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FINALS

DRUG RECEPTORS AND Tolerance


PHARMACODYNAMICS - ↑ sensitivity as a result of exposure
POTENCY
Tachyphylaxis
- Amount of drug needed to produce a
- Develop tolerance after a few doses
given effect
- Graded Dose-Response Curve
AUTONOMIC PHARMACOLOGY
o Effect chosen is the 50% of
maximal effect
CHOLINERGIC TRANSMISSION
o Dose is EC50
Acetylcholine (Ach)
- Quantal Dose-Response Curve - Primary transmitter in all autonomic
o Variables used: ganglion and parasympathetic
 ED50 postganglionic synapses
 Median effective - Synthesis
dose o Synthesized from:
 50% individuals  Acetyl-CoA
manifested  Choline
therapeutic effect o Synthesized by:
 TD50  Choline acetyltransferase
 Median Toxic Dose - Release
 LD50 o Release from vesicles in the
 Median Lethal nerve endings require entry of
Dose calcium and interaction
between several proteins in the
vesicles
- Metabolism
o Metabolized to:
 Acetate
 Choline
o Metabolized by: (Enzyme)
 Acetylcholinesterase
o Not excreted but recycled
- Termination of Action
Drug B – More potent o By metabolism
Drug A, C, D  MAO (Monoamine
- Equal maximal efficacy Oxidase)
- Greater maximal efficacy than Drug B  COMT (Cathecol-O-Methyl
Variation of Responses in Individuals Transferase)
Idiosyncratic o By diffusing away from synaptic
- Differences in metabolism or cleft and being metabolized
immunologic mechanisms elsewhere
- Genetics  UPTAKE 1 – Presynaptic
- Response – unknown or unusual  UPTAKE 2 – Postsynaptic

Hypoactive Response DRUGS THAT INHIBIT


- Intensity of drug is ↓ Not very useful for systemic therapy
- Require larger dose - Hemicholinium – Synthesis of ACh
- Vesamicol– Storage of ACh
Hyperactive Response - Botulinum Toxin – Release of ACh
- Increased/Exaggerated intensity
ADRENERGIC TRANSMISSION

1|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
Norepinephrine Contraction of
intestin Relaxation of
- Primary transmitter at sympathetic sphincters
al tract sphincters
postganglionic synapses (alpha)
- Synthesis
o Tyrosine  DOPA by tyrosine
Sympatheti Parasympat
hydroxylase
Organ c hetic
o Decarboxylated to: Dopamine
Stimulation Stimulation
o Hydroxylated to: NE
- Storage Glycogenoly
o MAO inactivates NTA in the sis (beta2&
cytoplasm alpha)
- Release
o Same as ACh
Gluconeogen Glycogen
o Metabolism – not responsible for Liver
esis (beta2& synthesis
termination
alpha)
o Diffusion and Reuptake 1
 Reduce the concentration
Lipolysis
 Stop action
(beta2&
alpha)
DRUG EFFECTS
Renin
Used in several diseases; only block
Kidney secretion
sympathetic
(beta2)
- Metyrosine– Synthesis of NE
Detrussor
- Reserpine – Storage of NE Detrussor
relaxation
- Guanethedine– Release of NE contraction
(beta2)
- MAO Inhibitors – Metabolism of NE Bladder
Contraction
Relaxation of
of sphincter
sphincter
(alpha)
Parasympat Contraction
Sympathetic
Organ hetic of pregnant
Stimulation
Stimulation uterus
↑ heart rate (alpha)
↓ heart rate
beta1 (& beta2) Relaxation of
↑ force of Uterus
↓ force of pregnant
Heart contraction and non-
contraction
beta1 (& beta2) pregnant
↑ conduction ↓ conduction uterus
velocity velocity (beta2)
Constriction Constricts
Arteries (alpha1) Dilation pupil
Dilates pupil
Dilation (beta2) Eye ↓ lacrimal
(alpha)
Constriction gland
Veins (alpha1) secretions
Dilation (beta2) Submandi Viscous
Bronchial Watery
bular & salivary
Bronchial muscle salivary
parotid secretions
muscle contraction secretions
Lungs glands (alpha)
relaxation ↓ bronchial
(beta2) gland INTRO TO CNS
secretions
Gastro- ↓ motility (beta2) ↓ motility

