T s e n

Transcription

T s e n

Tseng’s Miniature Student Pharmacopeia
DRUGS OF THE PERIPHERAL NERVOUS SYSTEM (AUTONOMIC + SOMATOMOTOR)
MUSCARINIC AGONISTS
Drug (Generic Name)
Acetylcholine
Class, Mechanism
Receptor Activity
Natural Choline Ester
All M, All N
Actions and Therapeutic Uses
AR
Absolute Precautions
No therapeutic use since immediately hydrolyzed by
plasma cholinesterase.
Methacoline
Choline Ester Derivative
M>N
Provocative diagnostic test for airway hyperreactivity
Carbachol
M + NN
Post-operative miotic for cataract surgery (widens
the angle, reducing IOP)
Bethenecol
M3
Pilocarpine
Natural Alkaloid
M3
Urinary retention (atonic bladder) [contracts
detrussor]
GI atonia and gastroparesis (postoperative)
Xerostomia secondary to Sjogren’s
Second-line for open-angle glaucoma (miotic)
Clearance, Metabolism,
other Remarks
AChe and reuptake of
choline
Asthma, β2 blockers, peptic
ulceration
Has slight nicotinic affinity
Has slight nicotinic affinity
Not affine for hydrolysis by
AChE
Clearance by diffusion out
of synaptic cleft
Asthma
Iritis
Posterior adhesions
NICOTINIC AGONISTS
Nicotine
Veranicline
Exogenous Alkaloid
NN and NM
Smoking cessation
Downregulates sympathetic and
parasympathetic activity
(predominant tone)
Partial Nicotinic Agonist
α4β2 N and 5-HT3 in CNS
Smoking cessation
Renal insufficiency
Renal excretion without
transformation
ACETYLCHOLINESTERASE INHIBITORS
Simple Quaternary
Ammonium Alcohol
Competitive Inhibitor
Carbamyl Ester with
Quaternary Ammonium
(effectively irreversible)
Provocative diagnostic test for myasthenia gravis
Postoperative reversal of NMJ blockade
Physostigmine
Carbamyl Ester with Tertiary
Ammonium
(effectively irreversible)
Echothiophate
Organophophate
Irreversible Competitive
Inhibitor
Edrophonium
Neostigmine
GI obstruction, ileus
Urinary tract obstruction
Asthma
Asthma
Stimulate muscarinic
receptors at all targets
DOC for reversal of muscarinic antagonist poisoning
Second-line treatment of open-angle glaucoma
Asthma
Quaternary ammonium
derivatives are not
absorbed by the GI tract
Second-line treatment for open-angle glaucoma
(miotic)
Uveitis
DOC for treatment of myasthenia gravis
Some stimulation of
autonomic ganglia
ACETYLCHOLINESTERASE SALVAGE
Pralodoxime
Cholinesterase Reactivator
Activated Nucleophile
Reveral of AChE inactivation (phosphorylation) by
organophosphates
Neostigmine for myasthenia gravis
Renal insufficiency
Must be administered
within 24 h. after inhibition
Transformation in liver and
renal excretion
MUSCARINIC ANTAGONISTS
Atropine
Ipratropium
Tiotropium
Exogenous Alkaloid
Nonselective M
Quaternary Ammonium
Alkaloid (Atropine Congener)
Nonselective M3
Quaternary Ammonium
Alkaloid (Atropine Congener)
M3
Preoperative reduction of airway secretion
Bradycardia
Mydriatic for ophthalmic exam
DOC to reverse AChE inhibitor or M agonist
poisoning
Acute asthmatic attack (bronchodilator)
DOC for persistent bronchospasm with COPD
Closed angle glaucoma (increases IOP)
Acute MI
Bladder or UT obstruction
GI obstruction/ileus
Prominent dose response
hierarchy
Renal excretion
Long-term bronchodilation in COPD
Biliary excretion after
metabolism by CYP3A4
Oxybutinin
Synthetic Alkaloid
M3
Increase urinary retention (relaxes detrussor) with
urge incontinence secondary to neuroegenic bladder
Closed angle glaucoma (increases IOP)
Toxic megacolon
Ulcerative colitis
Bladder or UT obstruction
GI obstruction/ileus
Much more potent
antispasmodic activity than
atropine
GANGIOLINIC ANTAGONISTS
Mecamylamine
Alkaloid
(Gangionic) NN
Moderate – severe hypertension
Tourette’s Syndrome
ARs determined by predominant
autonomic tone
Trimethaphan
Quaternary S+
(Gangionic) NN
Hypertensive crisis
Aortic dissection
Autonomic hyperreflexia
ARs determined by predominant
autonomic tone
Does not cross BBB
NEUROMUSCULAR BLOCKERS (NON-DEPOLARIZING)
Tubocurarine
Benzolisoquinoline Dimer
Competitive NAchR
Antagonist
Atracurium
Cisatracurium
Benzolisoquinoline Derivative
Competitive NAchR
Antagonist
Mivacurium
Benzolisoquinoline Derivative
Competitive NAchR
Antagonist
Pancuronium
Vecruonium
Rocuronium
Rarely used
Increase surgical exposure
Intubation
Maintenance of skeletal muscular paralysis during
surgery
Blockade of ganglionic nicotinic
receptors (tachycardia and
hypotension)
Blockade of M2 (tachycardia)
Tubocurarine and Pancuronium
Histamine release
Tubocurarine and Pancuronium
Antagonism of M2 receptors
Pancuroniuma and Rocuronium
Aminosteriod Derivatives
Competitive NAchR
Antagonist
Slow renal excretion
Spontaneous hydrolysis in
plasma (Hoffman
elimination)
Hydrolysis by plasma ChE.
Hydrolysis by plasma ChE
only.
Transformation in liver
results in active metabolites
Pancuronium requires renal
excretion
Vecuronium and
rocuronium are exreted
into the biliary system
NEUROMUSCULAR BLOCKERS (DEPOLARIZING)
Succinylcholine
Acetylcholine Congener
Maximal Agonist (Phase I)
Competitive Antagonist
Rapid sequence intubation (e.g. with high risk of
gastric aspiration)
Permits rapid reversal of blockade
Myalgia
Hyperkalemia secondary to receptor
spreading
Clearance depends on
concentration and activity
(Phase II)
Risk factors are denervation
(demylinating disease, cord
lesion, stroke), myopathy,
immobility
Increased ICP and IOP
Histamine release
of plasma cholinesterase
(e.g. K-variant, atypical
variant)
Stimulation of ganglionic nicotinic
receptors (bradycardia and
hypertension)
Depolarizaiton of M2 (bradycardia)
CHOLINERGIC VESICULAR PACKAGING INHIBITORS
Botulinim Toxin A
Zinc Protease
Cleaves SNAP complex
Botulinum Toxin B
Zinc Protease
Cleaves synaptobrevin
Achalasia
Hemifacial spasm
Spasmodic torticollis
Strabismus
Cervical dystonia
Spasticity, dysphonia, hyperhydrosis, blepherospasm
Cervical dystonia
ADRENERGIC AGONISTS (DIRECT)
Phenylephrine
Catacholamine Analogue
α1
Nasal Decongestant (pressor effect)
Mydriadic (ophthalmic exam)
INCREASE MABP
DECREASE HR (CI Reflex)
Hypovolemic Shock
Hypotension
Narrow-angle glaucoma
Arrhythmia, CVD
Hypertension, Tachycardia
Labor
INCREASE MABP
DECREASE HR (CI Reflex)
Metabolized by MAO
Norepinephrine
Natural Catacholamine
α1, α2, β1
Epinephrine
Isoproterenol
Natural Catacholamine
α1, α2, β1, β2
β1 and β2
Bronchodilation (Anaphylaxis)
Mydriatic
Prolongation of local anesthesia (prevents vascular
absorption)
Stimulate conduction in AV nodal block
Acute bronchospasm
Asthma and COPD
Albuterol
β2
Rapid bronchidilation (asthma and COPD)
Dobutamine
β1 > β2
α2
Intraoperative treatment of CHF
(Increases ventricular contractility and CO)
Hypertension
Intrathecal injection for refractory opioid pain
Clonidine
Salmeterol
β2
Tertubaline
β2
Prophylactic treatment for asthma
Prophylactic treatment for acute bronchospasm in
COPD
Rapid bronchidilation
INCREASE SYSTOLIC BP
DECREASE DIASTOLIC BP
BIPHASIC MABP (increase, then drop
below baseline)
INCREASE HR
COMT and MAO
Narrow-angle glaucoma
Intra-arterial administration
Hypovolemic Shock
Labor (fetal anoxia)
INCREASED CO
(increased contractility and HR)
DECREASED MABP
COMT
Arrhythmias
Heart block due to Digoxin toxicity
DECREASE BP (there are someβ2Rs in
vascular smooth muscle)
INCREASE HR (CA Reflex)
NO EFFECT ON BP
COMT and glucoronidaiton
Abrupt discontinuation (causes rapid
development of hypertension)
Breastfeeding
Does not treat acute asthmatic
bronchoconstriction
ADRENERGIC AGONISTS (MIXED)
Ephedrine
Mixed Agonist
α1, β1, β2
Long-acting Bronchodilator (asthma)
PNS actions are diminished
by reserpine
Increase NE release
Not metabolized by COMT
or MAO
Metaraminol
Mixed Agonist
α1
Treatment and prevention of hypotension
Increases NE release
ADRENERGIC AGONISTS (INDIRECT)
Amphetamine
Inhibition of uptake
transporter
α1 and β1
ADHD
Narcolepsy
Anorexia nervosa
Advanced arteriosclerosis, CAD
Hypertension
MAO inhibitors
Renal excretion after
transformation by CYP and
MAO.
Abrupt discontinuation
Renal insufficiency
Intrinsic sympathomimentic
activity (ISA)
INCREASE HR (CA Reflex)
Orthostatic hypotension
Bolus of NE administered
immediately can reverse
PBA binding
ADRENERGIC AGONISTS (PARTIAL)
Acebutolol
Pindolol
β1
β1 and β2
Hypertension
Heart Failure
Hypertension
Angina
α-ADRENERGIC ANTAGONISTS
Phenoxybenzamine Irreversible α-adrenergic
antagonist
(PBA)
α1 >> α2
Phentolamine
Prazosin
Yohombine
Reversible α-adrenergic
antagonist
α1 and α2
antagonist
α1
antagonist
α2
Control of excessive sweating and hypertension
secondary to pheochromocytoma
Treatment of urinary obstruction secondary to BPH
(relaxes trigone sphincter)
Peripheral vasospastic pathology (e.g. acrocyanosis,
Raynaud’s disease)
Threat sudden hypertension during surgical resection
of pheochromocytoma
Prevent dermal necrosis secondary to extravasation
Hypertension
Off-label: urinary retention due to BPH (relaxes
bladder outlet)
Erectile Dysfunction
Large increase in HR (Reflex)
First-dose syncope
INCREASE MABP
INCREASE HR
β-ADRENERGIC ANTAGONISTS
Atenolol
Metoprolol
Propranolol
Timolol
Cardioselective β-adrenergic
antagonist
β1
Cardioselective β-adrenergic
antagonist
β1
Hypertension
Heart failure
Non-selective β-adrenergic
antagonist
β1 and β2
Hypertension, Angina, Tachycardia
Acute MI (decrease oxygen demand of myocardium)
Anxiety
Non-selective β-adrenergic
antagonist
β1 and β2
Hypertension
Angina
DOC for open-angle glaucoma (decreases IOP in the
anterior chamber by inhibiting secretion from the
ciliary body)
Abrupt discontinuation (causes
sudden ischemic injury)
Bradycardia
AV nodal block
Raynaud’s Disease
Bronchospasm
Insulin-dependent DM
(hypoglycemia)
Abrupt discontinuation (causes
sudden ischemic injury)
Bradycardia
AV nodal block
Raynaud’s Disease
Bronchospasm
Insulin-dependent DM
(hypoglycemia)
SYNTHESIS, RELEASE, and UPTAKE MODIFIERS
α-Methyltyrosine
α-Methyldopa
Reserpine
Paroxetine
Catecholamine Biosynthesis
Inhibitor
Tyrosine Hydroxylase
Catecholamine Biosynthesis
Inhibitor
Araomatic Amino Acid
Decarboxylase
False Neurotransmitter
α2 (in brainstem)
Neurotransmitter Storage
Inhibitor
VMAT-2
Catecholamine Reuptake
Inhibitor
Pheochromocytoma (preop or chronic)
Alcohol
DOC for hypertension during pregnancy
Pheochromocytoma (preop or chronic)
Historically significant antihypertensive
Major depression
Anxiety disorders
MAO inhibitors (may provoke
serotonin syndrome)
Major mode of excretion is
renal
Major mode of excretion is
renal
Atomoxetine
Cocaine
Dantrolene
Phenylzene
Specific to Serotonin
Post-traumatic stress disorder
Inhibitor
Specific to Norepinephrine
Inhibitor
Serotonin, Dopamine,
Norepinephrine
Plasma Membrane
Hyperpolarizing Agent
Excitation-Contraction
Decoupling Agent
No-stimulant treatment of ADHD
Irreversible MAO Inhibitor
Major depression
Anxiety disorders
Surgical use: diminish congestion, bleeding, and
hyperemia
Applied locally
DOC fro malignant hyperthermia (complication of
succinylcholine)
Mucosal injury at site of application
Blocks Ca2+ release from
the SR
DRUGS OF THE CARDIOVASCULAR SYSTEM
ACE INHIBITORS
Drug (Generic Name)
Captopril
Class, Mechanism
Receptor Activity
ACE inhibitors
Prevents formation of AngII
Prevents degredation of
Bradykinin
Hypertension
Renal protection in diabetics with proteinuria (DOC)
Systolic Heart Failure (reduce afterload)
USED IN CONJUCTION WITH DIURETIC OR CCB
Enalapril
Linisopril
Increase sodium secretion
(direct + aldosterone)
Vasodilation
AR
Pregnancy
Decrease renal perfusion
Hyperkalemia (aldosterone)
ACE cough (bradykinin → PG)
Angioedema / Laryngeal edema
other Remarks
Causes left-shift of
autoregulatory response:
normal flow can be
maintained to vascular beds
with low pressure.
