• Terbutaline• Metaproterenol• Pirbuterol
Long acting beta2 agonist
• Salmeterol• Formeterol
Mechanism • Bronchodilation• Vasodilation• Slightly decrease peripheral resistance• Increase muscle and liver glycogenolysis• Relax uterine muscles• Increase release of glucagon
Therapeutic use • Treat Asthma and COPD
Short acting beta2
agonist• Rapid onset of action and provide relief for 4 to 6 hours.• Indicated in symptomatic treatments, rescue agents, combat acute broncho-
constriction• Albuterol, terbutaline, pirbuterol has little alpha-1 and beta-1 effects.
• Does not effect by COMT enzymes because these are activated by nonCOMT (Catechol Amine O-Methyl Transferase)
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• Inhalation route has less toxic side effects than systemic routes.• Have less tachycardia, hyperglycemia, and hypokalemia effects with
inhalations routes.• Short acting are best reserved for treatment of acute exacerbations and
prophylaxis of exercise induce asthma
Long acting beta2
agonist
• Salmeterol has long duration of action, providing bronchodilation for at
least 12 hours, and slow onset of action.• Indicated in maintenance treatment in combination with corticosteroidsespecially for nocturnal asthma, EIA, and COPD
• Not indicated in acute asthmatic attacks
Mixed a and b agonist
Mixed a and b agonist • Dopamine• Epinephrine• Norepinephrine
Norepinephrine • a1, a2, b1 agonistMajor affects • Vasoconstriction
• ↑ Cardiac contractility• ↑ Systolic Blood Pressure (SBP)• ↑ Diastolic Blood Pressure (DBP)• ↑ Peripheral Resistance (PR)• Reex bradycardia• Vasoconstriction à causes peripheral resistance• Baroreceptor reexà stimulates cardiac contractility
Epinephrine (Adrenaline)
Action • a 1, a
2 at higher doses and b
1 and b
2 at lower doses
Cardiovascular • At low doses beta effectsà vasodilation• At high doses alpha effectsà vasoconstriction predominates.• ↑ oxygen demand• ↑ the rate of contraction (+ve chronotropic effect, b
1action)
• ↑ the contractility of myocardium (+ve inotropic effect, b1 action)
• ↑ systolic (SBP) and slight decrease diastolic (DBP)à reex bradycardia
Respiratory • Intense bronchodilatorà used for allergic and histamine induced bronchoconstriction
Hyperglycemia • Has signicant hyperglycemic effect (↑ glycogenolysis),• ↓ Release of insulin.• Causes lipolysis
Therapeutic use • Acute asthma• Anaphylactic shock (Type1 hypersensitivity)• Glaucoma (2% epinephrine solution)• In local anesthesia (1:100,000)à Due to vasoconstrictor
Side effects • CNSà Anxiety, fear, tension, headache, and tremor • Hemorrhageà Elevation of BP may cause hemorrhage• Arrhythmiasà Can trigger arrhythmias in patient using digitoxin• Pulmonary edemaà Can cause pulmonary edema
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Dopamine (Inotropin)
Mechanism • Act on D1, D
2, D
3, D
4, D
5, and Mixed a and b agonist
Major affects • Has +ve inotropic and +ve chronotropic effects
• Dilates renal arterioles by increasing blood ow to kidney
• Dopamine is drug of choice for shock given by continuous infusion.• Same as adrenergic agonist
• Metabolizes to homovanillic acid
Adrenergic Blockers
a1-antagonists
a1-antagonists • Prazosin
• Terazosin
• Doxazosin
• Tamsulosin (a 1A
)
• Alfuzosin (a 1A
)
Mechanism • ↓ BPà orthostatic hypotension
• ↓Total Peripheral Resistance
• No Reex tachycardia
• Vasodilations
• First dose effect (syncope)à Fainting
• Miosis
Therapeutics use • Antihypertensive
• Symptomatic Benign Prostate Hyperplasia
Side effects • Postural (Orthostatic) hypotension
• Headache, drowsiness, palpitation
Comments • Starting dose for doxazocin 1mg once daily and titrate slowly• Tamsulosin has no postural hypotension
• Tamsulosin is a selective a 1A receptor blocker
Adrenergic antagonists
Alpha-blockers
(Adrenergic blockers)
Beta blockers Neuronal blockers
Selective (α1
Doxazocin (α1)
Terazocin (α1)
Tamsulosin (α1a
)
Nonselective(α
1 and β
2
blockade)
blockade)ββ
1, 2 , &α1 blockade
Carvedelol
Labetelol
Selective (β1
EsmololMetoprolol
Atenolol
Acebutolol
Nonselective
(β1 and β
2 blockade)Propanolol
Pindalol
Nadolol
Timolol
Levobutalol
Reversible
Phentolamine
Irreversible
Phenoxybenzamine
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a2-antagonist
Yohimbine • Yocon and odan
Pharmacological
actions
• Blocks presynaptic a2
• ↑HR
• ↑BPTherapeutic use • For impotency treatment
Side effects • Postural hypotension
Contraindications • Renal and hepatic diseases
• Cardiovascular disease
Mirtazepine • Used as antidepressant
a1
& a2 antagonists
a1& a
2 antagonist
Phentolamine
(Reversible)
• Competitive, short acting agent
• a blockade
• ↓BP
• ↓Total Peripheral Resistance
• Reex tachycardia.
Therapeutic use • Used occasionally in patients to ↓BP
• Pheochromocytoma
Phenoxybenzamine
(Irreversible)
• Non-competitive long acting blocker
• NE release is enhanced due to blockade of presynaptic a receptors-causes excessive response.
• Used occasionally in patients to ↓BP
Pheochromocytoma • Type of adrenal gland cancer
• Can cause uncontrolled blood pressure
• Can cause uncontrolled tachycardia
• Increase heart rate and palpitation
b-blockers
Mixed b1 and b2-antagonists (non
selective)
• Propranolol ProPiNaTionaLe• Pindolol
• Nadolol
• Timolol
• Levobutolol
Mechanism • Reduce intra ocular pressureà Decrease secretion of aqueous humor
• Bradycardia
• Bronchoconstriction (Bronchospasm)
b1 antagonists
(cardioselective or
selective)
• Esmolol Selective EMAA
• Metoprolol
• Acebutolol• Atenolol
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Mechanism • Vasoconstriction
• No bronchoconstrictionMixed a and
b-antagonists
• Labetalol: acts a1, b
1 and b
2 receptor (Non-ISA/alpha)
• Carvedilol: acts a1, b
1 and b
2 receptors (Non-ISA/alpha)
Mechanism • Produce vasodilationà ↓ BP
• Peripheral vasoconstriction
• Does not alter serum lipid levelsPartial agonist andantagonist
• Acebutolol
• Pindolol
• Oxprenolol
Mechanism • Intrinsic sympathomimetic activity (ISA)
• Minimized disturbances of lipid and carbohydrate metabolism.
ISA: Intrinsic
Sympathomimetic
Activity:
• The partial agonist stimulates the beta-receptors to which they
are bound; yet inhibit stimulation by the more potent endogenous
catecholamines, epinephrine and norepinephrine.