2|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
EPSP IPSP - Oxidized in the liver
- Excretion: excreted partly unchanged
Excitatory Inhibitory
in the urine
Postsynaptic Postsynaptic
- Alkalinize urine
Potentials Potentials
- Half-life: 4-5 days
Depolarizing Hyperpolarizing - Require loading dose
Open K & Cl
Open Na, Ca
(Postsynaptic) ANTISEIZURE DRUGS
Close Ca PHENYTOIN
Close K
(Presynaptic) - Mephenytoin
↑ Na Ca, ↓ K ↑ K Cl, ↓ Ca o Congener of phenytoin
o Metabolized to 5,5-
SEDATIVE HYPNOTICS ethylphenylhydantoin
(demethylation)
BENZODIAZEPINES o Nirvanol
- Triazolam (Short)  Contributes most of the
- Alprazolam (Intermediate) antiseizure activity of
- Flurazepam (Long Acting) mephenytoin
 Therapeutic blood level:
BARBITURATES  25-40 mcg/mL
- Thiopental (Ultra-short) o Hydroxylated
- Secobarbital (Short) o Undergo conjugation and
- Phenobarbital (Long Action) excretion
o Therapeutic Level: 5-16 mcg/mL
MISCELLANEOUS o Above 20 mcg/mL – toxic
- Buspirone
- Ramelteon OXCARBAZEPINE
- Ezopiclone - Half-life of 8-12 hrs
- Chloral Hydrate - 10-hydroxy metabolite
- Zaleplon o Activity resides here
- Zolpidem
o Same half-life
o Drug is mostly excreted as the
BARBITURATES
- Eluxtensively metabolized glucuronide of 10-hydroxy
- Depress neuronal activity metabolite
- Facilitate & prolongs inhibitory effect
of GABA and Glycine OPOID ANALGESICS
- Blocks excitatory transmitter MORPHINE
glutamic acid Metabolism
- Block Na Channels at high - Metabolized by hepatic enzymes
concentration - Eliminated by the kidney
- Bind to multiple isoforms of GABAA - Converted to inactive glucuronide
- Not antagonized by flumazenil conjugates
- Except:
Thiopental o Morphine-6-Glucoronide
- Highest lipid solubility  Analgesic activity is
- Enter CNS rapidly similar to Morphine
- Induction agent in anesthesia o Morphine-3-Glucoronide
- Metabolism occur:  Primary Metabolite
o Oxidation  Neuroexcitatory
o Glucoronidation
MECHANISM OF ACTION
Phenobarbital A. RECEPTORS
Location of some opioid analgesics
3|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
- Ascending Pathways - Quetiapine
o Primary afferents - Risperidone
o Spinal cord transmission - Ziprasidone
neurons - Aripiprazole
- Descending Pathways
o Neurons in the: SCHIZOPHRENIA
 Midbrain - Symptoms:
 Medulla o Thought disorders
 Modulate pain modulation o Emotional withdrawal
o Hallucination
B. OPIOID PEPTIDES
o Delusions
- Modulate transmission in the:
- Not cured by drug therapy
o Brain, spinal cord, & primary
- Beneficial effects may take several
afferents
weeks to develop
o Also found in: adrenal medulla
- Individual patients – respond to
and gut specific drugs
o Unclear if they function as NTAs - Older drugs – lower cost
- Ameliorated by antipsychotic drugs
C. IONIC MECHANISMS
- POSTSYNAPTIC Treatment of Schizophrenia
o Open K Channels - Reduce some positive symptoms
o Cause membrane o Hyperactivity
hyperpolarization (IPSPs) o Bizarre ideation
- PRESYNAPTIC o Hallucination
o Close Voltage gated Ca o Delusions
o Inhibit NTA Release - Facilitate functioning in out and
 Serotonin inpatients
 Acetylcholine - Negative Symptoms
 NE o Older drugs – not much effect
 Glutamate o Newer (Atypical) improve
 Substance P
 Emotional blunting
 Social Withdrawal
ANTIPSYCHOTIC DRUGS
Antipsychotics Bipolar Drugs MECHANISM OF ACTION
Old
New A. DOPAMINE HYPOTHESIS
Old (D2) (Classic New
(5HT2) - Relative excess of functional activity of
)
Chlorproma
Clozapine Lithium
Carbamazep dopamine
zine ine - Not full satisfactory
Fluphenazin - Antipsychotic drugs – partly effective
Olanzapine Clonazepam
e
Haloperidol Quetiapine Olanzapine in most px
Risperidon - Many effective drugs have a higher
Thioridazine Valproic Acid
e affinity for other receptors other than
Trifluoperzin Ziprasidon D2
e e - Based on the ff:
o Antipsychotics block dopamine
receptors
 Those with D2 receptors
Newer Drugs o Dopamine agonists –
Heterocyclic exacerbate schizophrenia
- Clozapine  Amphetamine
- Loxapine  Levodopa
- Olanzapine
4|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
o Increased density of dopamine o Haloperidol
recptors have been detected in o Fluphenazine
untreated schizophrenia o Trifluophenazine
- Clozapine – Less frequent
B. DOPAMINE RECEPTORS - Newer Drugs – Less common
- 5 receptors (D1-D5) - Other neurologic dysfunction cause:
- G protein coupled o Akathisia
- Therapeutic efficacy of most older o Dystonia
antipsychotic drugs correlate with o Respond to:
relative affinity to D2  Diphenhydramine
- Correlation between blocking:  Muscarinic blocking
o D2 receptors agents
o Extrapyramidal dysfunction
B. TARDIVE DYSKINESIA
C. OTHER RECEPTORS - Choreoathethoid movements of the
- Newer Atypical AP muscles of the lips and buccal
o Have higher affinities for other activity
receptors - Irreversible
than for D2 receptors - Develop after years of therapy
o 5HT2 receptors - Appear as early as 6 years
- Alpha Adrenoreceptor Blockade - No effective drug for treatment
o Responsible for the - Antimuscarinic drugs
antipsychotic effect o Increase severity of symptoms
o Olanzapine, Quetiapine, - Switching to clozapine
Risperidone o Does not exacerbate the
 New condition
 High affinity for 5HT2 - Maybe caused by dopamine
 May also interact with D2 receptor sensitization
o Clozapine - Improved by: increasing neuroleptic
 D4 and 5HT2 receptor dosage
blocking
 Low affinity for D2 C. AUTONOMIC EFFECTS
 Less extrapyramidal
- Due to: blockade of peripheral
dysfunction
muscarinic receptors and alpha
- H1 Receptor Blockade
adrenoceptors
o All antipsychotic except
- Thioridazine– strongest autonomic
haloperidol effects
- Haloperidol – weakest
SIDE EFFECTS/TOXICITY - Clozapine and Atypical –
intermediate
A. REVERSIBLE NEUROLOGICAL EFFECTS - Cause: Atropine like effects
- Dose dependent extrapyramidal o Dry mouth
effects
o Constipation
o Parkinson-like syndrome
o Urinary retention
 Rigidity
o Visual problems
 Akinesia
 Flat faces - Not a problem with ziprasidone and
 Tremor aripiprazole
- Solution: - Alpha receptor blockade
o Decrease in dose o Cause postural hypotension
o Antagonized with muscarinic o All atypical
blocking agents - Phenothiazines(Chlorpromazine,
- Occur frequently with: Thioridazine, Triflu, Fluo)