NO RELFEX TACHYCARDIA
NSAIDs reduce efficacy
Selective dilation of efferent
glomerular arteriole
ANGIOTENSIN II RECEPTOR ANTAGONISTS (ARBs)
Losartan
Valsartan
Candesartan
Competitive antagonists at
AT1 receptors
Hypertension
USED IN CONJUCTION WITH DIURETIC
Equivalent actions to ACE
inhibitors. Blocks all sources of
AngII.
Pregnancy
Hyperkalemia
Renal impairment
Note that the cough and
angioedema are rarely seen
with ARBs.
Pregnancy
Hyperkalemia
Renal impairment
AngI can be generated by
pathways independent of
Renin. Thus, ARBs actually
potentiate the effect of
Aliskerin.
RENIN INHIBITORS
Aliskerin
Competitive antagonist of
Renin
Prevents formation of AngI
Hypertension
NITROVASODILATORS
Nitroglycerin
Isosorbide Dinitrate
(ISDN)
Organic Nitrates
Decay to NO requires reaction
with tissue thiols
NO → GC → increase cGMP →
PKG → SMC relaxation
Angina Pectoris
Acute Coronary Syndrome (UA, NSTEMI, STEMI)
Treatment of HTN requires high doses!
Selective dilation of coronary
collaterals
Venous > Arterial vasodilation
Susceptible to tachyphylaxis (requires
long maintenance dose interval)
Headache
Flushing
Palpitations
Orthostatic Hypotension
Interactions with DHP CCBs, Diuretics,
β-blockers, PDE inhibitors
(potentiation of NO)
Reduces preload
Reduces CO → reduced
afterload
Amyl Nitrate
Organic Nitrite
Nitroprusside
Oxidation of HbFe2+ to
HbFe3+ (methemoblibin)
Direct NO donor
CN poisoning
Reversal of Nitroprusside toxicity
Hypertensive Crisis (acute HF, malignant HTN)
Usually administered with
thiosulfate to sequester CN
CN toxicity
Does not require carriage of
NO by thiols
Arterial > Venous vasodilation
Requires constant BP
monitoring
DIRECT ARTERIAL VASODILATORS
Hydralazine
Direct Arterial Vasodilator
Most selective to renal
arteries
No effect on skeletal muscle or
cutaneous arteries
Involves increased production
of PG
Hypertension
DOC for patients with renal insufficiency
CHF
Tachycardia
Possible exacerbation of angina
Headache
Palpitations
Orhtostatic Hypotension
Acetylated in hepatocytes
Decreased fluid retention
compared to other
vasodilators
CALCIUM CHANNEL BLOCKERS (DIRECT VASODILATORS)
Amlodipine
Nifedipine
Nimodipine
Dihydropyridine (DH) Calcium
Channel Blockers (CCB)
Blockade of L-type calcium
channels in vascular smooth
muscle
Does not require intracellular
signal
Hypertension
Angina Pectoris (selective dilation of coronary
arteries)
Hypertensive crisis
Headache
Palpitations
Orhtostatic Hypotension
Peripheral edema (due to hyperemia
secondary to arterial dilation)
Exhibits use-tolerance:
Most effective with
greater L-type Ca2+ opening
probability. Loss of potency
as channels adopt a closed
state.
Hypertension
Angina Pectoris (reducedO2 demand and increased
supply)
GERD (relaxation of UES)
Bradycardia (SA)
Heart block (AV)
Reduced systolic function
(exacerbation of CHF)
No tachycardia since
sympathetic reflexes are
diminished
Fluid retention
Decreased renal perfusion →
activate RAAS
Tachycardia
Palpitations
Increased hair growth
Usually administered with a
loop diuretic (e.g.
furosemide)
Arterial >> Venous
vasodilation
Diltiazem
NO EFFECT on visceral SM or
conducting myocytes
Non-Dihydropyridine (DH)
Calcium Channel Blockers
(CCB)
Selective to cardiac L-type
Verapamil
Block L-type and T-type
channels → reduces
automaticity, contractility, and
AV conduction
Decreased fluid retention
compared to other
vasodilators
Reduces GI and other SM
motility
POTASSIUM CHANNEL AGONISTS
Minoxidil
Diazoxide
Agonist at leak-type K+
channels
Hyperpolarize RMP → reduced
entry of Ca2+ through L-type
channels → vasodilation
Hypertension
Diazoxide only used in hypertensive crisis
Diazoxide inhibits insulin secretion
Hyperglycemia
DRUGS OF LIPID METABOLISM
LDL-C SUPPRESSORS
Drug (Generic Name)
Atorvastatin
Lovastatin
Simvastatin
Rosuvastatin
Pravastatin
Fluvastatin
Colestipol
Cholestyramine
Colesevelam
Ezetamibe
Sterols
Stanols
Class, Mechanism
Receptor Activity
Statins
Inhibit HMG-CoA reducase →
decrease intracellular free
cholesterol
→ decrease VLDL secretion
and
→upregulation of LDL-R
expression → decreased
serum LDL-c
Bile Acid Resins
Bind BAs → reduce uptake of
cholesterol derivatives →
increased LDL-R synthesis →
decrease plasma LCL-C
Increased conversion of
intracellular cholesterol to BAs
→ activate HMG-CoA
reductase
Competitive inhibitor at
enterocyte sterol transporter
Inbibits absoption of dietary
cholesterol and bile salts →
increase LDLR expression
Plant cholesterol analogues
→ competitively inhibit the
DOC for elevated LDL-C
Decreased TG → decrease VLDL-C
Possible due to increased uptake by LDL-R and
decreased secretion
Slight increase in HDL-C
Also TX highly elevated LDL-C with TG < 400 mg/dL
Decrease LDL-C
Potentiated when used concurrently with a statin or
niacin
Increased TG due to increased VLDL secretion
AR
AR: rhabdomyolysis when combined
with gemfibrozil, transient rise in
hepatic transaminase levels
other Remarks
All statins except pravastain
are metabolized and
inactived by CYP450.
CI: pregnancy
Inhibited transformation via CYP450 if
concurrent with macrolide antibiotics
(erythromycin), cyclosporine,
diltiazem, verapamil
AR: bloating, constipation,
sequestration of anionic and
amphipathic lipid-soluble drugs
(thyroxine, digoxin, coumadine,
furosemide) and Vit A, D, E, K.
Most effective during meal (with bile acid release)
Decrease LDL-C when not responsive to statins
Decrease TG
Monotherapy with stain intolerance
Lowed LDL-C
Minimal absorption
Hepatic inactivation
However, only 10% of drug
is present systemically
Psyllium (Fiber)
intestinal sterol transporter →
reduced cholesterol
absorption
Soluble Fiber
Small reduction in LDL-C
Weak BA sequestrant (forms
micelles)
TG Suppressors
Niacin (Nicotinic
Acid, B3)
VitB3
Decreases TG in VLDL
Increases HDL-C
Inhibits lipolysis at
extrahepatic tissues →
decreased FFA presentation to
liver → decrease TG synthesis
→ decreased VLDL production
Increased VLDL uptake
Decreased HDL-C clearance
AR: niacin flush (blunt with NSAIDs),
pruritis, GI distress, hyperglycemia,
uric academia
Heaptic metabolism
Time-release: high risk of hepatitis
Inhibit synthesis of TGs in
hepatocytes
Fibrates
Gemfibrozil
Fenofibrate
EPA/DHA
Reduction of VLDL synthesis →
large reductions in TG
DOC doe severe hypertriglyceridemia (TG > 300
mg/dL)
Chylomicronemia syndrome
Prevention of pancreatitis
Acts via PPARs
Decrease lipolysis
Increased CMR clearance
Increased LPL activity
Decreased cholesterol and BA
Synthesis
Decreased VLDL
Increased HDL-C
Omega-3 FAs
Slight decrease in VLDL
Reduces VLDL production
AR: rhabdomyolsis when gemfibrozil
iscombined with a statin
The only lipid drug with
mixed renal and hepatic
clearance!
Relative CI in renal
insufficiency
DRUGS OF THE CARDIAC CONDUCTION SYSTEM
CLASS I : SODIUM CHANNEL BLOCKERS
Drug (Generic Name)
Procainamide
Class, Mechanism
Receptor Activity
CLASS IA
Block fast Na+ channels (intermediate recovery
rate):
Slows AP conduction velocity selectively in ischemic
myocardium
Suppress ectopic foci (decrease threshold)
Blocks delayed rectifier K+ channel:
Prolongation of APD and refractory period
Slows AV node conduction
AR
AR: slow AV node conduction,
hypotension (ganglionic block +
reduced contractility)
other Remarks
ECG: Increased QT
+widened QRS
CI: prolonged QRS, prolonged QT
interval, AV block, escape rhythm,
heart failure
TX: DOC for WPW and WPW + Afib
Slows conduction velocities through accessory
pathways (e.g. bypass tracts in WPW)
Lidocaine
CLASS IB
Maintain sinus rhythm
Block fast Na+ channels (rapid recovery rate):
Slow conduction in ischemic myocardium
Suppresses ectopic foci
AR: CNS effects
CI: amide anesthetic hypersensitivity
ECG: no visible changes
CI: AV block, BBB without pacemaker,
cardiogenic shock, structural heart
disease, CAD, post-MI
ECG: Increases PR interval
(due to slowed AV
conduction) and widens
QRS
APD prolongation is not
singnificant, so no increase
TX: DOC for post-MI VTach
Not effective in AVNRT and PSVT (does not increase
APD)
Flecainide
CLASS IC
Block fast Na+ channels (slow recovery rate):
Slow conduction in ischemic myocardium
Suppresses ectopic foci
Block delayed rectifier and transient K+ channels :
Prolongation of APD and refractory period
Slows AV node conduction
in QT interval
Slows conduction velocities through accessory
pathways (e.g. bypass tracts in WPW)
CAST Trial: increased
mortality when used after
MI.
DOC for reentrant atrial tachycardias, Afib, atrial
flutter, and WPW
CLASS II : β-BLOCKERS
Propranolol
Non-selective β-antagonist
Decreases cAMP → decrease L-type Ca2+ channel
and fNa+ channel permeability
→ Slows AV node conduction
Decreases Phase 4 diastolic depolarization rate
→ decreases nodal automaticity
TX: Atrial flutter, Afib
Pheochromocytoma
Improved survival post-MI (prevention of
arrhythmias)
ECG: increased R-R (slowed
sinus rate), increased PR
No changes in QRS or QT
AR: CNS effects, hypotension
CI: reactive airway disease (COPD +
asthma), insulin-dependent DM
Severe sinus bradycardia, AV block,
hypotension
Not DOC in WPW since it may increase conduction
through accessory pathway
Esmolol
Cardioselective β-antagonist
IV in emergent tachyarrythmias
Afib, SVT, acute arrhythmias during surgery
Metoprolol
Cardioselective β-antagonist
Similar effects to propranolol
Rapid hydrolysis by plasma
esterases → short action
No biliary or renal
clearance.
CLASS III : APD EXTENDERS
Dofetilide
Pure Class III
DR K+ inhibitor
Blocks DR K+ current (rapid phase, IK+r):
Prolongs APD and associated refractory period
Slows nodal automaticity (prevents repolarization)
AR: TDP secondary to excessive QT
length.
CI: Baseline prolonged QT, prior
episode of TDP, polypharmacy with
ECG: QT interval prolonged
independently
May be used in CHF!