Summary of the side effects of adrenergic Drugs(Sympathetic drugs)
Adrenergic agonists
Alpha agonist • a 1 agonist
• Phenylephrine• Pseudoephridine
Increase BPInrease TPR • Vasoconstriction• Mydriasis
• a 2 agonist
• Clonidine• Methyl dopa
• Decrease lipolysis
• Decrease insulin secretions• Sexual dysfunction
Beta agonist • b1 agonist
• b2 agonist • Tremors
• Palpitations• Hyperglycemia• Tachycardia
• Mixed a and b agonist
AdrenergicantagonistsAlpha antagonists
(a-blockers)
• a1 antagonists (a
1-blockers)
• Doxazocin• Prazocin• Terazocin• Tamsulosin
• Orthostatic hypotension
• Tachycardia (No reex tachycardia)• Vertigo• Sexual dysfunction• First dose effects (syncope)
• a 2 antagonists (a
2-blockers) • Hypotension
• a 1 and 2 antagonist • Orthostatic hypotension
• Reex tachycardia
Beta antagonists(b-blockers)
• Non selective b-blockers• Propranolol• Pindolol
• Nadolol• Levobutalol• Timolol
• CNSà insomnia, fatigue,hallucinations, impotency (libido)
• CVSàDecrease HDL and increase
TG, bradycardia, orthostatichypotension
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• Cardioselective b-blockers• Esmolol• Metaprolol• Atenolol• Acebutalol
• Partial alpha and beta blockers• Carvedilol
• Labetelol• Partial agonist and antagonist
• Acebutalol• Pindolol• Oxyprenolol
Adrenergic Drugs Tips
• Drugs that have +ve inotropic and +ve chronotropic effect is: dopamine.
• Inotropic is: force of contraction (+ve increase in force of contraction)• Chronotropic is: heart rate (+ve increase in heart rate)
• Drugs that have +ve inotropic and –ve chronotropics is: Digoxin
• Drugs that have +ve inotropic are: ACE Inhibitors.
• Epinephrine is used for: Anophylactic reaction or hypersensitive reactions.
• Epinephrine is: a1, a2, b
1 and b2 agonist
• Xylometazoline action is on alpha-adrenergic receptors.
• Salbutamol is b2 agonist
• Summary of b2 agonist:
• b2 agonist drugs have no anti-inammatory effect and act as branchodilators
• SABA always used as prn and tolerance can occur with regular use and also mask the symptoms
of inammation.• SABA has additive effect with anticholinergic drugs (Ipratropium)
• LABA always used as daily dose.
• LABA has same effect as SABA but long duration of action.
• LABA has synergistic effect with corticosteroids. (Products available: Fluticosone + Salmeterol
= Advair)
• SABA and LABA are branchodilators.
• Beta-blockers are drug of choice for uncomplicated hypertension in patient age under 65 years
old.
• Beta-blockers are used cautiously in: Asthma, CHF, Diabetes and sever peripheral vascular
diseases.
• Diabetic patient taking beta-blockers monitor? Blood sugar levels
• Digoxin, non-DHP CCB may cause additive Bradycardia with beta blockers.
• b-blockers are drug of choice for orthostatic hypotension.
• What adrenergic blockers are useful in treating Tachycardia? b blockers (Propranolol)
• The longest acting beta-blockers is? Nadolol
• Example of irreversible and noncompetitive a1 and a2 blocker isà Phenoxybenzamine
• Examples of drugs that reverse effect of epinephrine associated vasocontriction à a1 blockers.
• Examples of sympathomimetic that should be avoided in Glaucomaà Phenylephrine,
pseudoephridines.
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Abbrevation and Terminology
Generic and Brand
NE Norepinephrine
CNS Central Nervous System
CO Cardiac Output
HR Heart RateCOPD Catechol Amine O-Methyl TransferaseEIA Exercise Induce AsthmaSBP Systolic Blood PressureDBP Diastolic Blood PressurePR Peripheral ResistanceTPR Total Peripheral ResistanceBPH Benign Prostate HyperplasiaIOP Intra Ocular PressureBP Blood PressureEMAA Esmalot, Metopralol, Acebutalot, AtenalolISA Intrinsic Sympathomimetic Activity
HDL High density LipoperteinsACE Angiotism Converting EnzymesSABA Short Acting b
2 Agonist
LABA Long Acting b2 Agonist
CHF Congestive Heart FailureDHP DihydropyridineCCB Calcium Channel Blockers
Xylometazoline Otrivin
Fluticasonet + Salmeterol Advair
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3 Cholinergic Drugs
(Parasympathetic Drugs)
Acetylcholine is not reuptaken, it is terminted by enzyme Acetylcholine esterase. This enzyme
hydrolyse Acetylcholine into choline and acetate. This Acetylcholine esterase only found in synaspe.
• Choline can be recycled but not ACh
• Muscuranic innervation
Hearts have too kiond of tissue, muscle tissue such as atrial tissue and ventricle tissue also
specialized cells called Nodal cells. Node cells are highly innervated by parasympathetic system.
There is no innervations of the parasympathetic system in ventricle and purkinje bre.
Only sympathetic system can innervate the blood vessels.(Smooth muscle)
Blood vessels (endothelium) - Muscuranic Receptors present
This endothelium Muscuranic receptor stimulation result in NO release.
This endothelium derived NO release.
This endothelium derived NO diffuses into smooth muscle and mediates relaxation of smooth
muscle by ↑cAMP
So the only true Muscuranic agonist have the above action.
Nicotinic receptors (N N, NM)
• NN → Adrenal medulla, autonomic ganglia
• NM→ Neuromuscular junction
Cholinergic
agonists
Antiacetylcholinesterases
Choline
estere
Pilocarpine
Cevimeline
Bethanechol
Carbachol
Quarternary
alcoholsCarbamate Organo-
phosphate
Edrophonium
TacrineDonepezil
Physostigmone
NeostigmineDemecarium
Pyridostigmine
Echothiophate
MalathionParathion
Sarin
Soman
Acetylcholine
agonists
Direct
cholinergic
agonist
Indirect
cholinergic
agonists
Classication of Choliinergic Agonist
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Direct acting muscuranic agonist recluse (Braolyeardia)
The heart rate directly affectin on M3 receptors. Also their effect on endothelial blood vessel release
NO, which dialte, the smooth blood vessels. This will cause reux Tachycardia.
Atropine overdose
Atropine is lipid soluble only physostigmine can enter CNS, so it will be used as Atropine antidote.
Summary of Cholinergic receptors effects:
Muscarinic Receptor EffectEye –sphincter muscle M
3Contraction- causes miosis
Heart – SA node AV node
M2
M2
Decrease HR (-ve chronotropy)-vagal arrestDecrease conduction velocity (-ve dromotrophy)
Lung- branchioles Glands
M3
M3
BranchospasmIncrease secretions
GI tract M3
Stomach-increase motility causes crampsIntestine-increase motility causes diarrhea
Blood vessels M3
Vasodilation but no innervation (to stimulate for action)
Nicotinic NAdrenal medullaGanglia
Neuromuscular junction
N Increase secretion of epi and norepinephrine
Stimulation causes muscle hyperactivity
Side Effects
Cholinergic drugs AnticholinergicMyopic accommodation
Bradycardia
SalivationLacrimation
Flushing
Diarrhea
Hypotension
Tremors
Hyper optic
accommodation and
increased intraocular pressure
Tachycardia
Dry mouth
Blurred vision and
mydriasis
Constipation
Urinary retention
Dizziness and
drowsiness
Direct acting cholinergic drugs
Direct acting
Cholinergics
• Acetylcholine
• Pilocarpine
• Bethanechol
• Carbachol• Methacholine
Acetylcholine
Synaptic
vesicle
Choline
Choline
Acetate
Choline
Presynaptic
receptor
Acetylcholine
INTRACELLULAR
RESPONSE
Acetylcholine
CoA
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Muscarinic antagonists
Nicotinic Blockers (Ganglionic blockers)
Nicotine: Depolarizes ganglia, resulting rst in stimulation and followed by paralysis of all ganglia,
increase in BP, HR, inceased peristalsis, and secretion.
a-Bungarotoxin
a -Bungarotoxin is a postsynaptic neurotoxin found in the venom of the Braided Krait snake
(Bungarus Multictus). Like other neurotoxins it blocks neuromuscular transmission.