5|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
o Failure to ejaculate
OPIOID ANALGESICS
D. ENDOCRINE AND METABOLIC EFFECTS MORPHINE
- D2 receptor blockade in pituitary Metabolism
- Cause: - Metabolized by hepatic enzymes
o Hyperprolactinemia - Eliminated by the kidney
o Gynecomastesia - Converted to inactive glucuronide
o Amenorrhea-galactorrhea conjugates
syndrome - Except:
o Infertility o Morphine-6-Glucoronide
- Clozapine & Olanzapine  Analgesic activity is
o Weight gain similar to Morphine
o Hyperglycemia o Morphine-3-Glucoronide
 Primary Metabolite
 Neuroexcitatory
E. NEUROLEPTIC MALIGNANT
SYNDROME (NMS)
MECHANISM OF ACTION
- Signs and symptoms:
A. RECEPTORS
o Muscle rigidity
Location of some opioid analgesics
o Impairment of sweating
o Hyperprexia - Ascending Pathways
o Primary afferents
o Autonomic instability
o Spinal cord transmission
- Developed by those who are sensitive
to extrapyramidal effects neurons
- Life threatening - Descending Pathways
- Treated by: o Neurons in the:
o Dantrolene  Midbrain
o Dopamine agonists  Medulla
 Modulate pain modulation
F. SEDATION
B. OPIOID PEPTIDES
- Phenothiazines (Chlorpromazine)
- Modulate transmission in the:
o More marked sedation
o Brain, spinal cord, & primary
- Fluphenazine& Haloperidol
afferents
o Less sedating among older
o Also found in: adrenal medulla
- Aripiprazole
and gut
o Less sedating among newer
o Unclear if they function as NTAs
G. MISCELLANEOUS TOXICITIES
- Thioridazine
o Visual impairment due to retinal
C. IONIC MECHANISMS
deposits
- POSTSYNAPTIC
o Fatal ventricular arrhythmias (at
o Open K Channels
high doses)
o Cause membrane
- Ziprasidone – arrhythmias
hyperpolarization (IPSPs)
- Clozapine
- PRESYNAPTIC
o at high doses: agranulocytosis &
o Close Voltage gated Ca
seizure
o Inhibit NTA Release
H. OVERDOSAGE TOXICITY  Serotonin
- Not fatal  Acetylcholine
- Cardiotoxicity – difficult to treat  NE
- Hypotension – fluid replacement  Glutamate
- Seizures – diazepam/phenytoin  Substance P

6|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
- Well absorbed most sites of
administration
CHOLINOMIMETIC/SYMPATHETIC DRUGS
- Excreted chiefly by kidneys
- Mimic acetylcholine - Aidification of urine accelerates
clearance of these amines
Classified by:
 PILOCARPINE
o Spectrum of Action (type of  NICOTINE
receptor activated)  MUSCARINE
- Muscarinic  LOBELINE
- Nicotinic NICOTINE
o MOA
- Direct-acting: - Liquid, lipid-soluble: absorbed across
Binding/activate the skin
cholinoceptor MUSCARINE
- Indirect-acting: Inhibit
hydrolysis of endogenous - Quaternary amine
ACh - Less completely absorbed from GIT
- Toxic when ingested
BASIC PHARMACOLOGY OF DIRECT- - Eg. In certain mushrooms
ACTING CHOLINOMIMETICS - Enters the brain