TX: Afib, Aflutter
Reentrant ventricular tachycardia (PSVT)
Amiodarone
Block fast Na+ channels
Decreased SA nodal automaticity
Decreases HP conduction velocity
Blocks DR K+ current (rapid and slow phases):
Increased APD
Mixed Classes I - IV
DR K+ inhibitor
Na+ channel blocker
L-type and T-type CCB
β-adrenergic blocker
other drugs that increase QT (increase
APD)
AR: pulmonary fibrosis,
hyperthyroidism, hepatitis
(ECG: Prolonged QT,
Prolonged PR, Increased RR, Widened QRS)
CI: severe sinus bradycardia or escape
rhythms, AV block without pacemaker
Block DHP channels + β1R
Decrease AV node conduction velocity
TX: stable Vtach, Vfib and Vtach resistant to electrical
cardioversion, Agib, Aflutter, WPW, AVRNT
Sotalol
Mixed Class II + Class III
d-Sotolol has pure DR K+
antagonistic activity
l-Sotolol has pure β-blocking
activity
Β-blockade
Reduce nodal automaticity
Decreased AV conduction velocity
DR-K+ (rapid) blockade
Increased APD duration and refractory period in atria
and ventricles
AR: TDP
CI: reactive airway disease, long QT,
hypokalemia
ECG: increased R-R interval,
increased PR and QT
TX: Aflutter, WPW
Vtach
Afib
AVRNT
CLASS IV : NON-DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS
Verapamil
Non-DHP CCB
Blocks L-type Ca2+ channels in myocardium and
vascular SM
Slows Phase 4 depolarization in SA node
Decreases AV node
Slows ventricular rate with Afib or Aflutter
AR: headache, flushing, hypotension
NO reflex tachycardia
CI: systolic heart failure (depressed
contractility), post-MI, severe
bradycardia, AV block
ECG: increased PR sue to
slow AV conduction velocity
TX: Afib and Aflutter (ventricular rate control)
Ectopic + multifocal atrial tachycardias
Chronic AVNRT
WPW
Diltiazem
Non-DHP CCB
Very similar to verapamil
AR: same as verapamil + bradycardia
CI: systolic dysfunction
CLASS V : OTHERS
Digoxin
Cardiac Glycoside: Positive
Inotrope
Inhibits cardiac and ganglionic Na2+/K+ ATPase
Causes increased intracellular Na+ and Ca2+ (via
gradient inhibition of the Na+/Ca+ exchanger)
Stimulates carotid and aortic sinuses (baroreceptors)
→ increased vagal tone to SA and AV
Slows Phase 4 depolarization in the SA node
Decreases conduction velocity though AV node
Depolarization (increased Na+) and accommodation
of t-type Ca2+, L-type Ca2+ and Na+ channels
L-type Ca2+ is activated in late in Phase 4
AR: AV block, sinus bradycardia,
digoxin toxicity → Ca2+ overload and
delayed ADs (triggered Vtach).
ECG: increased PR,
decreased HR
CI: sinus bradycardia, AV block, WPW
(increases conduction through
accessory path)
Increases AV node refractory period
Decreased intracellular K+ (dissipated gradient)
Decrease AV node automaticity
Vagal tone and decreased K+ gradient
TX: DOC for Afib and Aflutter (atrial rate control) with
LV systolic dysfunction
AVNRT
Adenosine
Endogenous Purinergic Agonist
Binds A1 purinergic receptors → Gi → βγ subunit→
increased permeability K+ channels (similar to Ach
mechanism)
Shortened APD
Hyperpolarization → slowed automaticity
Inhibits AC → decrease cAMP from β agonists
Decreases permeability of L-type and RyR Ca2+
channels
Decreased intracellular Ca2+
AR: Flushing, dyspnea, sinus arrest
CI: sinus bradycardia, AV block,
reactive airway disease
ECG: decreased HR,
increased PR
Slowed Phase 4 depolarization of SA node
Decreased conduction through AV node
Increased AV refractory period
TX: AVNRT and WPW (acute cardioversion)
DRUGS USED IN THE TREATMENT OF HEART FAILURE
DIURETICS
Drug (Generic Name)
Furosemide
Bumetinide
Torsemide
Class, Mechanism
Receptor Activity
Loop Diuretics
Inhibit Na+/2Cl-/K+
cotransporter in ATL of LoH
Hydrochlorothiazide Thiazide Diuretics
(Spirinolactone)
Inhibit Na+/Cl- cotransporter
in DCY
K+-sparing Diuretic
Inhibits aldosterone receptor
in DCT
(downregulate Na+
conductance channel)
Actions and Therapeutic Uses in Heart Failure
Diuresis of fluid overload
This decreases preload without a decrease in CO (in
advanced systolic failure)
Tolerance:
TG feedback (increased Na+ reaborption in DCT and
CD with prolonged therapy)
Decreased renal perfusion (volume depletion,
decompensation with loss of CO, ACEIs)
Used at onset of tolerance to loop diuretics
Advanced heart failure
AR
AR: hypokalemia, hypochloremic
alkalosis
(supplement K-sparing diuretic)
Hyperglycemia
other Remarks
RAAS antagonists actually
compensates via inhibition of
aldosterone (decreased K+ secretion)
AR: gynecomastia
Shown to decrease
mortality in advanced SHF
unresponsive to adrenergic
blockers and other diuretics
VASODILATORS
Lisinopril
ACE inhibitor
Arterial and venous vasodilation
Decreased afterload → increase SV and EF
Decrease venous return → decreased EDV
Valsartan
ARB
Similar effects to ACEIs
Inhibits ectopically produced AngII
Venous vasodilation
Reduced preload
Epicardial coronary artery dilatation → increase CBF,
increase systolic and diastolic function
Shown to decrease
mortality
Not used in DHF
Nitroglycerin
Organic Nitrate
Susceptible to tolerance
ARs: orthostatic hypotension,
tachycardia, palpitaitons, flishing,
headache
Shown to decrease
mortality when
coformulated with
hydralazine.
Hydralazine
Nitroprusside
Nesiritide
Direct Vasodilator
Direct NO donor
Recombinant BNP
Arterial vasodilation
Reduces pulmonary vascular resistance (PVR)
→ decreased preload on RV and LV
Used in CHF with renal insufficiency (preferentially
increases renal arterial perfusion)
Parenteral
Arterial > venous vasodilation
Reduces preload and afterload
Parenteral
Bind to soluble GC → increase cGMP → vasodilation
AR: similar to nitrates
CN toxicity
AR: hypotension
TX: bolus of continuous infusion for acute heart
failure (dyspnea at rest or minimal exertion)
ADRENERGIC ANTAGONISTS
Carvedilol
Metorpolol
Non-selective β antagonist
α1 antagonist
Cardioselective β antagonist
Prevents adrenergic stimulation of ventricular
remodeling.
Transient suppression of contractility
Prevention of ventricular arrhythmias associated
with ischemia and hypertrophy
CI: rapid titration (may lead to
decompensation)
Increase EDV and EF
Bisoprolol
Prazosin
Cardioselective β antagonist
Must be titrated from a
very low concentration (10fold lower than therapeutic
dose)
α1 antagonist
Arterial and venous vasodilation
Reduced afterload
CALCIUM CHANNEL BLOCKERS
Amlodipine
Transient decrease in
systolic function. Gradual
recovery and improvement
due to prevention of
adverse neurohormonal
remodeling.
Shown to reduce mortality
due to Vfib.
Second-generation DHP CCB
Arterial vasodilation (highly selective)
Used when hypertension cannot be controlled with
other drugs
TX: diastolic heart failure (use first-generation CCBs)
Heart failure due to SVT without systolic dysfunction
CI: use of first-generation CCBs in
systolic dysfunction (verapamil,
diltiazem, nifedipine) causes a severe
reduction in inotropy
INOTROPES
Milrinone
Digoxin
PDE inhibitor
Cardiac Glycoside
Inhibits PDE3 in myocardium and vascular SM
In cardiac muscle:
→ increased PKA → increased L-type Ca2+ channel
permeability → increased contractility
In vascular SM:
→ increased PKA → activate K+ channels →
hyperpolarization → relaxation
TX: acute heart failure
Actually increases mortality
Increases intracellular Ca2+
Inhibit sacrolemmal Na+/K+ ATPase → increased
intracellular Na+ → gradient inhibition of Na+/Ca2+
exchanger (Na+ is normally transported into the cell)
→ increased intracellular Ca2+ → increased
sequestration in SR → increased CICR → increased
contractility
Increased permeability of RyR channels
Na+/Ca2+ may actually reverse direction during AP
→ Ca2+ transported into cell
Positive inotropy
Negative chronotropy at AV node (dissapte K+
gradient → prolonged repolarization and refractory
period)
Sensitive autonomic ganglia → increase vagal tone
→ reduce AV conduction velocity
End result:
Increase CO
→ decrease neurohormonal compensation
AR: ventricular arrhythmias, extopy,
Vtach, hypotension
AR: narrow therapeutic margin,
triggered arrhythmias (delated Ads)
Interactions
Increased binding with hypokalemia
(inhibited Na+/K+ ATPase)
Quinidine reduces the volume of
distribution of Digoxin by displacing it
from non-target binding sites
Potentiated by drugs that decrease
nodal automaticity and conduction
Dobutamine
β1and β2 agonist
Parenteral
Circulatory support in acute heart failure
AR: tachycardia, tolerance
Increased contractility
Decreased SVR (racemic formulations do not cause
vasoconstriction)
Dopamine
Endogenous catecholamine
Parenteral
Low dose (renal): DA1 receptors in renal vessels →
increased RBF → increased GFR → natruiresis
Inhibits tubular Na+ reabsorption
Intermediate dose (cardiac): β1 receptors → increase
CO and MABP
Also triggers NE release from sympathetic axons
High dose (vascular): α1R → vasoconstriction
AR: tachycardias, arrhythmias,
ischemia with CAD
DRUGS OF AUTOCOID METABOLISM
ANTIHISTAMINES: H1 RECEPTOR ANTAGONISTS
Drug (Generic Name)
Diphenhydramine
Chlorpheniramine
Class, Mechanism
Receptor Activity
First-Generation H1
Antagonists (competitive)
Non-selective to H1R
Hydroxyzine
Fexofenadine
Loratidine
Second-Generation H1
antagonists (competitive)
Selective to HIR
Allergic Rhinitis
Do not alleviate congestion (requires direct
vasoconstrictor)
Urticaria
Allergic conjunctivitis
Motion sickness (CAN anticholinergic effects)
Sedation
Parkinsonism
AR
Sedation
Anticholinergic effects
Teratogenicity
Allergic Rhinitis
Urticaria
Allergic conjunctivitis
Sedation
other Remarks
Metabolized in liver
Inherit ethylamine moiety
from histamine
Production of active
metabolites
Inherit ethylamine moiety
from histamine
Desloratidine
Ceterizine
ANTIHISTAMINES: H2 RECEPTOR ANTAGONISTS
H2 antagonists (competitive)
Cemetedine
Ranatidine
Famotidine
Blocks H2 receptors on serosal
membranes of parietal cells
Gastric and duodenal ulcers
GERD
Cimtidine : gynecomastia (M),
galactorrhea (F)
Inherit imidazole moiety
from histamine
Nizatidine
HISTAMINE RELEASE INHIITORS
Cromolyn Sodium
Histamine Release Inhibitor
Asthma (inhaled)
Allergic and vernal conjunctivitis
Hyperpolarization → decrease
degranulation of mast cells
HISTIDINE SYNTHESIS INHIBITORS
α-F-Me-Histidine
Inhibitor for His decarboxylase
Allergic rhinitis
Peptic ulcer
GLUCOCORTICOIDS
Glucocorticoids
Prednisone
Fluticasone
Decrease COX-2 gene
expression
Decrease expression of
cytokines involved activation
of COX-2
Increase lipocortin synthesis
→ inhibit lipolysis by PLA2 →
decrease free arachidonic acid
Eosinophil apoptosis
RA, Gouty Arthritis
SLE
Dermatoses
Alligraft Rejection
IBD (UC, Crohn’s)
HRT in Addison’s disease
Dermatoses
Psoriasis
Allergin + nonallergic rhinitis
Asthma prophylaxis
AR: weight gain, suppression of HPA,
slowed wound healing, opportunistic
infections
Oxidized by CYP3A4:
generates the
active metabolite
(predisolone)
CI: Cushing’s, abrupt discontinuation
AR: pruritis, hypertrichosis, erythema,
slowed wound healing, weight gain,
HPA suppression
No active metabolites
CI: Cushing’s, abrupt discontinuation
NON-OPIATE ANALGESIC (NOT AN NSAID)
Acetominophen
(APAP)
COX-3 inhibitor
Increases pain threshold via
inhibition of Substance P
TX: Analgesia in geriatric patients with chronic pain,
or when aspirin is contraindicated
Has antipyretic and analgesic activity
No anti-inflammatory effects!
ARs
Analgesic nephropathy (similar to
renal dysfunction seen with all
NSAIDs)
Hepatic Toxicity
CYP2E1 → converts APAP to NAPQI →
covalent biding to subcellular
structures → fatal hepatic necrosis
TX with N-acetylcysteine (restore
glutathione reservoir)
EtOH increases CYP2E1
expression. It also
decreases glutathione
levels. Thus, it increases
production of NAPQI with
APAP.
NONSELECTIVE NSAIDs
Acetylsalicylic acid
Aspirin
Choline Magnesium
Trisalicylate
Irreversible (covalent)
inhibition of COX-1 and COX-2
Acetylataiton of Ser in the
active site
Nonacetylated Salicylates
Salsalate
Diflunisal
Ibuprofen
Ketoprofen
Naproxen
Propprionic acids
Acetic acid derivatives
Diclofenac
Etodelac
Ketorelac
Indomethacin
Enolic Acids
Meloxicam
Nabumetone
Analgesic
Inhibits PG synthesis → decrease response of central
afferents to Glu and Substance P
AND desensitization of peripheral nociceptors
Antipyretic
Inhibit PG synthesis → hypothalamic nuclei →
peripheral vasodilation → dissipation of heat
Anti-Inflammatory
Reduced synthesis of PG and TXA2
Regulation of Platelet Agglutination
Only mixed inhibitors reduce aggregation (platelet do
not have COX-2)
Occurs at low doses only (75 – 81 mg/d)
High doses lead to GI bleeding
Thus, COX-2 inhibitors are used concurrently with
aspirin to reduce risk
Aspirin can be used as an antithrombotic since it
causes irreversible inhibition
Reduced uterine contraction
Alleviates spasm in dysmenorrheal
Nociceptive and inflammatory pain
Analgesic ceiling
Rheumatoid Arthritis
PGE2 synthesis is upregulated in the synovium
Dysmenorrhea
Decreased synthesis of PGF in the myometrium
Gout
Not DOC for analgesia in geriatric patients due to
increased risk of GI bleed
Use APAP
Diclofenac can be administered transdermally
GI Hemorrhage
Decreased PGE3 synthesis →
acidification of the GI lumen →
increased risk of ulceration and
perforation
RFs: > 65 years, previous GI event,
corticosteroid taper, SSRIs, antiplatelet therapy, alcohol, smoking
Thus, non-selective NSAIDs are
combined with misoprostol or PPI.