α-Bungarotoxin (α Bgtx) is a toxin known to interact with muscle nicotinic receptors and with some
neuronal nicotinic receptors.
NMJ blockers
These agents are used for surgical patients to relax the muscles during surgery. .Pharmacological actions:
• Blocks the cholinergic transmission between motor nerve and nicotinic receptors.
• Antagonizes (non depolarizing type) and agonist (polarizing) the effect of acetycholine.
Classied as two categories of NMJ blockers:
Depolarizing: Succinylcholine
• Depolarizing drug attaches to nicotinic receptors and act like acetylcholine to depolarize the
junction.
• Causes opening of sodium channel associated with nicotinic receptors, which results in
depolarization of receptors.
Non-depolarizing:
• Prevents the binding of acetylcholine.
• Inhibits muscular contraction
Anticholinergic
drugs
• Atropine
• Ipratropium
• Scopolamine
• Benztropine• Tropicamide
• Glycopyrrolate
• TrihexyphenidylPharmacological
actions• ↓ in salivationà cause
dry mouth (xerostomia)
• ↓ intestinal secretionà Constipation
• Increase HRà Tachycardia
• Mydriasisà Pupil dilatation
• Relaxation of detrussor muscleà Urinary retention
• Blurred visionAnticholinergic
side effects
• Dry mouth
• Blurred vision
• Tachycardia
• Constipation
• Urinary retention
Tertiary amines
Atropine
Scopalamine
Muscarinic antagonist
Quarternary amine
Ipratropium
Tiotropium
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• Antagonist for non depolarizing agents are: neostigmine, edrophoniuum (cholinesterase
inhibitors)
• At higher doses, these (non depolarizing) drugs block the ion channels of end plate and
reduced the ability of antagonists.
• Indicated in anesthesia during surgery to relax skeletal muscles.
• Side effects: Decrease the BP, paralysis of diaphragm
Abbrevation and Terminology
Generic and Brand
Depolarizing NMJ Blockers
Depolarizing – Noncompetitive
• Succinylcholine
Mechanism • Blocks the cholinergic transmission between motor nerve and nicotinicreceptors.
• Antagonizes (non depolarizing type) effect of acetylcholine.Therapeutic use • Clinically used in surgery to produce complete muscle relaxation.
SA Sinoatrial Node
AV Atroventricular Node
PR Peripheral Resistancea -BgTx a -BungarotoxinACh Acetyl Choline
NMJ Neuro Muscular JunctionBP Blood PressureHR Heart Rate
Non-depolarizing NMJ Blockers
Non Depolarizing -competitive • Atracurium• Tubocurarine• Doxacurium• Pancuronium• Vecuronium• Mivacurium
Mechanism • Prevents the binding of acetylcholine• Inhibits muscular contraction.• At higher doses, these (non depolarizing) drugs block the ion channels
of end plate and reduced the ability of antagonists
Therapeutic uses • Indicated in anesthesia during surgery to relax skeletal muscles.
Side effects • Decrease BP• Paralysis of diaphragm
Antagonist for nondepolarizing agents
• Neostigmine, edrophonium (cholinesterase inhibitors)
Pilocarpine IsotoCarpine
Atropine Atreza, AtroPen, Atropine Care, AtropisolIpratropium Atrovent, Atrovent HFAScopolamine Isopto Hyoscine, Maldemar, ScopaceBenztropine Cogentin
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4 Antihypertensive Drugs
Blood Pressure is caused by Cardiac Contraction
• Systole (contraction)
o When the heart beats (systole) the pressure in the arteries leaving the heart
rises to about 120 mm Hg.
• Diastole (relaxation)
o Between beats (diastole) the arterial pressure drops to about 80 mm Hgo The 80 mm Hg DBP keeps the blood owing between beats
• Blood pressure is reported as SBP over DBP
o Example: 120/80
• Optimal BP is 120/80
• Normal BP is 130/85
• High normal BP is 130-139/85-89
• Grade 1 (mild hypertension) 140-159/90-99
• Grade 2 (moderate hypertension) 160-179/100-109
• Grade 3 (severe hypertension) >180/>110
• Isolate systolic hypertension >140 / 130/>80
Laplace’s Law
Laplace’s law describes how tension in the vessel wall increases with transmural pressure.
According to Laplace’s law, the PRESSURE GRADIENT ACROSS THE VESSEL WALL is given
by: tiwhere Pout and Pin are the pressures outside and inside the vessel, respectively. T is the vessel
wall tension, and r is the vessel radius. If the vessel wall is completely attened against a smooth
sensor surface (r→∞), the measured pressure will be equal to the intra-luminal blood pressure
(DP→0).
Systemic Blood Pressure Depends Upon1-Cardiac Output and Resistance to Flow (TPR): CO = HR X SV
2-Kidney provide long term control of BP
X Total Peripheral Resistance (TPR)= Cardiac Output (CO)Blood Pressure
Angiotensin
antagonistAlpha
2
agonists
Alpha1
Blocker
Calcium
Channel
Blockers
Beta
Blockers Diuretics
AT1 Receptor
Blocker ACE inhibitors
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Nonselective (β
1 & β
2)
Cardioselective
(β 1
only)
Beta & Alpha blockers
Partial agonist &
antagonist
• Propranolol• Pindolol• Nadolol• Timolol• Levobutolol
• Esmolol• Metoprolol• Acebutolol• Atenolol• Bisoprolol
Betoxalol
• Labetalol• Carvedilol
• Acebutolol• Pindolol• Oxprenolol
VasoconstrictionReduce intra
ocular pressure
(IOP) = ↓ secretion of
aqueous humor
Bradycardia
Alpha receptorsProduce
vasodilatation =
↓BPBeta blocker
cause Peripheral
vasoconstriction
Does not alter
serum lipid
levels
Intrinsicsympathomimetic
activity (ISA)
Minimized
disturbances
of lipid and
carbohydrate
metabolism
By altering blood volume: Sympathetic stimulation releases the enzyme renin. Angiotensinogen and
angiotensin I & angiotensin II.
Angiotensin II is the bodies most potent circulating vasoconstrictor causing increases BP.
Angiotensin II stimulates aldosterone (ADH) secretion leading to increase kidney sodium reabsorption
and increase in blood volume, which contributes to increase in BP.
Systemic blood pressure depends upon cardiac output and resistance to ow
β-blockersBeta-blockers are used to treat hypertension and angina. These drugs act by slowing the heartbeat,
which results in lowered blood pressure since blood pressure is affected by the heart rate and
peripheral resistance. Because of its action on the lining of arteries, propranolol is also used to treat
migraines.