1. CHOLINE ESTERS : including ACh LOBELINE


2. ALKALOIODS : Muscarine and Nicotine
- Plant derivative
ACETYLCHOLINE - Similar to Nicotine
- Very rapidly hydrolyzed ORGAN SYSTEM EFFECTS
- Large amounts must be infused IV
1. Eye
METHACHOLINE - Instilled to conjunctival sac
- Contraction of sphincter muscle of
- Addition of methyl CH3
iris (Miosis)
- 3x more resistant to hydrolysis
- Ciliary muscle cnraction
CARBACHOL and BETHANECOL (accommodation)
2. CVS
- Carbamic acid ester derivative of ACh - Reduction of peripheral resistance
- More resistant to hydrolysis by and changes in heart rate
Cholinesterase 3. Respiratory System
- Addition of beta-methyl group - Contraction of Sooth muscles of
bronchial tree
- Stimulate glands of
tracheobronchial mucosa to
secrete
ALKALOIDS 4. GIT
- Same w/ parasymphathetic
- Act mostly w/ muscarinic receptors
nervous system stimulation
(muscarine, pilocarpine)
- Increase I secretory & motor
- Act w/ nicotinic receptors (nicotine,
activity of the gut
lobeline)
- Stimulate salivary & gastric glands

7|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
- Increases peristaltic activity - Diminish its secretion
- Relaxation of Sphincters  PILOCARPINE
5. Blood Vessels  ECHOTHIOPHATE (long-acting
- EDRF (Endothelium Derived effect)
Relaxing Factor)
- Dilation of Arteries 2. GIT & GUT
 Post-Op Ileus
- Dilation of Veins
 Urinary Retention Post-Op
- Constriction  Disorders that involve depression of
6. GUT smooth muscle activity w/o
- Stimulate the detrusor muscle obstruction
- Relax trigone& sphincter  BETHANECOL
- Promote voiding 3. Neuromuscular Junction
7. GLANDS - Myasthenia Gravis
- Stimulate thermoegulatory sweat, - Disease affecting skeletal muscles
lacrimal & nasopharyngeal neuromuscular junc.
glands - Autoimmune process
INDIRECT-ACTING CHOLINOMIMETIC - Production of antibodies that decrease
DRUGS the functional nicotinic receptors at
postjunctional end plates
SIMPLE ALCOHOLS
Cholinesterase inhibitors are used for
- Quaternary NH4 group therapy
- 2-10 mins.
EDROPHONIUM – diagnostic test
- Reversible
- EDROPHONIUM NEOSTIGMINE, PYRIDOSTIGMINE – long
term therapy
CARBAMIC ACID ESTERS OF ALCOHOL
4. Heart
- Quaternary or tertiary NH4 group - Supraventricular Tachycardia
- 30mins to 6 hrs - Treated by short-acting cholinesterase
- Reversible inhibitor (Edrophonium)
- Carbamates - Replaced by newer drugs (Ca+2
 NEOSTIGMINE Channel blockers)
 PHYSOSTIGMINE 5. Antimuscarinic Drug Intoxication
Exception, Lipid-soluble - ATROPINE intoxication
ORGANIC DERIVATIVES OF PHOSPHORIC ACID - Lethal in children
- Prolonged sever behavioral
 Highly lipid soluble disturbances and arrhythmias in adults
 Very long duration - Severe muscarinic bloackade
 Irreversible  PHYSOSTIGMINE
 ECHOTHIOPHATE -Antidote of Atropine poisoning
ORGAN SYSTEM EFFECTS 6. CNS
1. Eye - Alzheimer’s isease
- Glaucoma - Tacrine
- Reduce IO pressure - w/ anticholinesterase activity
- Contraction of the ciliary body - w/ cholinomimetic action
- used for therapy
- Facilitate outflow of aq. Humore

8|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
TOXICITY - Competitive (surmountable)
A. Direct-Acting Muscarinic Stimulants pharmacologic antagonists
o Nausea & Vomiting - Reversible blockade of
o Diarrhea cholinomimetic actions at the
o Salivation muscarinic receptors
o Sweating - Blocking effects, overcome by
o Cutaneous vasodilation increase conc. of muscarinic
o Bronchial constriction agonists
o Excitation
o Lacrimation ORGAN SYSTEM EFFECTS
o Blocked by ATROPINE - Peripheral effects mostly
Acute Toxicity predictable
o 4omg or 1drop of pure liquid is fatal
- Ocular, GIT, GUT & secretory
(2 cigarettes)
effects
CHOLINOCEPTOR BLOCKING DRUGS - CNS effects are less predictable
- ANTIMUSCARINIC
EFFECTS OF INCREASE DOSE OF
- ANTINICOTIC ATROPINE
- Decrease bronchial & salivary
Muscarinic Antagonists
secretions
o M1 receptor
- Decrease sweating
- Selective
- MYDRIASIS
- Only few receptor-selective
- Tachycardia
M1 antagonists reached clinical trial
 PIRENZIPINE - Urinary hesitancy
o Non-selective - Decrease Intestinal Motility
- Most of drugs in market - Decrease gastric secretion