Decreased risk with COX-2.
Decreased Renal Function
COX-1 and COX-2 are concentrated in
renal tissue and indispensable for
normal function
Aspirin Intolerance
Generated by all nonselective NSAIDs
COX-1/COX-2 inhibition → increase
flux through 5-LOX pathway →
increased synthesis of CysLTs →
anaphylactoid reaction
For patients with Aspirin-Sensitive
Respiratory Disease
TX with COX-2 inhibitors
Bronchospasm, urticaria, shock
Vascular
COX-2 → decreased PGI2 synthesis
without decreased TXA2 synthesis →
increased thrombosis
CI: pregnancy (late), febrile pediatric
patients
(COX-2) SELECTIVE NSAIDs
Celecoxib
Selective inhibitor
TX: use in ASRD and patients with high risk of GI
bleed
PROSTANOID AGONISTS
Alprodastil
PGE1 analog
Latanoprost
Relaxation of the trabecular
smooth muscle
Dilates arteries supplying the
corpus cavernosum
PGF2α analog
Erectile dysfunction
Maintains patency of ductus arteriosus (continuous
infusion)
AR: priapism
DOC in open-angle glaucoma and intraocular
hypertension
AR: blurred vision, conjuctival
hyperemia, iris pigmentation,
epithelial keratopathy, iritis, uveitis
FP receptors → increases
uveoscleral flow → decreases
IOP
Misoprostol
PGE1 analog
EP receptors on parietal cells
→ Gi → inhibit AC → decrease
cAMP → inhibit H+/K+ ATPase
→ decreased H+ secretion
Increases HCO3- secretion
Prevents gastric ulcers in patients undergoing chronic
NSAID therapy
Abortion, following mifepristone (increases
amplitude of myometrial contractions and causes
dilation of the cervix)
CI: history of iritis or uveitis, active
intraocular inflammation
CI: pregnancy
LOX INHIBITOR
Zileuton
Irreversible 5 –LOX inhibitor
Chelates a Fe2+ cofactor
Decreases synthesis of all LTs
→ decreased granulocyte
chemotaxis, control of
bronchospasm
Prophylaxis and chronic TX for asthma
AR: hepatotoxicity (requires pretreatment and continued assessment
of ALT for length of therapy)
LEUKOTRIENE RECEPTOR ANTAGONISTS
Montelukast
Zafirlukast
CysLT1 antagonist (G-protein
coupled)
→ blockade of CysLT actions
on the airway and
inflammatory cells
CysLT1 antagonist (G-protein
coupled)
→ blockade of CysLT actions
on the airway and
inflammatory cells
Chronic TX of asthma
Allergic rhinitis
CI: acute asthmatic episode
Reduces dose when formulated with glucocorticoids
Prophylaxis and chronic TX of asthma
Less efficacy than fluticasone (inhaled corticosteroid)
CI: acute asthmatic episode
DRUGS used in the treatment of MYCOBACTERIAL INFECTION
FIRST-LINE AGENTS
Drug (Generic Name)
Isoniazid (INH)
Rifampin
Class, Mechanism
Activity
Cidal Drug
Inhibits cell wall synthesis
INH → isonicotinic acid →
inhibit generation of mycolic
acid
Cidal Drug
Inhibits RNA and protein
synthesis
Effective against intracellular
and extracellular infection
Rifapentine
Treatment of active TB disease
Prophylaxis for LTBI
TB meningitis
Prophylaxis for LTBI
Leprosy
TB meningitis
Aliphatic side chain causes
conformational distortion of
M. tb RNA polymerase
Pyrazinamide
Cidal Drug
Unknown mechanism of action
Requires actively dividing
organisms
Ethambutol
Static Drug
Inhibits incorporation of
mycolic acid into the cell wall
Chelates metals → inhibits
protein synthesis
TB meningitis
AR
Delayed Hepatic Toxicity
Discontinue if AST > 3 X NML
Peripheral neuropathy
Prevent by co-treating with
pyridoxine (VitB6)
Hepatitis
RF: chronic liver disease,
alcoholism, age
Increased CYP450 expression
Accelerate metabolism of
other drugs (including
antiretroviral agents)
Arthralgia (70%)
Hepatotoxicity
CI: any evidence of liver
failure
Gout
CI: Gestation
Optic Neuritis
Loss of color discrimination
(typically reversible)
Gout
Resistance
Pharmacology
6
Resistance rate is 1:10
Missense mutation of InhA
gene (mycolic acid
synthesis)
Distributes into CSF, ascites,
and pleural fluid
Resistance rate is 1:108
Mutations in β-domain of
the RNA polymerase
Decrease permeability to
drug
Distributes to the CSF
Some strains lack
pyrazinamidase, and do not
transform drug into active
form
If resistant to INH,
organisms will not be
resistant to ethambutol!
Dapsone
Requires actively dividing
organisms
Sulfone
Interferes with folate acid
synthesis
Leprosy
GI distress
Hemolytic anemia
Leukopenia
Hepatities
Cholestasis
SECOND-LINE AGENTS
Ethionamide
Aminosalicylic Acid
Cycloserine
Streptomycin
Kanamycin
Amikacin
Inhibits mycolic acid synthesis
Used with resistance to first-line drugs or RFs (HIV coinfection)
PABA analogue
D-Alanine analogue
Inhibits cell wall synthesis
Aminoglycoside ABx
Capreomycin
Cyclic peptide
Ofloxacin
Ciprofloxacin
Fluoroquinolone ABx
With failed regimes, add > 1 drug class to prevent
resistance
GI distress
Hepatitis
GI distress
Psychosis
Seizures
Ototoxicity (sensorineural hearing
loss)
Nephrotoxicity
Ototoxicity
Nephrotoxicity
GI distress
ANTIBACTERIAL DRUGS derived from the β-LACTAM SUBSTRATE
PENICILLINS (PCNs)
Mechanism of Action (All β-Lactam Drugs)
GPOs: diffusion across PG layer
GNOs: transport through porin into the periplasmic space
→ bind PBPs (transpeptidase, carboxypeptidase, endopeptidase) → inhibit transpeptidation of PG → loss of cross-linking → bacterial autolysis
Can Tx meningitis due to low toxicity (high therapeutic index and Certain Safety Factor)
These are the most allergenic ABx
PCN G is acid-labile, so must be administed parenterally (IM)
The semisynthetic PCNs are resistant to hydrolysis by β-lactamse. Resistance is conferred by altered PBP (e.g. MRSA, MRSA)
Effeciveness is determined by time above the MIC
Drug (Generic Name)
Class, Mechanism
Penicillin VK
Penicillin G
Natural Penicillins
Penicillin G
Benzanthine
Spectrum and Therapeutic Uses
GPOs: streptococci, enterococci, pneumococci,
peptostreptococcu, Listeria, Clostridia
GNOs: meningococcus
Triponema pallidum, Borrelia, Leptospira
Nafcillin: Neutropenia
Resistance
Pharmacology
Resistance is due to βlactamase, porin variation,
and altered PBPs
Peperacillin + Ticarcillin: salt retention
Streptococcal pharyngitis and endocarditis
Syphilis (Triponema)
Gas Gangrene
Periodontal Infection
PCN G Benzathine reduces clearance rate →
increased efficacy against Treponema and Strep
Amoxicillin
Ampicillin
AR
Hypersensitivity Reactions
Aminopenicillins
GPOs: same as PCN
GNOs: same as PCN + E. coli + Proteus + Haemophilus
Respiratory Tract Infections (upper and lower)
Uncomplicated UTI
Enterococcal infections
Listeriosis
Crystalline PCN G: IV for
endocarditis and brain
abscesses
PCN VK: resistant to
destruction by gastric acid
Short half-life
Dicloxacillin
Nafcillin
Oxacillin
Methicllin
Ticarcillin
Piperacillin
AmoxacillinClaculanate
Semi-synthetics
GPOs: Staph and Strep
No activity for GNOs, enterococci , and anaerobes
These drugs are PCNaseresistant!
DOC for Staphylococcal infections
Extended Spectrum
PCN + β-lactamase Inhibitor
AmpicillinSulbactam
PiperacillinTazobactam
GPOS: streptococci, enterococci (piperacillin)
GNOs: aerobes, pseudomonas
Short half-life
Pseudomonas infections: requires β-lactamase
inhibitor
Spectrum is equivalent to parent PCN + β-lactamase
+ve S. aureus, E. coli, H. influenza, M. catarrhalis,
Klebnsiella, and Bacteroides
Inhibitors are no
antibacterial
Respiratory Tract Infections
Head and Neck Infections
Cellulitis
Bite infections
Intra-abdominal Infections
CEPHALOSPORINS
Mechanism: Inhibit cell wall synthesis
DOC: CAP and meningitis
Generation IV: covers GNOs (pseudomonas) + GPCs with high-level activity against Staph
Cephamycins: only group with anaerobic coverage
No drugs against enterococci, Listeria, MRSA, ESBL
Efficacy is determine by time above MIC
Cefazolin
Generation I
GPOs: GPCs
GNOs: E. coli, Klebsiella
Streptococcal and staphylococcal skin and soft tissue
infections
Cross-reactivity with the PCNs
Ceftriaxone: biliary sludging
Cefepime: non-focal neurologic
deficits
and altered PBPs
Generation II :
Cefuroximes
Cefuroxime
Generation II :
Cephamycins
Cefoxitin
Cefmetazole
Respiratory Tract Infection (upper and lower)
Equivalent to Generation I + anaerobes + various
GNOs
Cefexime
Ceftriaxone
Ceftazadime
Intra-abdominal and pelvic infections
GPOs: streptococcus
GNOs: nearly complete coverage (including
pseudomonas: ceftazadime)
Generation III
Equivalent to Generation I + Haemophilus +
Moraxella
NO ACTIVITY: Staph
Generation IV
(Cefepime)
Cefepime
Meningitis
CAP
Gonorrhea, UTI
Pseudomonas Infections
GPOs: Generation I
GNOs: Generation III
NO ACTIVITY: anaerobes
Nosocomial Infections
Febrile Neutropenia
Pseudomonal Infections
UTI
CAPBAPENEMS
Broad Spectrum
Imapenem
Meropenem
Doripenem
Ertapenem
Coverage: almost all bacteria
NO ACTIVITY: MRSA, methicillin-resistant coagulase –
ve staph, enterococcus, Clostridium.
ALL EXCEPT Ertapenem have activity against
Pseudomonas and anaerobes
Severe infection with resistant pathogens
Meningitis (Peds)
Hypersensitivity
Cross-reactions with PCN
Imapenem: causes seizures with
decreased renal function
and altered PBPs
Mixed infections (intra-abdominal and soft-tissue)
MONOBACTAM
Coverage of Gm-ve bacilli
No activity against GPOs or anaerobes
Aztreonam
Hypersensitivity
Thus, the spectrum is Gm-ve aerobes (similar to
aminoglycosides)
Resistance is due to βlactamase
Effectiveness is determine
by time above MIC
DOC for Pseudomonas infection with PCN or other βlactam allergy
GLYCOPEPTIDE
Vancomycin
Binds to D-ala-D-ala dipeptide
moiety of the PG precursors →
prevents binding of
peptidoglycan polymerase
(this is the biosynthetic step
that precedes cross linking) →
bacterial autolysis
Covers GPOs
Aerobes (including MRSA, MRESE, VRE) and
anaerobes
Neutropenia
Nephrotoxicity
Red Man Syndrome
NO ACTIVITY AGAINST GNOs!
Enterococcal resistance
(VRE): modification of the
peptidoglycan dipeptide
precursor (encoded by
VanA)
DO NOT USE FOR SYSTEMIC INFECTION (poor GI
absorption)
VanA gene transferred to S.
aureus (VRSA)
MRSA + coagulase-negative staphylococcal infections
Ampicillin-resistant enterococcal infections
Resistant pneumococcal infections (e.g. meningitis)
C. diff colitis (oral formulation)
Concentrated in GI tract
(minimal absorption)
Does not cross BBB
Slowly cidal ABx
Static activity against enterococci, so add
aminoglycoside
CYCLIC LIPOPEPTIDE
Daptomycin
Causes rapid membrane
depolarization upon binding →
loss of membrane potential →
inhibition of protein synthesis
→ bacterial autolysis
Covers GPOs
Aerobes (including MRSA, MRESE, VRE) and
anaerobes
NO ACTIVITY AGAINST GNOs!
Less toxicity compared to Vancomycin
Concentration-dependent
response!
The cidal activity is more
rapid than Vancomycin
Emerging therapy for severe MRSA, VRE, and
coagulase-negative staphylococcal infections
NOT USED FOR PNEUMONIA (inactivated by
pulmonary surfactant)
ANTIBACTERIAL DRUGS : TRANSLATIONAL INHIBITORS
Drug (Generic Name)
Class, Mechanism
AR
Resistance
Pharmacology
AMINOGLYCOSIDES
Gentamycin
Tobramycin
Streptomycin
Natural Aminoglycosides
(generated by Streptomyces)
Oxygen-dependent transport
→ irreversible binding of 30S
ribsosome → inhibits
elongation cycle +
translational misreading →
bacteriocidal activity
GNOs: all aerobic Gm –ve bacilli
Enterobacteriaciae
Some coverage of Staph
With combination Tx: Staph, Strep, enterococci
Tobramycin has greatest cidal activity against
Pseudomonas
Streptomycin + Amakacin: Mycobacteria
NO ACTIVITY: ANAEROBES!