Nonselective (β1
& β2)
CardioSelective
(β 1
only)
Beta & Alpha blockers
Partial agonist
& antagonist
Beta Blockers
►
►
►
►
• The more blood pumped into the arteriesthe higher the pressure
• Pressure also goes up if there is moreresistance to ow- this occurs when largenumbers of arterioles constrict
• The body changes both CO and resistanceto adjust blood pressure, the higher the
blood pressure the more work the heartmust do to pump blood.
Renin
Angiotensin I
Angiotensin II
Aldosterone
Na/H2O retension
PR
BP
Blood
Volume
ACE
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Mixed β1 and β
2-
antagonists (non
selective)
• PropranololProPiNaTionaLe
• Pindolol• Nadolol• Timolol• Levobutolol
Mechanism • Reduce intra ocular pressureà Decrease
secretion of aqueous humor • Bradycardia• Bronchoconstriction (Bronchospasm)
β1 antagonists
(cardioselective)• Esmolol• EMAA Selective• Metoprolol• Acebutolol• Atenolol
Mechanism • Vasoconstriction• No bronchoconstriction
Mixed a and
β-antagonists
• Labetalol
• CarvedilolMechanism • Produce vasodilationà ↓ BP
• Peripheral vasoconstriction• Does not alter serum lipid levels
Partial agonist andantagonist
• Acebutolol• Pindolol• Oxprenolol
Mechanism • Intrinsic sympathomimetic activity• Minimized disturbances of lipid and
carbohydrate metabolism.
ISA: Intrinsic
SympathomimeticActivity:
• The partial agonist stimulates the beta-
receptors to which they are bound; yetinhibit stimulation by the more potentendogenous catecholamines, epinephrine andnorepinephrine.
• The result of opposing actions is a much-diminished effect on cardiac rate and cardiacoutput.
• Compared to β-blocker without ISA.Side effects
Slowed heartbeat (bradycardia), profound low
blood pressure (orthostatic hypotension), dizziness,depression, drowsiness and some stomach upset andhypoglycemia. Because of the effect of βeta-blockeron the βeta-receptor of smooth muscle, the lining ofthe bronchioles may be affected. These drugs canaggravate asthma, breathing difculty or shortnessof breath in some sensitive patients. These drugsshould not be given to asthma patients unless noother class of drug can be used. However, esmalol,acebutol, atenolol, bisoprolol, betaxolol andmetoprolol are selective β-blockers and generally,have less or no bronchospasm side effects. Theselective β-blockers may be given to lower doses to
patients sensitive to these drugs if no other class ofmedication can be used.
Mechanism of action of beta-blockers
β1 receptors
↑ CO
↑ HR
↑ Force
blood
β receptors
peripheral
vasodilation
Effect of B receptor
on heartCardiac output
Renin Angiotensin II Preripheral
resistant
Aldosterones
Na, H2O levelsBlood volume
Cardiac output
BP
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Contraindications
• Bradycardia• Heart blockage• Asthma and bronchospasm (avoid non selective)• Peripheral vascular diseases such as Raynaud’s
phenomenon and intermittent claudication except
carvedilol and labetelol can be tried.• Caution in congestive heart failure.• Left ventricular dysfunction
Drug and food interactions
• Propranolol is best absorbed with food butconsistency is the most important factor
• Metoprolol is best taken with meals• These drugs should be taken at about same
time every day
• Beta blocekers that have Ist pass metabolism; propranolol, timolol
• Beta blocekers that have no biotransformation;atenolol
• Beta blocekers that have α blockadeeffect:labetalol, carvedilol
• Beta blocekers that act as membrane stabilizer;
propranolol
Alpha-blockers are the drug of choice in
Decrease in contractility of heart and decrease
in oxygen consumption
Propranolol Used for hypertension, angina, post MI, migraine, essential
tremor, performance anxiety,
Hyperthyroidism (acute-
thyroid storm)
Timolol Used for hypertension, postMI, migraine. Chronic
treatment of Open angle
glaucoma
Pindolol Used for hypertension
Metaprolol Cardioselective, used forhypertension, angina
Atenolol Cardioselective, used forhypertension
Esmolol Cardioselective used forhypertension, tachycardias
Acebutolol Cardioselective, used forhypertension, angina
Beta-blockers therapeutic uses:
In addition to being used for hypertension, terazosin, doxazosin, tamsulosin and alfuzosin which are
chemically related to prozasin are often used to treat benign prostatic hypertrophy (BPH), the medical
term for enlarged prostate. These drugs cause the muscles of the bladder neck and prostate to relax,
thereby making it easier for patients to urinate. As Antihypertensives, they help control pressure by
relaxing blood vessels and permitting them to expand.
α1-antagonist α
2-agonist
Indication Hypertension
Benign Prostatic Hypertrophy
(BPH or enlarged prostate)
DOC for pheochromacytoma
hypertension
Hypertension
Treat withdrawal
symptoms in recovering
drug and alcohol abusers
(Clonidine)ContraindicationSide Effects Orthostatic hypotension
Tachycardia
Vertigo
Sexual dysfunction
Decrease lipolysis
Decrease insulin secretion
Sexual dysfunction
α-receptors
a1 antagonists
• Doxazosin mesylate
• Prazosin hydrochloride• Terazosin hydrochloride dehydrate
• Alfuzosin
• Tamsulosin
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pheochromacytoma hypertension.
Pharmacological actions of a 1 anatagonist:• ↓ BP
• ↓Total Peripheral Resistance (TPR)
• No Reex tachycardia
• Vasodilations• First dose effect (syncope)
• Miosis
Side effects: Orthostatic hypotension, Tachycardia (No reex tachycardia), Vertigo, Sexual dysfunction
to avoid the rst dose effect of hypotension and occasional syncope, the starting doses should be small
and given at bedtime.
a2 agonist – Centrally acting antihypertensive
a2 agonist used to treat hypertension are centrally acting agents, which act directly in the brain tochange the signals send to the heart and blood vessels. These drugs are not commonly used, as it is
difcult to achieve the proper dose with these agents. They are generally reserved for people who
fail to respond to other therapies.
Other uses have been found for clonidine. Clonidine is sometimes used to treat withdrawal
symptoms in recovering drug and alcohol abusers.
a2 agonists
• Methyldopa
• Clonidine• Guanabenz
Pharmacological actions a 2 agonist:• Decrease Central adrenergic outow
• a2 receptors have inhibitory action on epinephrine and NE• Increase a2 receptors increase inhibitory action on epi and NE• ↓ Blood Pressure
• ↓ insulin secretions
• ↓ NE
• Bradycardia
• Side effects: Decrease lipolysis, Decrease insulin secretions, Sexual dysfunction
Methyldopa (Aldomet)
Mechanism • a2 agonists
• Inhibit norepinephrine release
• Inhibit insulin releaseTherapeutic use • Indicated in moderate to sever hypertension
• Produced active metabolite (Methyl dopaà Alpha methyl
norepinephrine)
• Methyl dopa is prodrug• Drug of choice for hypertension in pregnancy.
cAMP
ATP
α
Norepinephrine
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Side effects • Cardiovascularà Bradycardia, orthostatic hypotension
• Blood relatedà Hemolytic anemia, thrombocytopenia
• Bone marrow depression
• GIà Dry mouth, nausea, diarrhea
Clonidine (Cataprex)
Chemistry • Clonidine contain imidazoline ring.
Therapeutic use • Used in non complicated hypertension to lower BP.