ATROPINE CLINICAL USES


- Prototype non-selective muscarinic 1. CNS
blocker - Scopolamine,
- Derivative of deadly nightshade antimuscarinicfr.Hyoscyamusniger
Atropabelladone& others - Tertiary amine
- Tertiary amine - Lipid sol.
- Lipid soluble - Widely distributed
- Crosses membrane barrier - Excreted rapidly
- Well distributed in CNS & other - For MOTION SICKNESS
organ  DICYCLOMINE
- Eliminated partially by Liver
- Partial Renal Excretion 2. Eye
- Dilate pupil
- Half-life: 2hrs
- Paralyzed accommodation
- Duration of Action: 4-8 hrs in all
organ in normal doses - Well absorbed from conjunctival
- For EYE, last 72hrs sac
 ATROPINE, HOMOTROPINEM
- Salivary or bronchial glands are
CYCLOPENTOLATE,
sensitive to the effect of Atropine TROPICAMIDE
MOA 3. Bronchi
 IPRATROPIUM
9|A s t o r, G a r c i a , M e d i n a [ 3 G - P H ]
- Quaternary antimuscarinic agent 1. Ganglion-blocking drugs
- Used Inhalational - Competitive antagonists
- Asthma & COPD - 1st treatment of Hypertension
- TETRAETHYLAMMONIUM,
4. GIT HEXAMETHONIUM
 PIRENZIPINE - MECAMYLAMINE (inc. oral absorp.)
- M1 selective inhibitor - TRIMETHAPAN (hypertensive
 ATROPINE emergencies)
- Reduce acid secretion - Adverse in HTN is severe
- Not as effective as H2 antagonists - Both sympathetic &para are
blocked
5. GUT - Averse: Dry Mouth, Blurred
- OXYBUTYNIN< GLYCOPYRROLATE, Vision< Sever Sexual dysfuntion
METHSCOPOLAMINE< MIPRAMINE
- Tx of Enuresis 2. Neuromuscular-blocking drugs
- Reduce urgency in mild cystitis - For producing complete muscle
- Reduce bladder spasm ff. urologic skeletal relaxation in surgery
surgery
Classified into 2:
6. CHOLINOCEPTOR POISONING o Non- depolarizing
- Antidote for organophosphate -TUBOCURARINE : prototype
insecticide poisoning Competitive block at the end plate
nicotinic receptor
7. CHOLINESERASE REGENERATOR -Causes flaccid paralysis
-30-60 mins.
 PRALIDOXIME
-PANCURONIUM, ATRACURIUM,
VECURONIUM
TOXICITY
- Atropine poisoning
o Depolarizing
Dry as bone
-Nicotinic agonists not antagonists
Blind as Bat
that cause flaccid paralysis
Red as a beet
-SUCCINYLCHOLINE: only member
Mad as a hatter
- Atropine Fever SYMPATHOMIMETICS/ADRENOMIMETICS/
Blockade of thermoregulatory sweating, PARASYMPATHETIC DRUGS
result to Hyperthermia - Imp. Regulator of activities of the
- Sweating, lacrimation & salivation heart & peripheral vasculature
- Atropine Flush - Stress (adrenal medulla: secretes
- Dilation of cutaneous vessels of epinephrine)
arm, head, neck & trunk
- Sedation ADRENOMIMETIC AGONISTS
- Amnesia  Direct-Acting
- Delirium o Alpha agonist
- Hallucinatiom - Norepinephrine (Non-selective)
- Hyperhydosis - Phenylephrine (Alpha 1-
selective)
- PHYSOSTIGMINE given w/ caution
- Clonidine (Alpha 2-selective)
for atropine toxicity
o Beta agonist
NICOTINIC ANTAGONISTS - Dobutamine (Beta 1-selective)
- Albuterol (Beta 2-selective)
10 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
 Indirect Acting ritodrine
o Releasers Dopamine
- Tyramine, Amphetamine agonists
o Reuptake inhibitors Dopamine D1=D2 >> B
- Coccaine, TCAs >> a
Fenoldopam D1 ?? D2
Adrenomimetics
ORGAN SYSTEM EFFECTS
- For Cardiovascular
1. CNS
- Respiratory, etc. - Reduction of fatigue, anorexia,
DIRECT ACTING
euphoria, & insomnia.
- Bind to activate the adrenoceptors
- Very high dose: anxiety,
- Sympathetic stimulation aggresivenessm paranoia
INDIRECT-ACTING &rarelcnvulsions
- Displacement of stored 2. Eye
cathecolamines in synapse - Dilation (Mydriasis)
- Releasers: Tyramine, - Reduce IO pressure: increase aq.
Amphetamine
humor
- Inhibit reuptake of cathecolamines 3. Bronchi
by nerve terminals - Relaxation of Smooth M.
- Reuptake: Cocaine, Tricyclic
- Reversing bronchospasm
Antidepressants
4. GIT
DOPAMINE
- Relaxation of Smooth M.
- Third class of adrenoceptors
5. GUT
- Potent dopamine receptor itself
- Bladder relaxation & sphincter
- Intermediate does: activate Beta contraction
receptor
- B2: uterine relaxation
- Large doses: activate alpha 6. Vascular system
receptors o Alpha2 agonists
- D1-D5 receptor subtypes - When IV or Nasal 
- -D1: renal vasculature Vasoconstriction
- D2: brain - Oral  Reduce sympa. Outflow &
BP
Alpha - B2: reduce PVR & BP
agonists
- Dopamine  vasodilation in
Phenylephrine, a1 > a2
methoxamine splanchic& renal vascular beds
Clonidine a2 > a1 7. Heart
Mixed alpha - B1 predominates
& beta - Increase in Heart rate
agonists &Contractiob
NE a1 = a2; B1 > - Increase BP
B2 8. Metabolic & Hormonal Effects
Epineprhine a1 = a2: B1 = - B1 increases Renin secretion
B2
- B2 increase in Insulin
Beta agonists
(Gluconeogenesis)
Dobutamine B1 > b2
Isoproterenol B1 = B2 - Increase
Terbutaline, B2 >> B1 GlycogenolysisHyperglycemia
metaproterenol - Lipolysis
, albuterol,
11 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
- Anaphylactic Shock