Plague
Tuleremia
Complicated UTI involving GNR
Combination Tx with β-lactams: Pseudomonas,
staphylococcal, streptococcal, enterococcal
endocarditis
The β-lactams destabilize the cell wall and
allow greater influx of aminoglycosides into
the GPCs
Mycobacterial infection
Amikacin
Semisynthetic
Kanamycin + OH-Butyric Acid
Nephrotoxicity
Binds at the brush border of the
apical side (PCT) → pinocytosis →
tubular necrosis
Preferentially affects renal cortex
Saturable kinetics: less tubular uptake
with single large dose
Ototoxicity (Irreversible)
Binds vestibular and cochlear
membranes → concentrates in
endolymph
Concentration-dependent
activity
Large bolus is preferred
regimen of dosing
Prolonged effects
Resistance
Chromosomal mutations:
within the ribosomal
binding domain
Increased efflux: prevalent
in Pseudomonas
Inactivation: some enzymes
encoded by plasmids →
acetylation, adenylation,
phosphorylation of drug
Low volume of distribution
due to high water-solubility
Low GI absorption
Does not cross BBB
Renal elimination
The OH-Butyric acid moiety
inhibits bacterial
inactivating transferases
TETRACYCLINES
Polycyclic antibiotic (four
rings): semisynthetic
derivatives
Doxycycline
Minocycline
Tigecycline
Inhibits binding of activated
transfer RNA to the 30S
ribosome → bacteriostatic
activity
Binding is reversible
Broad spectrum
GPOs: all EXCEPT enterococci
GNOs: all EXCEPT Pseudomonas
Atypical: Mycoplasma, Chlamydia, Clamydophila,
Rickettsia, Spirochetes, Malaria
Discoloration of teeth and bones
GI distress (NVD)
Fungal superfinfection: candidiasis
Time-dependent killing
(levels > MIC)
Prolonged effects
Resistance
Major mechanism of
resistance is increased drug
efflux
Widespread crossresistance seen with
tetracyclines
NO ACTIVITY: enterococci and Pseudomonas!
Second-line Tx for CAP (including atypicals)
Non-specific urethritis, gonorrhea, syphilis
Lyme Dz
RMSF (Rickettsia)
Malaria
CA-MRSA infections: minocycline
Anthrax prophylaxis and treatment
Lipid-soluble: rapid
absorption with high Vd.
Tigeclycline (IV, glycylcycline) → Tx MRSA and VRE
(no efflux and high ribosomal affinity)
Currently no resistance to Tigecycline
CHLORAMPHENICOL
Chloramphenicol
Nitrobenzene pole
Broad spectrum
Binding to 50S ribosome →
inhibits peptidyl transferase →
cessation of elongation cycle
→ bacteriostatic activity
NO ACTIVITY: Psuedomonas and Legionella
Severe typhoid fever due to Salmonella infection
Bacterial meningitis with β-allergy
CNS abscess with anaerobic infection
Myelosuppression
Inhibits host protein synthesis
Reversible
Aplastic Anema
Toxicity to marrow stem cells; thus it
is dose-independent
Gray Syndrome
Seen in neonates
Lack of glucoronidation → vascular
collapse
Resistance
Acetylation of the nitro
group by Chloramphenicol
Acetyl Transferase (CAP);
encoded by plasmid
Lipid soluble: high
bioavailability and Vd
MACROLIDES
Erythromycin
Clarithromycin
Azithromycin
Natural Macrolide
Binds 23S subunit of the 50S
ribosome → inhibits
attachement of tRNA
Semisynthetic
GPOs: streptococci, pneumococci
Atypical: Legionella, Mycoplasma, Cglamydia,
Chlamydophila, some Mycobacteria
GNOs: H. pylori
GI distress (NVD)
Hepatitis during pregnancy
Slow cidal activity
Time-dependent activity
Prolonged Effects
NO ACTIVITY: Staph
Respiratory Tract Infection
Sinusitis, AOM, exacerbations of chronic
bronchitis, CAP (covers atypicals)
Streptococcal pharyngitis and cellulitis (PCN-allergy)
Atypical Mycobacterial Infection
H. Pylori infection (cotreat with PPI and another ABx)
Treatment and prophylaxis of Pseudomonas infection
in CF
No activity against Pseudomonas, but
inhibits biofilms
Resistance
Methylation of the 23S
ribosomal subunit
Erm genes: pneumococcal
resistance in Europe
Increased efflux
Mef genes: pneumococcal
resistance in US
Genomic mutation of the 52
ribosome
Inactivation
GNRs may produce
esterases
Erythromycin is acid-labile
(low GI absorption)
The semi-synthetics have
improved absoption
Concentrated within the
pleural fluid
LINCOSAMINE
Clindamycin
Binds 23S ribsosomal subunit
→ inhibits attachment of tRNA
GPOs: Staph and Strep
Anaerobes (including Bacteroides fragilis)
NO ACTIVITY: Mycoplasma, Legionella, Chlamydia
Equivalent mechanism to the
macrolides (same binding site)
Supradiaphragmatic anaerobic infections (e.g. lung
abscess)
Streptococcal infection (Group A)
Diarrhea
Pseudomembranous Colitis
Selects for clindamycinresistant C. difficile →
enterotoxins and cytotoxins
Lipid soluble: high
Staphylococcal infection (CA-MRSA)
Toxyplasmosis
Pneumocystis
STREPTOGRAMINS
Dalfopristin (A)
Quinopristin (B)
Typically coformulated
IV only
Quinopristin: equivalent action
to clindamycin and macrolides
Dalfoprisitin: bind to novel 50S
site
GPOs: virtually all EXCEPT Enteroccocus faecalis
Good coverage of Staph, MRSA, Strep, Enterococcus
faecium, VRE
Only route of
administration is IV
Resistance
Methylation of 23S:
quinupristin only → renders
combination therapy
bacteriostatic
Genomic mutation of 23S:
dalfoprisitn
NOT effected by efflux
pumps (MDRD)
VRE infections
MRSA infections
Static when Tx in isolation
Cidal when Tx in conjunction
Moderate serum levels and
tissue distribution
OZAZOLIDINONE
Linezolid
Bind 50S → inhibit
congregation of 70S initiation
complex
GPOs: virtually all
Good coverage of Staph, MRSA, MRSE, Strep,
pneumococci, enterococci, VRE
Static + slow cidal activity
VRE infections
MRSA infections (DOC for MRSA pneumonia)
MRSE infection
Thrombocytopeni+ Anemia (> 2 wks)
Peripheral neurpathy (> 4 wks)
Resistance
Seen in E. faecium: genomic
mutation of the 50S
ribosome
High Cost
Lipid soluble: high
KETOLIDE
Telithromycin
Derived from macrolides: long
alkyl side-chain allows dual
binding to a remote sute on
23S ribosome
Spectrum is equivalent to macrolides + resistant
streptococci and pneumococci
GI distress (NVD)
Hepatitis during pregnancy
DOES NOT COVER Staph! (Note that Staph is resistant
Transient loss of visual acuity
Slow cidal activity
Time-dependent activity
Prolonged Effects
Equivalent mechanism to
macrolides
to macolides)
Liver failure
DOC for CAP with macrolide resistance
CI: myasthenia gravis
NITROFURANS
Nitrofurantoin
Synthetic Nitrofuran
Nitrofuran → transformed by
Nitrofuran Reductase →
radicalized derivatives → bind
to cytosolic proteins
GPOs: enterococci
GNOS: E. coli, some Enterobacter and Klebsiella
Tx and prophylaxis of UTI
GI distress
Pulmonary hypersensitivity (pleural
effusion, IPF)
Rapid spontaneous
degradation in the plasma
→ only attains therapeutic
concentrations in urine
ANTIBACTERIAL DRUGS : TRANSCIPTIONAL INHIBITORS
Drug (Generic Name)
Class, Mechanism
AR
Resistance
Pharmacology
QUINOLONES
Ciprofloxacin
Inhibit DNA gyrase (Top II) and
Top IV
Cidal Activity
GPOs: Pseudomonas, GPCs (pneumococcus)
GNOs: aerobic GNRs
Atypicals: Mycoplasma, Chalmydophila, Legionella
GEN1 agents (Ciprofolxacin): NO ACTIVITY against
GPOs or anaerobes
GEN2 agents (Levofloxacin, Moxifloxacin): extend
coverage to GPOs
Use these for RTIs!
Levofloxacin
Moxifloxacin
Phototoxicity
Cartilage damage (animal models)
Hepatities
Prolonged QTc interval
Vertigo
Dysglycemia
Lipid soluble: high
Hepatitis
Drug Interactions: increased CYP450
expression → increase clearance of
other meds
Urine discoloration
Resistance
Mutations of the β-subinit
of DDRNAP.
Rifamycin cannot be used
alone to Tx M. tb
Cannot be administered
with divalent cations (e.g.
Ca2+, Mg2+)
Enteric infection with aerobic GNRs
Severe GNO infection
Severe Pseudomonas infection
RTIs
Mycobacterial infection
Prostatitis
UTIs
RIFAMYCINS
Rifampin
Rifabutin
Rifapentine
Rifaximin
Inhibit DNA-dependent RNA
polymerase (DDRNAP)
Cidal Activity
Broad spectrum
Good coverage of Staph, Mycobacteria, ETEC
Tx Active TB
Prophylaxis and Tx atypical mycobacterial infection
Staph osteomyelitis, abscess, endocarditis
Prosthesis infections
ETEC diarrhea
Recurrent C. diff infection
METRONIDAZOLE
Metronidazole
Converted to active
metabolite by bacterial nitro
reductase → binding and DNA
damage
Cidal Activity
Anaerobes (including Bacteroides)
Protozoa: Giardia, Trichomonas vaginalis
Peripheral Neuritis
Emesis with EtoH intake
NO ACTIVITY: aerobes
Lipid soluble: high
Resistance
No expression of nitro
reductase
Subdiaphragmatic anaerobic infection
Bacterial vaginosis
C. difficile infection: diarrhea and
pseudomembranous colitis
SULFONAMIDES
Sulfadiazine
Lipid-soluble PABA analogue
Complexed with Ag2+for
topical burn therapy
PABA analogue → competitive
inhibition of Dihydropteroate
Synthetase → no generation of
DHF
Sulfamethoxazole
Broad Spectrum
Covers Nocardia, Toxoplasma, Pneumocystis
Hypersensitivity Reactions
Urine crystals
UTI (with TMP)
Nocardia infection
Toxoplasmosis
Pneuocystis pneumonia (with TMP)
Burns (silver sulfadiazine
Resistance
Mutations leading to
decreased drug affinity
Increased PABA synthesis
Decreased Permeability
Lipid soluble: high
Sulfadiazine crosses the
BBB
Cidal with TMP
Water-soluble PABA analogue
TRIMETHOPRIM
Trimethoprim
(TMP)
Inhibits DHF reductase → no
formation of THF
Highly selective for bacterial
isoform of DHF reductase
GPOs: Staph, pneumococci (with PCN-susceptibility)
GNOs: GNRs
NO ACTIVITY: Pseudomonas
UTI
RTI: exacerbations of chronic bronchitis, sinusitis,
AOM
Pneumocystis pheumonoa
Typhoid fever
Enteric infections
Folate deficiency
Megalobalstic anemia,
leukopenia
Resistance
Mutations resulting in
reduced affinity
Seen in GNRs and
pneumococcus
Lipid soluble: high
CA-MRSA
DRUGS used in the TREATMENT OF FUNGAL INFECTIONS
POLYENE ANTIFUNGALS
Drug (Generic Name)
Amphotericin B
Class, Mechanism
Polyene
Plasmalemma Inhibitor
Fungicidal against most pathogenic organisms
Intercalation with ergosterol
→ formation of pore
complexes → depolarization
→ influx of H+ and efflux of K+
→ lysis
Oxidation of AmB by
lipoxygenases → generate
ROSs → membrane damage
AZOLES
ALL AZOLES ARE FUNGISTATIC
RESISTANCE
C. albican and C. krusei have intrinsic to fluconsazole
Alteration in 14α-demethylase
Increased ATP-binding cassette transporters
MDR efflux
Typically seen with prolonged therapy + treatment of oropharyngela candidiasis with fluconazole in AIDS patients
AR
Acute Infusion Toxicity
Seen with high dose rates. Fever,
chills, anorexia, nausea, myalgia,
headache, vomiting.
Delayed Nephrotoxicity
Results in renal tubular injury, but
typically does not lead to permanent
renal isufficiency.
Distal Tubular Acidosis
Inhibits secretion of H+ into urine,
resulting in Type I RTA.
Normochromic Normocytic Anemia
Suppresses EOI synthesis, but is
readily reversible.