• Indicated in opioids and benzodiazepine withdrawal symptoms (CNS
symptom)Side effects • CVSà bradycardia orthostatic hypotension, severe rebound hypertension
• CNSà drowsiness, dizziness, agitation
Dosage • Transdermal patch
• Pruritus and rash at the site of transdermal• Patch (TT1 (release 0.1 mg/24 h), TT2 (0.2 mg 24/h). TT3 (0.3 mg/24 h)Precautions • Don’t discontinue abruptly, reduce dose over 2-3 days to reduce sever
hypertension
Counselling • Don’t miss any pill, Don’t stop suddenly
• Causes drowsiness
• Need gradual withdrawal
Diuretics
• Often called water-pills, diuretics increase urine production,
• Reducing the body of sodium and water, thereby reducing the volume of blood that the heart
must pump, and in this manner decreasing blood pressure.
• Side effects: stomach upset, frequent urination, potassium depletion, and dizziness.
• Potassium blood levels should be monitored.
• Foods rich in potassium may be ingested (eaten) daily. These are potatoes, bananas, cantaloupe,
and citrusfruit.
• If potassium levels are very low, potassium chloride or potassium oral liquids may be used.
• Mechanism of hypokalemia induced by CA inhibitors, loops and thiazide diuretics: Because of
upstream blockade of NaCl reabsorption there is ↑ Na+ consequently there is ↑ reuptake of Na+. ↑
+ve charge in the cell. The increase +ve charge then pushes out K + into the lumen.
Thiazide
DiureticsLoop
DiureticsK-sparing
diuretics
Carbonic acid
Inhibitor
Osmotic
diuretic
Chlorothiazide
Hydrochlorothiazide
Chlothalidone
Furosemide
Ethacrynic acid
Bemetanide
Spirolactone
Triamterene
Amiloride
Acetazolamide Mannitol
Classication of Diuretics
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• Nephritis (intestinal)
• Gout arthritis
• Sequence of ototoxicity (etharynic acid>furosemide>bumetanide)
Do not use • If patient has renal stones
• If patient has gout do not use loop and thiazides
Ethacrynic Acid • Does not contain sulfonamide functional groupà no sulfa allergy
Potassium sparing
Potassium sparing • Amiloride (Midamor)
• Triamterene (Dyrenium)
• Spironolactone (Aldactone)
• The K + STAys
• Spironolactone
• Triamtereneà blue color urine
• AmilorideMechanism • Act in the early collecting duct to
inhibit the electrogenic reabsorption
of Na+ by blocking the Na channels
and hence the exchange of sodium for potassium.
• After administration: ↑ Na+, Cl- elimination, ↓K+, Ca++ (amiloride).
• Increase Na, H2O, HCO
3 excretion (decrease levels in body)
• Decrease K +, H+ excretion
• Alkaline urinary pHà Increase excretion of HCO3
Aldosteroneantagonist
• Spironolactone (Aldactone): competitive inhibits aldosterone at minorAldocorticoid receptors. Decreases potassium excretion.
Non aldosterone
antagonist
• Amiloride and triamterene
• Act directly on late distal tubule and collecting duct. They disrupt
sodium exchange with Potassium and hydrogen by blocking sodium
channel
• Decrease in the driving force for secretion of potassium and hydrogen.• Used in nephrogenic diabetic insipidus
• Amiloride, spironolactone and trianterene act as competitive antagonists of aldosterone in the
kidney. Because they are weak diuretics when given alone, they are often used in combination
with hydrochlorthiazide, as in Aldactazide, Apo-Triazide, Apo-Amilzide.
• A side effect may be hyperkalemia, an increase in potassium levels, so that potassium
supplements are usually not taken with these drugs. If they are needed, the dose of potassium is
frequently administered three times a week instead of daily.
Osmotic Diuretics
Osmotic • Mannitol, and Urea
Mechanism • Increase excretion of H2O, Na, Cl and HCO
3 (decrease levels in body)
• Increase alkaline urinary pHàIncrease excretion of HCO3• Increase tubular osmolarityà Increase urine ow
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Carbonic anhydrase Inhibitors
• Acetazolamide
• Increase excretion of H2O, Na, K, and HCO
3 (Decrease levels in body)
• Increase alkaline pHà Inc. exc-HCO3
• Cause metabolic acidosis
Serum Electrolyte of Diuretics
In general, the opposite ndings of serum electrolytes are seen in urine
Diuretics Tips
• Diuretics that cause metabolic alkalosis:
• Diuretics that cuase intracellular alkalosis:
• Diuretics that act on distal convoluted tuble:
• Diuretic that cause metabolic acidosis:
• Diuretics that have greater vasodilation effect:
• Hyperlipidemia NOT generally siginicant at low doses, (
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Ramipril, Trandolapril
Pharmacological actions
• ↓ sympathetic output
• Vasodilation of smooth muscles• ↑ levels of bradykininàcauses dry cough
and vasodilation
• ↓ retention of Na and H2O
• Above combined effect produce ↓ in preload
and after load
• ↑ cardiac output (CO).
• Dilation of venous blood vessels leads to
decrease in cardiac preload by ↑ venous
capacitance.
• Arterial dilator reduces systemic arteriolar
resistance and ↓ after load.• Lower BP by reducing peripheral vascular
resistance with reexly increasing cardiac output rate.
• By reducing circulating angiotensin II levels ACE ↓ the secretion of aldosterone, resulting ↓
retention of Na and H2O.
• Little change in HR, or GFR.
Therapeutic use • 1ST LINE: Heart Failure
• Diabetes nephropathy
• Post MI
• Uncomplicated hypertension,and pre-hypertensive patient
• LVH (Left ventricularHeart failure)
• Prior CVA/TIA (CardiovascularAttacks/ Transient Ischemic attacks)& in renal disease
Side effects • Dry cough (5-15%)• Hypotension• Hyperkalemia• Renal insufciencies
• Angioedema (rare)• Reversible neutropenia• Proteinuria (presence of protein in urine)• Fatigue
ContraIndications:
• Pregnancy (absolute): Can produce hypotension in the fetus leading renal failureand death, skull hypoplasia and death.
• Documented angioedema-secondary angioedema,
• Bilateral renal artery stenosis.• Captopril should be taken one hour before meals.• High fat meals may reduce absorption of Accupril
• Food does not effect the other drugs in this class
Angiotensinogen
(alpha globulin in blood)
Na & H2O levels
Bradykinin
Sympathetic action
VasodilationRenin
(kidney)
BP
Angiotensin IIAngiotensin I
ACE I
Angiotensin II Formation
Angiotensinogen
Liver
Bloodstream
Renin
Angiotensin I
Angiotensinconverting
enzyme
Angiotensin II
Kidney Lung
Vasoconstriction
Aldosterone secretion
ADH secretion
Thirst
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Vasodilators cause the smooth muscle in
blood vessels to relax. Relaxed or dilated
blood vessels allow more blood to ow
through, causing a reduction in blood
pressure by decreasing peripheral resistance.
As vasodilators work, the blood vessels
become dilated causing a drop in pressure because there is less blood volume to ll
the vessel. The body can compensate for
this by retaining enough uid to ll the
blood vessel sufciently to raise the blood pressure again.
Hydralazine and minoxidil are direct vasolidators not usually used a sole therapy for high blood
pressure, as their effect is usually short-lived when administered alone. Minoxidil is available in
tablets and also as a topical lotion for treatment of male-pattern baldness).