NOREPINEPHRINE

- Pressor agent
CLINICAL USES ISOPROTERENOL
o ANAPHYLAXIS
- Potent vasodilator
EPINEPHRINE
- For immediate Tx of Anaphylactic DOBUTAMINE
shock
- Rapid acting - Congestive heart failure
- Pressor agent - Inotropic effect
- For Cardiac arrest DOPAMINE

o CNS - Inotropic
AMPHETAMINES - Low dose: renal vasodilation
(PHENYLISOPROPYLAMINES) - High: Vasoconstriction
- Narcolepsy
NON-CATHECOLAMINES
- Attention Deficit Disorder
- Weigh reduction (approp. Control) PHENYLEPRHINE

o Eye - Pressor agent


PHENYLEPHRINE - Mydriatic
- Mydriasis, topical - Decongestant
- Reduce Conjunctival itching &
METHOXAMINE
congestion by irritation & allergy
- Pressor agent (lim. Clin.
o Bronchi Application)
TERBUTALINE, ALBUTEROL, - IV form only
METAPROTERENOL
- Tx of Acute Asthmatic attacks MIDODRINE
SALMETEROL
- Pressor
- Long-acting
- Orthostatic hypotensiom
- For Prophylaxis
OXAMETOZALINE, XYLOMETAZOLINE
o GUT
RITODRINE, TERBUTALINE - DRIXINE ( brand name )
- To suppress premature labor - Topical decongestants
- Cardiac stimulant
EPHEDRINE
TERBUTALINE
- Urinary incontinence in children &
elderly with Enuresis - Bronchial asthma
CATHECOLAMINES RITODRINE
EPINEPRHINE - Inhibits premature labor
- Pressor agent COCAINE
- Cardiac Arrest