Resistance
Pharmacology
Resistance is rare
Typically solubilized in
micellar formulations with
deocycholate (a bile salt)
for IV administration
No dose adjustment in
preexisting renal or hepatic
failure
Lipid formulations prevent
oxidation to LDL:AmB,
resulting in less renal
tubular uptake and
nephrotoxocity
AmBisome
AmB lipid complex
AmB cooiloid
dispersion
Itraconazole
Triazoles
Bind and inhibit CYP450 14αDemethylase → inhibit
transformation of lanosterol to
ergosterol → increased 14αmethysterol:ergosterol →
membrane disruption
Fluconazole
Spectrum
Sporothrix schenkii, Aspergillus, Penicillium,
Dermatiaceous fungi (phaeohyphomycetes)
Sporotrichosis
Limited Aspergillosis
Endemic infections: Blastomycosis and
Histoplasmosis
Oral + esophageal candidiasis in AIDS patients, if
resistant to fluconazole (C. glabrata, C. krusei)
Spectrum
Candida spp
Albicans > parapsilosis> glabrata > krusei
Dimorphic Systemic Fungi
Ci > Hc > Bd
Cryptococcus Neoformans
Drug Interaction
Via metabolism by CYP450.
May increase bioavailability of codrug or decrease availability of azole
Endocrine Effect
Via occupation of normal CP450
involved in steroid synthesis
Testosterone depletion →
gynecomastia
Glucocorticoid depletion → adrenal
insufficiency
Hepatotoxicity
Limited CNS or ocular
penetrance
Good CNS and ocular
penetrance
NO ACTIVITY: Aspergillus and other hyphal pathogens
Mucosal candidiasis
Invasive candidemia
Cryptococcal meningitis
Endemic infections: Blastomycosis and
Histoplasmosis
DOC: coccidioidomycosis meningitis
Spectrum
EQUIVALENT to Fluconazole + Aspergillus + C. krusei,
C. glabrata + T. biegillii + P. boydii (mycetoma)
Voriconazole
Good CNS and ocular
penetrance
DOC: aspergillosis
DOC: most hyphal fungal infections
ALLYLAMINES
Terbinafine
Bind to squalene epoxidase →
depletion of lanosterol and
egosterol → disruption of cell
membrane → lysis
Fungicidal Activity
Spectrum
Dermatophytes, Apsergillus, Dimorphics,
Pneumocystis
Very low Vd due to portien
binding (non-saturable)
Concentrated in the
stratum corneum
Onychomycosis
Cutenaous dermatophyte infections
Requires prolonged therapy
ECHINOCANDINS
Capsofungin
Inhibits β(1,3) glucan
syntehtase → depletion of cell
wall glucans → lysis
Similar to PCNs
Spectrum
Fungicidal: Candida (including C. glabrata and C.
krusei)
Fungistatic: Aspegillus (inhibits apical growth of
hyphae)
IV formulation only
NO ACTIVITY: Cryptococcus, systemic dimorphics
DOC: invasive candidiasis
Combined with voriconazole for invasive aspergillosis
FLUOROPYRIMIDINES
5-Fluorocytosone
(5-FC)
Fungal cytosine permease →
transport into cell → convert
to 5-FU via cytosine
deaminase in cytosol →
phosphorylate to F-UTP →
interfers with RNA synthesis
AND
Conversion to F-dUMP →
inhibit thymidylate synthetase
→ inhibit DNA synthesis
Fungistatic activity
Spectrum
Yeast forms > hyphae
DOC: 5-FC + AmB for cryptococcal meningitis
Monotherapy: Candida UTI
Myelosuppression
Mammalian cells lack
cytosine deaminase, but 5-FC
is converted to 5-FU by NF in
the gut
DRUGS used in the treatment of VIRAL INFECTIONS
ANTIVIRAL AGENTS
General Features
CLINICAL USES
Influenza A only: Amantadine and Rimantidine (not approved)
Influenza A and B: Oseltamivir and Zanamivir (N inhibitors)
HSV-1 and HSV-2 (susceptible): Acyclovir, Valacyclovir, Famcyclovir
CMV: Ganciclovir, Valganciclovir
Resistant HSV and CMV: Cidofivir
HCV: IFN-α, Adefovir, Tenefovir
HBV: Equivalent to HCV + Telbivudine
Interference with other nucleoside and nucleotide analogs occurs in concurrent treatment of HIV and HBV
Most anti-herpes drugs are nucleoside analogs
Drug (Generic Name)
Amantadine
Rimantidine
Oseltamivir
Zanamivir
Acyclovir
Famciclovir
Class, Mechanism
Receptor Activity
Anti-Influenza
Tricyclic Amine
Influenza A serotype only
AR
CNS effects: excitability
Rimantadine does not cross BBB.
Block M2 protein channel and
prevent uncoating
Blocks influx of protons
from endosome into viral
capsid
Anti-Influenza
Sialic acid analog
Competes with N for cellular
sialyl groups → no cleavage of
virus during budding (remains
bound to H)
G Nucleoside Analog
Resistance, Metabolism,
other Remarks
Res: point mutations in
transmembrane domain of
M2
Cross-resistance
Influenza A and B
NV
Res: mutations in N
HSV-1 > HSV-2
VZV
NVD
Headache
Transient renal dysfunction
Res: mutations or
deficiency in TK
Valacyclovir
No activity: CMV (does not encode the TK)
Phosphorylated by viral TK →
additional phosphorylation
cellular kinases → active
triphosphate form
Mutations in viral DNA Pol
(these are not common)
Termination of chain synthesis
(no free 3’ OH)
Inhibition of viral DNA
Polymerase
Ganciclovir
Valganciclovir
G Nucleoside Analog
CMV
HSV, VZV
Severe neutropenia
Res: mutations in UL97
kinase
HSV and CMV
if RESISTANT TO Acyclovir and Ganciclovir
Renal toxicity
Leukopenia
No cross resistance
HBV
HCV
Broad viral activity
Fever, lethargy
Myelosuppression
Hypersensitivity
CHF
Res: seen in HCV
Due to inhibition of PKR
Phosphorylated by CMV UL97
kinase or HSV TK →
additional phosphorylation by
cellular kinases → active
triphosphate form
Termination of chain synthesis
Polymerase
Cidofovir
C Nucleotide analog
Activation to triphosphate
form by cellular kinases only :
does not require viral
activation
Interferon-α
Competes with dCTP →
polymerase
Recombinant cytokine
Increases expression of
2’-5’ oligoadenylate synthase
Adefovir
Tenefovir
PKR
RNAase L
AMP Nucleotide Analog
(Acyclic nucleoside
phosphonates)
Hepatic failure
Pulmonary fibrosis
HBV
HCV
Phsophorylation via cellular
kinases → active diphosphate
form
Chain termination
Inhibit DNA polymerase
Telbivudine
T Nucleoside Analog
HBV only
Does not inhibit human cellular
polymerase
RSV in peds with severe respiratory distress
Broad spectrum DNA + RNA viral activity
Transient hemolytic anemia
Inhibits HBV RT
(also a DNA polymerase)
Does not require
phosphorylation
Ribavarin
G Nucleoside Analog
Active as triphosphate
Inhibits IMP DH → decrease
GMP
Interferes with early
replication (5’ mRNA capping)
via depletion of GTP pools
Direct inhibition of HCV RNA
polymerase
Combination with IFN-α: HCV
HCV has RNA-dependent RNA polymerase
ANTIRETROVIRAL AGENTS
Enfuviritide
Viral Fusion Inhibitor
Salvage therapy if infection is refractory to multiple
drugs
Must be given by subcutaneous
injection → results in injection site
reactions
Res: mutation of env region
encoding GP41
R5 HIV infection
AR: WNV infection due to CCR5
blockade
Must determine viral
tropism
Conserved 36-residue peptide
sequence from GP41 (HR2
domain)
Maraviroc
Inhibits folding of HR1 and
HR2 → results in loss of
conformational change upon
binding of GP120 with CD4
Viral Entry Inhibitor
Inhibits binding of GP120 with
CCR5 co-receptor (R5 tropic
strains)
This is the main viral
type in early
infection, with
conversion to X4
Zidovudine (AZT)
Lamivudine (3TC)
Stavudine (D4T)
Abacivir
Various nucleoside analogues
Nucleoside RT Inhibitor
NRTIs
Phosphorylated by host
cytoplasmic enzymes or HIV-1
TK
Phosphorylation state
determines absorbance
Incorporation into strand
duplex → chain termination
Inhibits HIV-1 RT (p66 domain)
Res: mutations in GP120
restoring ability to bindto
CCR5
Main mechanism:
development of mixed
tropism
Lactic Acidosis
Inhibit mitochondrial DNA
Pol-γ: cessation of
mitochondrial DNA
replication → increased
lactate and TGs
Hepatic Steatosis
Presentation: NV, abdominal pain,
dyspnea, AGMA, pancreatitis
Hypersensitivity
Myelosuppression
Peripheral Neuropathy
Res
Mutations in RT
nuceleotide-binding
domain: decreased affinity
for NRTIs
Mutations in RT nuclease
domain: increased
hydrolysis of terminal NRTI
from the leading strand
(TAMs)
(Increased affinity for
dNTPs)
Results in extensive
cross-resistance
Nevirapine
Etravirine
Delaviridine
Efavirenz
Various non-nucleoside
structures
Non-Nucleoside RT Inhibitor
NNRTIs
Rash
Hepatotoxicity
Efavirenz: CNS effects, teratogenicity
Drug interactions: CYP3A4
metabolism
Non-competitive irreversible
inhibitors of RT
If resistant to single firstgeneration drug, crossresistance is expected
(use Efavirenz)
Bind allosterically near the
active site → conformational
shift of catalytic Aspartate
residues
May potentiate effects of
NTRIs
Mutation → decreased 3’
hydrolytic activity →
increased NTRI
incorporation
Does NOT require
phosphorlyation
Indanivir
Saquinavir
Atazanavir
Ritonavir
Lopinavir
Protease Inhibitors
Binds to the protease active
site → prevents cleavage of
Gag-Pol polyprotein
Zidovudine antagonizes
Stavudine due to
competition for TK site
Res
Mutations in the NNTRI
binding site → extensive
cross-resistance
Typically arises early with
NNTRI monotherapy
Lopinavir is coformulated with ritonivir (inhibits
CP450 and increased bioavailability
Hepatotoxicity
GI distress
Adipose redistribution
Hyperlipidemia
Insulin resistance
ALSO potentiated by
resistance mutations to
NTRIs
Res: mutations within
protease binding site
Drug class most likely to result in
metabolic dysfunction
Raltegravir
Integrase Inhibitor
Binds to the active site of HIV
integrase and interferes with
strand transfer
Mutations in integrase
DRUGS used in perioperative course of SOLID ORGAN TRANSPLANTATION
GLOBAL IMMUNOSUPPRESSION
Drug (Generic Name)
Prednisone
Class, Mechanism
Activity
Glucocorticoid
Blocks MHC II expression on APCs
Decreases synthesis and secretion of cytokines
(primarily from monocytes and macrophages)
Blocks adhesion and extravasation of leukocytes
Decreased synthesis of acute phase reactants
High dose: direct lysis of lymphocytes
Low-Dose: maintenance therapy
High-Dose: acute rejection crisis
Autoimmune diseases (hemolytic anemia, RA, SLE)
ALL
CLL
AR
Growth inhibition
Protein catabolism and muscle
wasting
Adipose redistribution
Suppression of the hypothalamicpituitary-adrenal axis
Salt retention
Cataracts
Hyperglycemia
Osteoporosis
Psychosis
Pharmacology
A prodrug: must be
metabolized to 11β-OH
derivative for activity
CALCINEURIN INHIBITORS
Cyclosporine (CsA)
Tacrolimus (FK506)
Calcineurin Inhibitor
Enters cell → binds cyclophilin
(CsA) or immunophilin FK506
(Tactolimus) → complex with
calmodulin and Ca2+ →
cyclophilin:CsA and
FK506:Tacrolimus inhibit the
phosphatase activity of
calcineurin → no
dephosphorylation of NF-AT →
remains inactive → no
transcription of IL-2
Standard for primary immunosuppression
Solid organ transplants (with other ISDs)
Nephrotoxicity
Neurotoxicity (tremor, headache,
motor dysfunction, seizures)
Hypertension
Hyperglycemia, Hyperlipidemia
Highly diabetogenic with prednisone
Very narrow therapeutic
window (plasma levels 150
– 200 ng/mL)
Limiting factor is
nephrotoxicity, although
the drug is eliminated in the
bile
Metabolized by CYP3A4
Vastly increased potency (100X) compared to CsA
Liver transplantation
Rescue of acute kidney allograft rejection (refractory
to cyclosporine)
Mainly bound in plasma by
albumin and α1glycoprotien
Metabolized by CYP3A4
ANTI-METABOLITES
Azothioprine
Mycophenylate
Mofetil
Rapamycin
(Sirolimus)
Purine Synthesis Inhibitor
Renal Transplants
A complex mechanism of
action
Azothioprine → [glutathione
and other SH groups] → 6mercaptopurine → [HGPRT] →
6-mercaptopurine ribose
phosphate (6-thionosinic acid)
→ inhibit de novo synthesis of
purines → conversion to 6thio-GMP and 6-thio-dGTP →
inhibit DNA and RNA synthesis
→ global inhibition of cell
proliferation
Purine Synthesis Inhibitor
No effect for ongoing chronic graft rejection!