Pharmacological action
Vasodilators reduce excessive preload and after load.Elevated after load causes the heart to work harder to pump blood into arterial system.
Dilation of venous blood vessels leads to decrease in cardiac preload by increasing venous
capacitance.
In arteries dilators reduce systemic arteriole resistance and decrease after load.
Minoxidil (Rogaine)
• A prodrug, which must be conjugated with a sulfate to form the activedrug.
Mechanism • Minoxidil is potent renal vasodilator and stimulator of renin release.Therapeutic use • Hypertension and alopecia treatment
Side effects • Salt and water retention (use a diuretic)• Reex tachycardia• Pulmonary hypertension• Blurred vision• Hypertrichosis - topical solution is now marketed for baldness.
For alopecia • Each mL of clear, colorless to slightly yellow solution contains:minoxidil 20 mg (2%), in alcohol (63%), propylene glycol (20%) andwater.
• For external use only. Store at controlled room temperature (15 to
30°C).• Hypertrichosis (excessive hair growth) occurs continued treatment over
4 weeks
Emergencey use drugs
Hydralazine (Apresoline)
Mechanism Acts directly relaxing arteriolar smooth muscle. Orthostatic hypotension is
not a problem.Therapeutic use • Indicated in pregnancy induced hypertension (PIH)
Vasodilators
Direct Vasodilators:
Hydralazine
Sodium NitroprussideMinoxidil
Indirect Vasodilators:
ACE inhibitors
Calcium channel blockers
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Side effects • Salt and water retention, which may lead to CHF (use a diuretic).
• Hematologic-neutropenia,
• Leucopenia,
• Agranulocytosis,
• Muscle cramps,• Orthostatic hypotension
• Tachycardia• Lupus like syndrome (Systemic Lupus Erythromatus)
Diazoxide (Hyperstat)
Mechanism • Dilates arterial smooth muscle.
• Used IV for the treatment of hypertensive emergenciesTherapeutic useSide effects • Salt and water retention
• Hyperglycemia (↓ release of insulin)
• Hypertrichosis
Sodium Nitroprusside
Mechanism • Dilates both resistance and capacitance vessels,
• Nitroprusside when come in contact with red blood cells (RBC) produces
nitric oxide (NO), which then stimulates guanylate cyclase.Therapeutic use • DOC for hypertensive crisisSide effects • Short term-excessive vasodilatation and hypotension. Long term-
accumulation of cyanide and thiocyanate (24-hours).• Concomitant administration of sodium thiosulfate decrease cyanide
accumulation by changing into thiocyanate.Thiocyanate
toxicity
• Nausea, disorientation and toxic psychoses
Antihypertensive Drugs Tips
• Targeted isolated systolic BP should beà
• Hypertension with diabetes DOC isà
• Hypertension with renal disease DOC isà
• Hypertension + pheochromacytoma which antihypertensive should be avoidedà
• Isolated systolic Hypertension which drugs should not useà
• Cardioselective beta-blockers areà
• What percent of patients diagnosed with high blood pressure have essential hypertension?à
• Name the cation most prevalent in the extracellular uid of the body.à
• Why is bedtime the best time to dose terazosin?à
• What is the recommended sodium intake for a patient diagnosed with hypertension?à
Summary of β - blockers
Pharmacological actions
• β1 = decrease heart rate
• β2 = bronchoconstriction
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• Peripheral vasoconstriction (Increase TPR )—β2
• ↓ Na/water retention
• ↓ glycogenolysis (glycogenà glucose)
• ↓ glucagon secretions
• Blocks the effect of isoproterenol
Antihypertensives Lowers blood pressure through reducing the PR or CO.
Diuretics
• Create a negative sodium balance, reduce blood volume, and decrease vasoconstriction.
Peripheral sympatholytics
• Blocks postganglionic adrenergic receptors, limiting release of neurotransmitters from
adrenergic receptors, or depleting intraneuronal catecholamine storage sites.
Central a2-sympathomimetics• Cause negative sympathetic outow and lowering peripheral resistance.
Calcium channel blockers
• Block voltage-gated calcium channels causes lower vascular resistance and blood pressure.
ACE inhibitors• Decrease Sodium retention by blocking the conversion of inactive Angiotensin I to
Angiotensin II.
Angiotensin II-receptor antagonist
• Produced vasodilation and causes loss of salt and water thus decreasing the plasma volume, and
myogenic activity.
Vasodilators
• Relaxes arterioles and veins, membrane hyperpolarization, decrease atrial resistance.
Abbrevation and Terminology
TPR Total Peripheral Resistance
DBP Diastolic Blood Pressure
SBP Systolic Blood PressureBP Blood PressureCHF Congestive Heart FailureCO Cardiac OutputADH Antidiuretic HormoneBPH Benign Prostate HyperplasiaACE Angiotensin-converting enzyme.HR Heart RateISA Intrinsic Sympathomimetic ActivityEMAA Esmalot, Metopralol, Acebutalot, Atenalol
NE NorepinephrineDHP Dihydropyridine
NDHP Non DihydropyridineGFJ Grape Fruit JuiceCA CalciumGFR Glomerular Filtration Rate.ARB Angiotensin Receptor Blocker
NO Nitric OxideRBC Red Blood CellsPIH Pregnancy induced hypertension
SV Stroke VolumeLVH Left Ventricular Heart FailureCVA Cardiovascular attacks
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5Antihyperlipedemic Drugs
Effects of Antihyperlipidemics on Lipoproteins
Drug class LDL HDL VLDL-TGBile acid sequesterants ↓ ↑ ↑
Nicotinic acid ↓ ↑ ↓HMG-CoA reductase inhibitors
↓ ↑ ↓ (TG)Fibric acid derivatives ↓
↑ ↓
Reference: Therapeutic Choices, 4th ed. page 242
Statins
Statins Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin
Mechanism HMG CoA reductase inhibitors (HMG = 3-hydroxy, 3-methyl glutaric acid)
Therapeutic use Decrease LDL receptors (18 – 55%)
Lower cholesterol synthesis (cholesterol pills)
Contraindicated In pregnancy and breast-feeding, children or teenagers.
Side Effects GI side effectsà GI upset, diarrhea, nausea and vomiting
Rhabdomyolysis (myopathy)àdisintegration and dissociation of muscles
Rhabdomyolysis is common in renal insufciency patients.
Drug interactions • Medication such as cyclosporine, itraconazole, erythromycin
(macrolide), gembrozil, niacin, brates and grapefruit juice increase
rhabdomyolysis, due to inhibition of CYP 34A enzyme, which isessential for metabolism of statins Niacin
Bile acid
sequeste-rants
Nicotinic
acid
HMG-CoA
reductase
inhibitors
Fibric acid
derivativesCholesterol
Absorption
inhibitors
Cholestyramine
Cholestipol
NiacinLovastatin
Simvastatin
Pravastatin
Fluvastatin
Atorvastatin
Cervastatin
Ezetimibe
Ezetrol
Classification of Antihyperlipidemic Drugs
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Management • Administration of aspirin prior to taking niacin decrease ush.
• Take with food
• Tolerance develops in 1 – 2 weeks
• Higher dose 2g/day may produce hepatic damage
No-ush prep • Contains Inositol + Niacin
Fibrates
Fibrates • Bezabrate
• Fenobrate
• Gembrozil
Mechanism • Decrease TG levels
• Increase HDL levels (moderately)
• Decrease LDL levels
• Inhibit cholesterol synthesis
• Fibric acid derivativesTherapeutic use • Treatment of choice in hypertriglyceridemia + diabetic patients.