12 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
- Local vasoconstrictive Intrinsic sympathomimetic activity (ISA)
- Anesthetic effect - Partial agonist action by adrenoceptor
blockers; typical of several β blockers (eg,
TYRAMINE pindolol, acebutolol)
- Byproductpf Tyrosine Irreversible blocker - A nonsurmountable
- Increase P inhibitor, usually because of covalent bond
- Found in Cheese and Wine: not formation (eg, phenoxybenzamine)
advised when taking MAO Membrane-stabilizing activity (MSA) -
Local anesthetic action; typical of several β
blockers (eg, propranolol)
TOXICITY
Orthostatic hypotension - Hypotension
- Little CNS toxicity when given that is most marked in the upright position;
systematically caused by venous pooling (typical of α
- Periphery: Excess vasoconstriction, blockade) or inadequate blood volume
cardiac arrhythmias, MI, (caused by blood loss or excessive diuresis)
Pulmonary edema or hemorrhage
Partial agonist - A drug (eg, pindolol) that
- Apha agonists  Hypertension
produces a smaller maximal effect than a full
- B1 agonists  sinus tachycardia & agonist and therefore can inhibit the effect of
serious arrthmia a full agonist
- B2 agonists skeletal muscle
tremor Pheochromocytoma A tumor consisting of
cells that release varying amounts of
ADRENOCEPTOR BLOCKERS norepinephrine and epinephrine into the
circulation
Adrenoceptor antagonists
o Alpha blockers ANTIHYPERTENSIVE AGENTS
Alpha1-selective (PRAZOSIN) Drugs used in hypertension
Alpha2-selective (YOHIMBINE)
o Diuretics
o Nonselective o Sympathoplegics— blockers of
Reversible (PHENTOLAMINE) - Alpha or Beta receptors
Irreversible (PHENOXYBENZAMINE) (PRAZOSIN, PROPANOLOL)
- Nerve terminals (GUANETHEDINE<
o Beta blockers
RESERPINE)
Nonselective (PROPRANOLOL)
Beta2-selective (BUTOXAMINE) - GANGLIA (HEXAMETHONIUM)
Beta1-selective (ATENOLOL) - CNS SYMPHATHETIC OUTFLOW
(CLONIDINE)
Competitive blocker - A surmountable o Vasodilators
antagonist (eg, phentolamine); one that can - Older Oral Vasodilators
be overcome by increasing the dose of (HYDRALAZINE)
agonist
- CALCIUM BLOCKERS (NIFEDIPINE)
Epinephrine reversal - Conversion of the - Parenteral vasodilators
pressor response to epinephrine (typical of (NITROPUSSIDE)
large doses) to a blood pressure– lowering o Angiotensin antagonists
effect; caused by α blockers, which unmask - ACE inhibitors (CAPTOPRIL)
the β2 vasodilating effects of epinephrine - Receptor blockers (LOSARTAN)
- Renin Inhibitor (ALISKIREN)
13 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
Systolic/Diastol Category  Minoxidil sulfate, its metabolite is a
ic Pressure potassium channel opener that
(mm/Hg) hyperpolarizes and relaxes vascular
<120/80 Normal smooth muscle
120-139/80-89 Pre—  Extremely efficacious
hypertension  Reserved for severe hypertension
≥ 140/90 Hypertension  Toxicity
140-159/90-99 Stage 1  Severe compensatory responses
≥ 160/100 Stage 2  Hirsutism
 Pericardial abnormalities

ANTIHYPERTENSIVES THAT ARE USED AS b) Calcium Channel Blockers


VASODILATORS  Verapamil
 Diltiazem
VASODILATORS  Nifedipine – Prototype
 Dilate blood vessels by acting directly Dihydropyridine Calcium
on the smooth muscle cells through Channel Blocker
nonautonomic mechanisms o Effective vasodilators
 Compensatory responses maybe o Orally active
marked and include salt retention and o Chronic use
tachycardia o Used in hypertension of
 FOUR MAJOR MECHANISMS:
any severity
- Release of Nitric Oxide o Fewer compensatory
- Opening of potassium Channels responses
- Blockade of Calcium Channels o IV vasodilators used in
- Activation of D1 Dopamine hypertensive
emergencies
Receptors
c) Nitroprusside and Diazoxide
 IV vasodilators used in
a) Hydralazine and Minoxidil hypertensive emergencies
 Older vasodilators
 More effect on arterioles than NITROPRUSSIDE
veins  Short-acting (duration is a few
 Orally active minutes)
 For chronic therapy  Infused continuously
Acts through release of nitric  Release of nitric oxide from the drug
oxide from endothelial cells which stimulates guanylcyclase
 Rarely used at high dosage and increase cGMP in the muscle
because of toxicity  Toxicity
 Efficacy is limited  Excessive hypotension
 Toxicity  Tachycardia
 Compensatory responses  Accumulation of cyanide or
(tachycardia, salt and thiocyanate in the blood if
water retention) infusion is continued for several
 Drug-induced lupus days
erythematosus DIAZOXIDE
(reversible upon stopping  Given as IV boluses or as an infusion
the drug) (duration of action of several hours)
(uncommon at doses  Opens potassium channels,
below 200 mg/d) hypepolarizes and relaxes smooth
MINOXIDIL muscles
 Prodrug  Reduces insulin release
14 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
 Used to treat hypoglycemia caused by  May require discontinuation of
insulin-producing tumors the drug
 Toxicity GUANETHEDINE
 Hypotension  Toxicity
 Hypergylcemia  Orthostatic hypotension
 Salt and water retention  Sexual dysfunction

d) Fenoldopam 4.)ANGIOTENSIN ANTAGONISTS


 Dopamine D1 receptor ANGIOTENSIN-CONVERTING ENZYME (ACE)
activation cause marked INHIBITORS
arteriolar vasodilation  Toxicity
 Given IV  Cough (30% of patients)
 Used for hypertensive  Renal damage in patients with
emergencies preexisting renal vascular
disease (protect the diabetic
kidney)
ADRENOCEPTOR BLOCKERS
 Renal damage in fetus
 Effective antihypertensive agents
ANGIOTENSIN II RECEPTOR BLOCKERS
 Toxicity
Alpha1-selective blockers
 Lower incidence of cough
 TERAZOSIN  Fetal renal toxicity
 DOXAZOSIN  Contraindicated in pregnancy
 PRAZOSIN  Reduce aldosterone levels
 Reduce vascular resistance and  Causes potassium retention and
venous return lead to accumulation
 Free of severe adverse effects  Patients with renal
impairment
SIDE EFFECTS OF ANTIHYPERTENSIVE  High-potassium diet
DRUGS  Taking drugs that
conserve potassium
1.) ALPHA2-SELECTIVE AGENTS
METHLYDOPA
 Causes hematologic
immunotoxicity (+ Coombs
test)---hemolytic anemia