MMF → hydrolysis in GI tract
→ mycophenolic acid (MPA) →
reversible non-competitive
inhibition of inosone
monophosphate
dehydrogenase (IMP-DH) →
cessation of de novo purine
biosynthesis
G1:S Transition Blockage
Similar structure to FK506
(Tacrolimus) → complexes
with FKBP → bind to mTOR →
inhibition of G1:S transition →
no proliferation in the
presence of cytokines
Highly selective to lymphocyte isoforms of IMP-DH
(Type II) due to increased de novo purine synthesis
Other cells use base salvage pathways
Cytostatic effect on lymphocytes
Inhibit glycosylation and expression of adhesions
via depletion of guanosine nucleotides
(decreased recruitment and inflammation)
Prophylaxis of transplant rejection
Used in combination with prednisone and
calcineurin inhibitors
Prophylaxis of transplant rejection
Used in combination with prednisone and
calcineurin inhibitors
Use with predisone and MMF to avoid
nephrotoxocity (main toxicity of calcineurin
inhibitors)
Use this to replace CsA and Tacrolimus
Widespread ARs:
Myelosuppression (leukopenia,
anemia, thrombocytopenia)
GI tract toxicity
Hepatotoxicity
Rashes
Renal excretion
Decreased toxicity compared to
Azothioprine
Renal excretion
Myelosuppression (attenuated)
GI tract toxicity
Myelosuppression (anemia,
leukopenia, thrombocytopenia)
Hepatotoxicity
GI tract toxicity
Metabolized by CYP3A4 and
eliminated in the bile
ANTIBODIES
ATG + ALG
(antithymocyte and
antilymphocyte
globulins)
OKT3
Polyclonal anti-T cell
antibodies
The immunoglobulins are
generated by immunizing
animal models with
thymocytes and whole
lymphocytes
Monoclonal anti-T-cell
antibody
ATG and ALG bind non-specifically to T-cell surface
antigens
Blockade of TCR transduction
Opsonophagocytosis in the RES
Destruction by complement
Rapid lymphocytopenia
Chills
Fever
Leukopenia
Thrombocytopenia
Acute allograft rejection (only with other ISDs)
Binds specifically to the CD3 protein (TCR subunit)
Disruption of TCR-MHC recognition
Opsonophagocytosis in the RES
Destruction by complement
Circulating T lymphocytes are depleted immediately
after infusion.
Acute allograft rejection (kidney, liver, heart)
Rejection refractory to GC therapy
Depletion of T cells from donor bone marrow (prep
for transplantation)
Cytokine Release Syndrome : highgrade fever, chills, NVD, myalgia,
arthralgia, shock
Premedicate with
prednisone and/or NSAIDs
Antibody response to
exogenous Abs prevents
repeated administration.
DRUGS used in the treatment of HEMATOLOGIC DISORDERS
HEMATOPOETIC DISORDERS
Drug (Generic Name)
Class, Mechanism
Receptor Activity
Iron deficiency anemia
Iron
AR
AR: GI effects (constipation,
abdominal pain, dyspepsia),
discoloration of teeth
CI: hemochromatosis (Tx with
deferoxamine)
Megalobastic anemia due to B12 deficiency
Cyanocobalamin
(B12)
Typically non-toxic
CI: hereditary optic nerve atrophy
(Leber’s disease)
Megaloblastic anemia
Supplementation to prevent neural tube defects
Folic Acid (B9)
Typically non-toxic
AR: CNS effects (irritability,
depression) with prolonged therapy
other Remarks
Various iron salts contain
different doses
Parenteral: iron dextran
Post-gastrectomy, duodenal
reseaction, IBD, shortbowel syndrome
Reticulocytosis within 2 -3
d.
Typically, empiric treatment
with B12 + folate is intiated
until definitive Dx
Inhibition of absorption
Phenytoin, OCs, INH
Inhibition of DHF
Reductase
Methotrexate, TMP,
Pyrimethamine
Erythropoetin
Filgrastim
Glycoprotein
Action on EPO receptors
expressed by erythoid
progenitor cells
Granulocytin colonystimulating fator (G-CSF)
Tx low EPO anemia due to CKD
Anemia in myelosuppression (secondary to ISD)
Bone marrow transplantation
Anemia of inflammation
Increased neutrophils count without affect on other
granulocytes
AR: headache, seizures, HTN, edema,
NVD, infusion toxicity (flu-like
syndrome), hypokalemia (due to rapid
erythropoeisis)
CI: uncontrolled HTN, hypersensitivity
to albumin
AR: medullary bone pain, anaphylaxis
Oprelvakin
Recombinant IL-11
Tx neutropenia in myelosuppression (ISD), bone
marrow transplant, aplastic anemia
With chronic neutropenia, may be used to harvest
peripheral progenitor cells
Provokes growth of myeloid and lymphoid cell lines
Accelerates megakaryocyte differentiation
Prophylaxis of thrombocytopenia secondary to
chemotherapy
AR: edema, increased ECF results in
hemodilution, transient loss of visual
acuity, atrial arrhythmia,
myelofibrosis
Renal elimination
May develop isoAbs, since Oprelvakin
is structurally similar to native
thrombopoeitin
Romiplostim
Second-generation
thrombopoeitic agent
Agonist at the TPO receptor
Tx thrombocytopenia in chronic immune
thrombocytopenic purpura (ITP)
Must be enrolled in institutional network
CI: renal failure and ESRD (relative)
AR: CNS effects, myalgia,
myelofibrosis
No development of autoAbs
ANTICOAGULANTS
General Features
These are used typically for venous thromboembolism (VTE) since clotting in the venous circulation preferentially involves the coagulation cascade
Enoxaprin is DOC for
Acute anticoagulation of DVT and pulmonary embolism
Anticoagulation during pregnancy
Post-op prophylaxis of DVT
Lepirudin and argatroban (small-molecule inhibitor) are DOC for
Anticoagulation in patients developing HIT (usually for post-op DVT prophylaxis)
Bivalirudin is DOC for
Prophylaxis of re-occlusion after coronary angioplasty in patients with HIT
Warfarin is DOC for
Long-term anticoagulation therapy, following short-course heparin, for prevention of VTE recurrence
Atrial fibrillation and intracardiac thrombosis
Unfractionated
Heparin (UFH)
5 – 30 kD
> 18 saccharides
UFH → bind antithrombin III → stabilize
antithrombin-III:thrombin complex → rapid
inhibition of thrombin
ALSO
Binding of UFH → conformational change in
AR: bleeding, HIT, osteoporosis,
hypersensitivity
Low bioavailability due to
binding to plasma proteins
Toxicity can be reversed via
protamine sulfate
Hepatic and renal
elimination
antithrombin III → increase affinity for Xa →
increased inhibition of Xa
2 – 10 kD
< 18 saccharides
Low Molecular
Weight Heparin
(LMWH, Enoxaprin) BUT > 25% of molecules can
inhibit thrombin
Fondiparinux
Lepirudin
Argatroban
Dabigatran
Bivilarudin
Warfarin
Analogue of minor chain of
heparin
Direct Thrombin Inhibitor
Small Molecule Direct
Thrombin Inhibitors
Inhibits thrombin and Xa
LMWH → bind antithrombin III → conformational
change → increased binding and inhibition of Xa
AR: bleeding, HIT, osteoporosis,
hypersensitivity
Increased bioavailability
Renal elimination
NO binding to thrombin
Predominantly inhibits Xa
High molecular weight heparin chains may inhibit
thrombin
Decreased risk of bleeding relative to
UFH
Toxicity is not readily reversed by
protamine sulfate
DOC: DVT, Pulmonary Embolism
DOC: anticoagulation during pregnancy
Prophylaxis of VTE
CI: renal insufficiency
Inhibition of Xa only (similar to Enoxaprin)
CI: renal insufficiency
Similar efficacy to Enoxaprin for DVT
Smaller molecule → direct inhibition of thrombin in
clots
Favors fibrinolysis
Inhibits platelet aggregation (via decreasing action of
thrombin)
Longer half-life since it is
not transformed
AR: bleeding, hypersensitivity
DOC: anticoagulation with HIT
Used as an alternative to heparin (e.g. with HIT)
Dabigatran: oral prodrug
Inhibit circulating and bound thrombin
Increased fibrinolysis
Thus, used as adjuvants in thrombolytic therapy
Factor Modification Inhibitor
Prevents reduction of Vit K (compentive inhibitor) →
inhibits γ-carboxylation of Gla domains on VitKdependent factors
AR: bleeding, fetal hemorrhage
(crosses placenta), warfarin-induced
skin necrosis (due to coagulation)
DOC: prophylaxis or recurrent VTE
Requires therapy for 3 – 6 mos.
Interactions
Inhibit metabolism: phenytoin,
Typically initiated with
heparin to prevent
coagulation
DOC: atrial fibrillation
metronidazole, cimetidine, acute
EtOH
Displace from albumin: aspirin
Potentiate via anti-platelet effects:
aspirin, phenylbutazone
Decrease VitK: ABx
Accelerate metabolism: barbiturates,
rifampin, chronic EtOH
ANTI-PLATLET DRUGS
General Features
These are typically used for arterial thromboembolism and thrombitc events secondary to atherosclerosis
Aspirin is DOC for
Unstable angina
(Nitrates are used for stable angina)
Prevention of thrombosis post-CABG
Coronary angioplasty (combination with dipyrimdamole)
Prevention of thrombosis with AV fistulae and valve prostheses
Clopidogrel is DOC for
TIA and ischemic stroke (note that prasugrel is actually contraindicated!)
Abciximab, Eptifibatide, and Tirofiban are adjunct therapies in all PCI
Aspirin
Clopidogrel
Prasugrel
NSAID
ADP receptor antagonist
ADP receptor antagonist
Irreversible inhibition of COX-1 in platelets and
endothelium
DOC: unstable angina
Prophylaxis of thrombosis post-CABG
Prophylaxis of thrombosis in stented coronary artery
Acute MI
TIA
Irreversible blockage of ADP receptor (purinergic) →
decreased platelet aggregation
TIA
Ischemic stroke
Irreversible blockage of ADP receptor (purinergic) →
decreased platelet aggregation
AR: bleeding, increased risk of
hemorrhagic stroke, GI bleeding,
gastritis, hypersensitivity
AR: immune-mediated
thrombocytopenia and neutropenia,
hemorrhage, drug interactions via
CYP450 inhibition
Ci: Hx of stroke of TIA
Low-dose: inhibit platelet
COX-1 without decreases
PGI2 synthesis by
endothelium
Percutaneous coronary interventions (PCI):
angioplasty, atherectomy, stenting
Dipyridamole
Phosphodiesterase Inhibitor
Inhibit platelet PDE → increase intracellular cAMP →
increase secretion of serotonin, ADP, ad TXA2
AR: headache, dizziness, flushing,
nausea, diarrhea
Aggrenox: dipyridamole +
ASA
Adjuvant with anticoagulants in patients with valve
prosthesis
Abciximab
Eptifibatide
Tirofiban
GpIIb/IIIa antagonist
RGD mimetic and GpIIb/IIIa
antagonist
Inhibits platelet aggregation (binding to fibrinogen
and vWF)
Adjunct therapy in PCI
Refractory unstable angina
Non-STEMI
Competitive inhibitor of GpIIb/IIIa at the fibrinogen
binding domain → inhibits aggregation
AR: bleeding, thrombocytopenia
AR: bleeding
Adjunct therapy in PCI
Unstable angina
Non-STEMI
FIBRINOLYTICS
General Features
DOC for thrombosis with imminent risk of vascular occlusion
Ischemic stroke
Acute STEMI
Typically co-infused with antiplatelet and anticoagulant drugs to prevent rebound thrombosis at original clot site (due to excess liberated thrombin)
Cleaves plasminogen to plasmin → fibronolysis
AR: bleeding
Tissue Plasminogen Serine protease
Specific
action
on
bound
thrombin
(this is still a significant side effect
Activator
despite limited activation of
(Alteplase)
DOC
circulating thrombin)
Acute MI
Restoration of flow through occluded coronary artery
Acute ischemic stroke
DVT, pulmonary embolism, peripheral arterial
Requires continuous
infusion due to extremely
short half-life
thrombosis
Urokinase
Protease
Cleaves plasminogen to plasmin → fibronolysis
Does not require binding of thrombin to fibrin
AR: bleeding, arrhythmia (due to clot
lysis)
HEMOSTATIC DRUGS
General Features
DDAVP can be used in most diseases causing thrombocytopenia or platelet dysfunction (e.g. vWD and uremia)
Desmopressin
(DDAVP)
Aminocaproic Acid
Thrombopoetin
(Romiplistim,
Eltrombopag)
Recombinant VIIa
Vit K
Vasopressin analogue
Anti-fibrinolytic
TPO analogue
Recombinant coagulation
factor
Increases secretion of vWF from endothelium
DOC
vWD
Limited hemophilia A and B
Thrombocytopenia
Binds to plasminogen → inhibits cleavage and
activation
DOC
Post-operative bleeding
Intraoperative for CABG to minimize blood loss
Thrombocytopenia
TPO receptor agonists
Triggers proliferation and differentiation of
megakaryocytes
DOC
ITP
DOC
Hemostatis in patients with hemophilia and
circulating inhibitors to replacement factors
Uncontrolled hemorrhage
Intracranial hemorrhage
DOC
Acute increase in INR with Warfarin therapy
Pre-operative therapy if increased INR
AR: water retention in collecting duct,
hyponatremia, headaches, nausea,
seizures
AR: NVD, abdominal pain, thrombosis
IV
Renal excretion
AR: thrombosis, rebound
thrombocytopenia with abrupt
discontinuation
Subcutaneous
IV
Typically low-dose therapy
due to risk of Warfarin
resistance
DRUGS used in the treatment of NEUROLOGICAL DISORDERS
PARKINSON’S DISEASE
Drug (Generic Name)
Class, Mechanism
Receptor Activity
AR
other Remarks
Levodopa:Carbidopa Dopamine precursor + DOPA
decarboxylase inhibitor
Increases synthesis of DA (via
DOPA-β-hydroxylase)