• HDL increase 10 –20%
• TG decrease 20 – 50% (Effective for TG)
Side Effects • Mild GI disturbances.
• Lithiasis: because these drug increase bilary cholesterol excretionà
predispose gallstone formation.
Contraindication • Sever hepatic and renal dysfunction, potentiates warfarin activity.
Preexisting gall bladder disease.
Monitoring • Liver Function test
• Creatinin Kinase• Complete Blood Count
• Renal function test
• At 3, 6 and 12 mo, and yearly
Drug interactions • Combination with Statins may lead to rhabdomyolysis
Resins
Resins • Cholestyramine
• Colestipol
Mechanism • Prevents absorption of cholesterol.
• Anion-exchange resins bind with the enzymes in intestine and inhibit
the synthesis of cholesterol. Bile acids are synthesized from cholesterol.
• Decrease LDL 15 – 30%
• Increase HDL 3 – 10%
• No change or increase in TG (disadvantage)
Therapeutic use • Drug of choice in pregnancy
• Cholestyramine also relieves pruritis caused by accumulation of bile
acids in patients with biliary obstruction in cholestasis
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Side Effects • Decrease absorption of ADEK fat-soluble vitamins.
• High doses of folic acid and ascorbic acid absorption is reduced.
• Most common GI problem: constipation.
Drug-Drug
interactions
• These drug interfere with intestinal absorption of many drugs
(tetracycline, Phenobarbital, warfarin, pravastatin, uvastatin, aspirin,
and thiazide diuretics)
Ezetimibe (Zetia)
Mechanism • Selectively inhibit the intestinal absorption of cholesterol and related
phytosterol.
Therapeutic use • Used in combination with statins (increasing dose of statins only
does not decrease LDL levels, hence combination Ezetimibe is
recommended).
Side Effects • GI effects: Abdominal cramps,• Liver problems
• Sexual dysfunction
• Weight loss
Advantage • Does not affects fat soluble vitamins
• Low potential for drug interactions
Antihyperlipidemic Drugs Tips
• Goal of antihyperlipidemic therapy isà• FLS = only taken at night (at bedtime), for maximum effect.
• Pravastatin and rosuvastatin have no drug interactions
• Statins increase risk of arrhythmias at night
• HMG Co A inhibitors are mainly metabolized byà
• HMG Co A inhibitors side effect rhabdomyolysis patient may notice byà
• Which antihyperlipedemic have no effect or increase triglyceride levelsà
• Which antihyperlipidemics have equal proportion effect on LDL, HDL and TGà
• Resins act what part of GIà
• Hydrochlorothiazide effect on lipids includeà
• ACE inhibitors effect on lipids includeà
• CCB effects on lipidsà
• Lovastatin is given with food becauseà
• DOC for cholesterol in DM patientsà
• Normal levels of lipids: LDL = 0.9 mmol/L; TG =
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Generic and Brand
TGCBC Complete Blood CountHMG 3-hydroxy, 3-methyl glutaric acidLFT Liver Function TestCPK or CK Creatinin KinaseADEK Vitamin A, D, E and K DM Diabees Mellitue
HMG 3- Hydroxy, 3- Methylglutaric acid
Atorvastatin Lipitor
Fluvastatin Lescol
Lovastatin Mevacor Pravastatin PravacholRosuvastatin Crestor Simvastatin Zocor
Bezabrate BezalipFenobrate LipidilGembrozil LopidCholestyramine QuestranColestipol ColestidEzetimibe Zetia
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6Coronary Artery Diseases
Coronary artery Diseases
The most common complications associated with Coronary artery disease include: Angina pectoris,
Myocardial infarction, post Myocardial infarction,and Ischemic stroke. Insufcient supply of oxygen
to heart can lead to Ischemic conditions.
• Myocardial ischemia is usually caused by coronary vessel atherosclerosis (High LDL
and high cholesterol is the most common risk factor). As the vessel lumen narrows blood
ow is reduced.
• Other causes that limit coronary blood ow include: Arterial thrombi and Spasm
Angina Pectoris
Angina are those symptoms of myocardial ischemia that occur when myocardial oxygen availability
is insufcient to meet myocardial oxygen demand.
These symptoms include:
• Chest discomfort often described as heaviness, pressure, and squeezing. The sensation is
localized typically in the sternal region.
• Symptoms often last one to ve minutes. Angina can radiate to the left shoulder, to both arms(ulnar surfaces of the forearm and hand), and can radiate to the neck, jaw, teeth, epigastrium and
back.
Types of angina
Angina Pectoris • Severe chest pain because of inadequate coronary blood ow to supplyoxygen demand.
• Which is usually aggravated by exertion or stress and relieved bynitroglycerine.
• The most common form of IHD.
Types of angina
Stable angina Unstable angina Exercise-induced
Prinzmetal angina
Or
Vasospastic angina
Nocturnal Angina
Chronic angina
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Types of angina pectoris
• Stable angina/ Classic angina (most common-90%)• Unstable angina• Exercise induced angina• Exertion angina• Chronic angina• Prinzmetal angina• Nocturnal angina
Stable angina orclassical
• Mostly secondary to atherosclerosis (high LDL)• Due to obstruction in coronary arteries• More predictable• Precipitated by exertion or emotional stress or by heavy meal.• Relieved by rest or using nitroglycerine’s
Unstableangina/resting/Crescendo
• The most serious one (worsening pain)• Thrombosis in a branch• Caused by formation atherosclerotic (disease of arteries, in fatty plaques
develop in inner wall), occurs at rest• ACE inhibitors are used as single treatment• Decreased response to rest and nitroglycerine
Nocturnalangina (anginadecubitus)
• This angina occurs in the recumbent position and is not specically relatedto either rest or exertion
• Nitroglycerine may relieve the paroxysmal nocturnal dyspnea
Prinzmetalangina(vasospastic orvariant angina)
• Coronary artery spasm that reduces blood ow precipitates this angina.• Secondary to coronary artery spasm• Usually occurs at rest (pain may disrupt sleep)• Calcium channel blockers are most effective
Treatment of angina
• The following beta-blockers are used in treatment of angina:
• Beta-blockers with Selective Intrinsic Sympathomimetic Activity (ISA):
Acebutolol hydrochloride Beta-blockers with Non-ISA: Atenolol
and Metoprolol tartrate can be used.
• Beta-blockers with Nonselective, ISA: Pindolol
• Beta-blockers with Nonselective, Non-ISA: Nadolol, Propranolol hydrochloride,
Timolol maleate
• Calcium Channel Blockers are used in treatment of angina:• Amlodipine besylate, Diltiazem hydrochloride, Nifedipine, Verapamil hydrochloride
• The following Coronary Vasodilators, Nitrates are used in treatment of angina:
Vasodilators
Calcium blockers, and ACE inhibitors
Nifedipine,
Verapamil,
Diltiazem
Cardiac depressants
β-blockersProponolol
Nitrates
Short duration
Inhaled amyl nitrite
Sublingual
Nitroglycerine
Isosorbide dinitrite
Intermediate
Oral regular or sustained-
release Nitroglycerine
Isosorbide dinitrite
Long duration
Transdermal
Ntiroglycerine patch
Drugs Used In Angina Pectoris
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• Nitroglycerin, Isosorbide dinitrate, Isosorbide-5-mononitrate.