2.) GANGLION-BLOCKING DRUGS DIFFERENT TYPES OF ANGINA


HEXAMETHONIUM and TRIMETHAPHAN 1. Atherosclerotic angina
 Toxicities reflect parasympathetic  Angina of effort or classic angina
blockade  Associated with atheromatous plaques
 Blurred vision that partially occlude one or more of
 Constipation the coronaries
 Urinary hesitancy  90% of cases
 Sexual dysfunction  When cardiac work increases (eg,
 Sexual dysfunction exercise), obstruction of flow results
 Orthostatic hypotension to accumulation of acidic metabolites
and ischemic changes that
stimulate myocardial pain endings
3.) POSTGANGLIONIC SYMPATHETIC NERVE  Rest leads to relief of pain in 5-15
TERMINAL BLOCKERS minutes
RESERPINE
 Toxicity 2. Vasospastic angina
 Behavioral depression  Rest angina, variant angina or
Prinzmetal’s angina
15 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
 Reversible spasm of coronaries, MECHANISM OF ACTION
usually at the site of an atherosclerotic  Denitration causes release of nitric
plaque oxide (NO) within smooth muscle cells
 Spasm may occur anytime, even stimulate guanylcyclase increase in
during sleep cGMP smooth muscle relaxation
 May deteriorate to unstable angina
EFFECTS OF NITRATES ON
3. Unstable angina CARDIOVASCULAR
 Crescendoangina, acute coronary  Smooth muscle relaxation
syndrome peripheral venodilation reduced
 Increased frequency and severity of cardiac size and CO reduced
attacks that result from atherosclerotic preload
plaques, platelet aggregation at  Reduced afterload because of
fractured plaques and vasospasm arteriolar dilation
 Immediate precursor of myocardial increase in ejectiondecrease in
infarction (MI) cardiac size
 Medical emergency  Venodilation decrease diastolic
heart size and fiber tension
 Arteriolar dilation reduced peripheral
NITRATES resistance and BP
NITROGLYCERINE (NTG) NITRATES
 Active ingredient in dynamite  Overall reduction in myocardial fiber
 Most important of the nitrates tension, O2 consumption and double
 Available forms product
 Sublingual (10-20 min)  No direct effects on the cardiac muscle
 Transdermal (8-10 h)  Can cause reflex tachycardia and
 Rapidly denitrated in the liver and increased force of contraction when
smooth muscle reducing BP
Nitroglycerin DinitrateMononitrate
 First-pass effect is 90% CLINICAL USES
 Efficacy of oral (swallowed) NTG  Sublingual tablet
results from high levels of  Standard form for
glyceryldinitrate treatment of acute
 Effect of sublingual NTG results from anginal pain
unchanged drug because it avoids  Transdermal formulations
first-pass effect  Ointment or patch
 Maintains blood level up to 24
ISOSORBIDE DINITRATE (ISDN) hours
 Another commonly used nitrate  Tolerance develops after 8-10
 Sublingual and oral form hours
 Rapidly denitrated in the liver and with rapidly diminishing effectiveness
smooth muscle to  Remove after 10-12 hours to
isosorbidemononitrate which is also allow
active recovery of sensitivity to the drug
Most common toxic effects are responses
ISOSORBIDE MONONITRATE evoked by vasodilation:
 Available as a separate drug  Tachycardia (baroreceptor
 Oral form reflex)
 Orthostatic hypotension
AMYL NITRITE (direct extension of
 Volatile and rapidly acting vasodilator venodilator effect)
 Inhalational route  Throbbing headache from
 Rarely prescribed meningeal artery
vasodilatation
16 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]
NITRATES
 Interact with sildenafil (Viagra) and
similar drugs promoted for erectile
dysfunction
 Synergistic relaxation of vascular
smooth muscle with potentially
dangerous hypotension and
hypoperfusion of critical organs
 Cause methemoglobinemia at high
blood concentration
 Potential antidote for cyanide
poisoning
 Cyanide ion complexes with iron in
cytochrome oxidase block of oxidative
metabolism cell death
 Iron in methemoglobinemia has a
higher affinity for cyanide
 Can be treated by a 3-step procedure:
1. Immediate exposure to amyl
nitrite, followed by
2. Intravenous administration of
sodium nitrite which rapidly increases
methemoglobin level necessary to
remove significant amount of cyanide
3. Intravenous sodium thiosulfate
which converts cyanmethemoglobin
resulting from step 2 to thiocyanate
(excreted by the kidney) and
methemoglobin
 Excessive methemoglobin is fatal
because it is a very poor O2 carrier

17 | A s t o r , G a r c i a , M e d i n a [ 3 G - P H ]

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