Nitrates• Organic nitrates act primarily by vasodilation (especially venodilation), which reduces
myocardial preload and therefore myocardial oxygen demand.
• Nitrates also promote redistribution of blood ow to relative ischemic areas.
Mechanism • Vascular smooth muscle relaxation
• Two major effects
• Dilation of the large veins (resulting of pooling blood in veinsà this
reduces preload and decrease work of heart.
• Dilates coronary vasculature, providing increased blood supply to the heart
muscles.
Side effects • The Most common side effect is headache.
• Higher doses: Postural hypotension, facial ushing and tachycardia.
• Toleranceàdevelops rapidly.
• This can be overcome by using “nitrate free period” and restore sensitivity
to drug.
Storage
Conditions
• Amber color, glass and metal capped
• Dispense in original container
• Discard cotton present on tablets in bottle.• Drug expires after 6 months from the day bottle open.
• Light sensitive, hygroscopic.
Drug
interactions
• Cause hypotension with Sildenal , Tadanal, Verdanal.
• Additive hypotension effectDosage forms • Nitroglycerine SLà Acute
• Nitroglycerine Pumpà Acute
• Nitroglycerine Patchà Maintenance
Nitrites
Therapeutic use • DOC for hypertensive crisis
Side effects • Cyanide toxicity (releases CN)
• Sodium thiosulte is an antidote
• (Cyanide (Intermediate) + Sodium thiosulteà Sodium thiocyanate
(water soluble)
• Photosensitive
Ca2+ channel Blockers
These agents are used to treat hypertension and are effective in treating angina as well. All muscles,
including the smooth muscle of the blood vessels, require calcium in order to contract. If the
Nitrates ↑ Nitrites ↑ Nitric oxide (NO) ↑ cGMP
↑ Dephosphorylation of
myosin light chain
Vascular smooth
muscle relaxation
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calcium-channel blocking agents block the entrance of calcium into the muscle, the muscle will not
contract. This will allow themuscle to relax and subsequently reduce the blood pressure. Other
therapeutic uses: angina, migraine, antiarrhythmic.
Non
dihydropyridines
• Diltiazem hydrochloride
• Verapamil hydrochloride
Mechanism • Verapamil is similar to Beta blockers in effect• Verapamil can cause bradycardia• The effect on Heart is graded from higher to lower: verapamil >
diltiazem > nifedipine
• Verapamilà avoid using in CHF (cause –ve inotropic effect) and
constipationDihydropyridine • Nifedipine
• Felodipine
• Amlodipine
• Nicardipine
Nifedipine is similar to Nitrate in effect (Peripheralà decrease afterload,
dihydropyridine can cause tachycardia.
Dihydropyridines Relax and dilating arteries. The effect on vascular smooth
muscles is high with dihydropyridine:
nifedipine > diltiazem > verapamil
Comparison of dihydropyridine and Non-dihydropyridine
DHP NDHP
Cause Reex tachycardia Cause Bradycardia
No heart blockade Cause Heart blockade
Peripheral vasodilation Myocardial vasodilation
Amlodipine long half-life Negative (-ve) inotropic(Only amlodipine does not cause effect (worsening CHF)
reex tachycardia)
Can be used in asthma
Avoid CYP3A4 Inhibitors/Inducers (GFJ)
Side effects: ushing, profound low blood pressure, swelling of legs and feet, constipation and
stomach upset. If edema (swelling) of the legs and feet occur, a diuretic may be added to the
regimen.
Nifedipine (Adalat)
Mechanism A calcium blocker which interfere with conduction of signals in the
muscles of the heart and vessels.Therapeutic use Given regularly to prevent Angina attacks.
Reduce high blood pressure and is often helpful in improving
circulation to the limbs in disorders such as Raynaud’s disease.Side Effects Blood pressure will fall too low’ and sometimes causes heart rhythm.
Tachycardia, ushing, headache, dizziness, Orthostatic hypotension,
and edema
Amlodipine (Norvasc)
Mechanism • A calcium blocker which interfere with conduction of signals in the
muscles of the heart and vessels.
Diltiazem
Coronary Dilatation
Veropamil
Av conductingdecrease
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Therapeutic use • Angina and Chest pain
• Can be safely used by asthmatic and non-insulin-dependent
diabetic.Side Effects • Blood pressure may fall too low
• Sometime may cause mild to moderate leg and ankle swelling
Diltiazem (Cardizem)
Mechanism • A calcium channel blocker that interfere with the conduction of
signals in the muscles of the heart and blood vessels.Therapeutic use • Angina
• Longer acting formulations are used to treat high blood pressureSide Effects • Usually well tolerated, occasional hypotension or orthostatic
hypotension, ushing, arrhythmia, and bradycardia. Use with
caution in patient with CHF
Myocardial Infarction (Heart attack)
Mechanism • Myocardial ischemia is usually caused by coronary vessel
atherosclerosis. As the vessel lumen narrows blood ow is reducedDrug of Choice
for Acute coronary
syndrome
• Acute MIà b-blockers, ACE, CCB,
• Prophylaxis (prevention)à ASA (60-81 mg/day), Nitroglycerine
• Severe chest painà Morphine
• AnticoagulantsàHeparins, LMWH,
Warfarin
• AntiplateletsàAspirin, clopidogrel,
ticlopidineASA • A = Analgesics
• A = Antipyretics
• A = Antiinammatory
• A = Antiplatelets (60-81 mg/day)
• Aspirin decrease morbidity and mortalityPost MI • No CCB
• Thrombolytic used for coronary perfusion, eg: streptokinase
• Also Glycoprotein IIB, IIIA inhibitors such Tiroban can be used
STEMI treatment: ASA, Beta-blockers, Nitrates, CCB, Thrombolytics NSTEMI treatment: ASA, Beta-blockers, Nitrates, Heparin
Coronary Artery Disease Tips
• Nitroglycerine spray storage and administrationà
• Nitroglycerine SL storage condition requireà
• Light sensitiveà
• Nitrates should be avoid taking withà
• What is active moiety of nitratesà • Nitroglycerine is chemically classied asà
• Nitroglycerine + seldanal can cause hypotension and this due to nitroglycerine and seldanal.
• The most common side effect of nitroglycerine is headache; therefore nitroglycerine should be
Coronary arteries
Zone 1: Necrosis
Zone 2: Injury
Zone 3: Ischemia
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taken while sitting position.
• Nitroglycerine patch can cause tolerance, to avoid tolerance use nitrate free period.
• What drugs effective in MI prevention and treatmentà
• What drugs should be avoided in MIà
• Severe chest pain associated with MI treated byà
• STEMIà
• NSTEMIà
• At what dose ASA act as Antiplateletà
• ASA act as irreversible Antiplatelet drug
• Nitratesà Increase nitritesàIncrease Nitric oxide (NO)à vascular smooth muscle relaxation
Abbrevation and Terminology
Generic and Brand
LDL Low-density Lipoprotein
IHD
SLCN
CCBMI
ACE Angiotensin-Converting EnzymeASA Acetyl SaliaylateSTEMI ST-Segment Elevation MI
NSTEMI non-ST-Segment Elevation MI
Verdanal Levitra
Sildenal Viagra
Tadanal Cialis Nitroprusside Nitropress
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