Highly effective with gradual development of
tolerance due to progressive loss of dopaminergic
neurons
2 – 5 yr duration of effect
Acute loss of efficacy
End-interval tolerance (CNS concentration drops
below therapeutic range)
Shorted maintenance dose interval
Entacapone or other metabolic inhibitor
Dopamine agonist
Abrupt “off” episodes
May occur with high plasma levels; correlated with
protein intake
NV
(activation of DA chemoreceptors
in medulla)
Dyskinesias
CV: orthostatic hypotension, cardiac
arrhythmias
Psychosis
(use atypical antipsychotics
instead of DA antagonists)
Discoloration of sweat and urine
Reactivation of malignant melanoma
Intake with food decreases
absorption due to
competition for enteric
amino acid transporters
Carbidopa does not cross
BBB: no effect of L-DOPA
conversion in CNS
Carbidopa
May reduce dosage of L-DOPA: decreased ARs
Entacapone
Tolcapone
Reversible COMT inhibitor
Used only with L-DOPA
Inhibits peripheral conversion
(GI and nerves) of L-DOPA to
3-O-MeDOPA
Decreases conversion of L-DOPA into inactive
metabolites: increased bioavailability and transport
into CNS
COMT inhibitor
Tx PD if other drugs cannot be used
Limit use to 3 wks if no response is observed
May potentiate ARs of L-DOPA
AR: hepatic failure
Requires periodic LFTs
CI: hepatitis, cirrhosis
Selegiline
Rasagiline
Irreversible MAO-B inhibitor
Adjunct to L-DOPA
Prevents metabolism of DA in the CNS
Tolerance develops within 2yrs
May slow progression of PD
Inhibits production of ROSs from crytic precursor
toxin
Similar efficacy to Selegiline
AR: excitability
Does not result in
malignant hypertensive
crisis due to selectivity for
MAO-B
Generalized flu syndrome, dyspepsia
Metabolized by CYP 1A2
Pramipexole
Dopamine receptor full
agonist
Selective binding to D2 and D3
Monotherapy for moderate PD
Adjunct therapy (with L-DOPA) for advanced disease
Selective binding to D2 and D3
Ropinirole
Bromocriptine
Trihexyphenidyl
D2 full agonist
D1 partial agonist
Antimuscarinic agents
Tx extrapyramidal symptoms (tremor, rigidity)
without affect on bradykinesia
Benztropine
Renal excretion
Combination Therapy
AR: dyskinesias, hallucinations,
orthostatic hypotension
Less frequent than combination
with Pramipexole
Nausea
Hallucinations, agitation, confusion
Dyskinesias
Orhtostatic hypotension
Retroperitoneal and pulmonary
fibrosis
CI: elderly, abrupt discontinuation
(may result in rebound tremors and
parkinsonian symptoms)
Hepatic elimination
Use for young pts with moderate symptoms
Diphenhydramine
Amantadine
Nausea, vertigo
Dopamine reuptake inhibitor
Stimulate DA release
Muscarinic receptor
antagonist
NMDA receptor antagonist
Second-line therapy
CNS effects: confusion, anxiety
Blurred vision, urine retention,
xerostomia, constipation
CI: combination with other
antimuscarinic drug
THE OPIOIDS
General Features
Receptors on the presynaptic terminal of the sensory afferent: µ, κ, δ
Binding decreases Ca2+ influx →decreases transmitter release
Receptors on the postsynaptic ascending (ALS) fiber: κ
Binding increases K+ permeability
Codeine and Hydrocodone: cannot be used for severe pain
Meperidine: cannot be used for chronic therapy
POTENCY
Hydromorphone, Oxymorphone > Morphine, Oxycodone > Codeine, Hydrocodone
Morphine
Codeine
Pure opioid receptor agonists
Moderate to severe neuropathic and nociceptive
pain
May be used post-MI
CNS effects
Sedation, euphoria, anxiety, ‘clouded
mentation’, dizziness, dyphoria
Acute pulmonary edema
Respiratory depression due to
accommodation of central
chemoreceptors to CO2
Depressed cough reflex
Antitussive
Antidiarrheal
Anesthetics for cardiac surgery (Fentanyl)
Hydromorphone
Hydrocodone
GI effects
NV
Simulation of medullary
trigger
Increased vestibular
nuclear activity
Diminishes with continued
therapy
Constipation
Increased resting tone in
GI smooth muscle
Gastroparesis
Biliary obstruction
Oxycodone
Oxymorphone
Meperidine
CV: Typically no clinical effects
Some peripheral vasodilation:
histamine release +
depression of VM center
Miosis
Antidiuresis: increased secretion of
Conjugated with glucuronic
acid to M6G and M3G
M66 has an extended
half-life and higher
receptor affinity
M3G has toxic effects
Converted to morphine by
0-demethylation
Thus, it is a pro-drug
Requires action of CYP2D6
This explains variability in
response to codeine
Less potent than morphine
Dose ceiling
Greater potency than
morphine
Only available in
coformulation with NSAID
Dose is limited by ASA and
APAP toxicity!
Equiavalent potency to
morphine
Greater potency than
morphine
Converted to
mormeperidine by
demethylation
This is a toxic metabolite
with excitatory effects
Restrict use to short
procedures
ADH
Methadone
Used to Tx opioid
dependence
Pruritis and Urticaria
Due to histamine release
Tolerance
Develops to analgesic effect
Tolerance to GI pr papillary effects
does not develop
Propoxyphene
Fentanyl
Dependence
Withdrawal syndrome (flu-like illness)
Similar to mepiridine
Converted to toxic
metabolite
Transdermal patch
formulation
Iontophoretic control
system
Trasnmucosal
Addiction
ARs can be minimized by opioid
rotation and multi-drug therapy
Buprenorphine
Partial agonist
Also considered a mixed
agonist-antagonist
Binds to the κ opioid receptor
variant (presynaptic only)
Analgesia (parenteral)
Tx heroin addiction (sublingual)
Low-dose: analgesic
High-dose: antagonism and initiation of withdrawal
syndrome
May be less effective than methadone in long-term
maintenance of opioid dependence
Naloxone
Pure opioid receptor
antagonist
Acts as antagonist at high
doses
Limited respiratory depression
Refractory to reversal by naloxone
due to slow receptor dissociation
Decreased risk of abuse due to
psychotropic effects
Reversal of respiratory depression
Heroin addiction
Naltrexone
Tramadol
Can result in withdrawal syndrome if
started on patient with chonic pure
agonist Tx
Binary analgesic
Weak binding to µ receptors
Inhibits reuptake of NE and
Seizures
Metabolite generate by Odemethylation → higher
receptor affinity
serotonin
Dextromethorphan
Opioid structural analog
Cough suppression
GENERAL ANESTHETICS
General Features
Complete anesthesia: hypnosis + amnesia + analgesia + relaxation
Emergence: passive process dependent on clearance and re-distribution
More rapid with volatile agents
Slower with IV due to solubility
Induction: typically achieved by IV
Rapid-sequence: IV + intubation + neuromuscular block (succinylcholine)
In peds: inhaled agents
Maintenance: inhaled agents preferred (low tissue solubility and rapid respiratory elimination)
DOC for induction without CV instability : Propofol, Thipental
DOC for induction with CV instability
: Etomidate (AR: apnea, adrenal suppression)
DOC for induction in peds
: Volatile agents
DOC for maintenance
: Volatile agents, Propofol
Hypotension: Propofol > Thiopental
Apnea
: Etomidate, Propofol, Ketamine
Increased CMRO2 : Ketamine
Decreased CMRO2: Thiopental, Etomidate, Propofol, Volatile Agents
Cerebral Vasodilation: Volatile Agents
Thiopental
GABA receptor agonist
Potentiate binding of GABA on
receptor
IV induction
Tx increased ICP
Vasoconstricts the cerebral vessels and decreases
oxygen demand
At low concentration: hyperalgesic
Venodilation
Reflex tachycardia
Respiratory depression (no apnea)
Rapid onset and emergence
IV induction in setting of cardiovascular dysfunction
(e.g. hypotensive, CHF)
Etomidate
Neuroprotection
Decreased CMRO2 and cerebral
vasoconstriction
Myoclonus
NO cardiovascular effects
Transient apnea
Adrenal suppression
IV induction
Antiemetic
Anesthetic maintenance (continuous infusion)
Propofol
Neuroprotection
Signifacant CV effects (hypotension)
Arteriolar and venous dilation
Decreased SVR
Decreased myocardial contractility
(negative ionotrope)
Transient apnea
Ketamine
Non-competitive NMDA
receptor antagonist
IV induction in setting of cardiovascular dysfunction
Results in dissociative cataleptic anesthetic
state
Nystagmus with no consciousness
Analgesia in burn dressings
Significant analgesia
Isoflurane
Sevoflurane
Desflurane
Increased conductance of
GABA ion channels
Agonism of glycine receptors
Blockade of T-type Ca2+
channels
Inactivation of fast Na2+
Induction in peds
Maintenance (preferred agents)
Tx status asthmaticus
status epilepticus (use volatile agents, not NO2)
Neuroprotection
Increased ICP
Increased cerebral oxygen demand
Emergence delirium
Increased sympathetic outflow
Increased myocardial oxygen
demand
Bronchodilation
Increased respiratory secretion
NO respiratory depression
Cerebral vasodilation (increased ICP)
Decreased cerebral oxygen demand
Stable BP with increased CO
Decreased SVR
Decreased cardiac contractility
Kinetics of onset and
emergence:
Determined by gas
partition coefficient
(solubility in plasma)
channels
No effect of APs
Activation of tandem-pore K+
channels → hyperpolarization
Nitrous Oxide
NO2: Blockade of NMDA
receptor
Reflex tachycardia
Respiratory depression
Bronchodilation
Mucociliary paralysis
Airway irritation and bronchospasm
Maintenance (preferred agents)
Malignant hyperthermia: myolysis,
hyperkalemia, hyperthermia, acidosis,
renal failure, tetany
Tx with dantrolene
Inconsistent hypnosis and amnesia
Must be given at 105% MAC (1.05
atm) for EC50
NO significant CV effects
Increased PVR
Expansion of pneumothorax or bowel
lumen
With chronic exposure
Oxidation of cobalt complexed with
B12 → homocysteinemia
(atherosclerosis), sabacute comined
degeneration (SCD) and neuroligc
deficits , megaloblastic anemia
LOCAL ANESTHETICS
General Features
STRUCTURE
Hydrophobic pole with aromatic ring
Hydrophilic pole (typically tertiary amine): required to bind to the Na+ channel from the cytoplasmic side
Ester or Amide linkage
Ester: degraded by plasma cholinesterases → amine + PABA (or derivative)
PABA compounds may result in anaphylactoid reaction
NO2 > Desflurane >
Sevoflurane > Isoflurane
Aminde: CYP1A2 and CYP3A4 N-de-alkylation, hydrolysis, hydroxylation
CHEMISTRY
Tertiary amines are weak bases: mainly protonated at pH 7.4
Lower pKa → faster onset due to ability to diffuse across membrane
Increase rate of action: lower pKa, infusion with sodium bicarbonate
Decrease rate of action: higher pKa, injection into inflamed and acidotic tissue
KINETICS
Fast onset: Cocaine, Benzocaine, Lidocain, Mepivicaine, Prilocaine
Slow onset: Prociaine
Open channel conformation → increased binding : use-dependent block
MECHANISM
Block fast Na+ channel ion pore from intracellular side
Binds to Domain IV, α-helix S6
Must be reprotonated in the cytoplasm to have activity
Binding → stabilize inactive state → prevent AP propagation
At low concentrations : selectively blocks small axons (sensory) with sparing of motor function
BLOCK TYPES
Topical block: affects sensory nerve endings
Subcutaneous infiltration (field block): minor procedures (IV insertion, suturing)
Peripheral nerve block: anesthesia in territory of nerve
Bier block (intravenous regional): exsanguinations of arm → occlude arterial flow → infusion of dilute lidocaine → reperfusion
Neuraxial block: epidural and subarachnoid; results in anesthesia of all caudal spinal roots
ABSORPTION
Typically coformulated with epinephrine → local vasoconstriction at site of entry → local concentration and reduced systemic absorption
Rate of absorption determine by regional perfusion: intercostals > epidural > brachial plexus > subcutaneous
Bound by albumin and α1 acid glycoprotein
GENERAL TOXICITY
A farily stereotyped progression of symptoms
CNS: sedation → excitation → circumoral paresthesias + tinnitus → NV, tremor, seizure → respiratory depression
CLINICAL INDICATIONS
Topical: cocaine, tetracaine (eye drops), benzocaine, prilocaine, lidocaine, EMLA
Bolus Spinal Blocks: procaine, lidocaine (intraoperative),
Continuous Spinal Block: bepuvicaine, ropivacaine
Subcutaneous Infiltration: lidocaine, mepivacaine, bepuvacaine, ropivacaine
Peripheral Nerve Block: same as SC
IV cardioversion and anesthesia: lidocaine
Beir Block: lidocaine
LOCAL TOXICITIES
Methemoglobinemia: benzocaine, prilocaine
Occurs in presence of oxidative drugs
Neurotoxicity (Cauda Equina Syndrome, Transient Radicular Irritation): lidocaine
Cardiac toxicity (arrhythmias): bepuvacaine
Ester-linked agent
Topical: oral, nasal, pharyngeal mucosa
Cocaine
Vasoconstriction to confine other drugs
(intraoperative)
Spinal block (short duration)
Procaine
Eye drops: corneal and conjunctival anesthesia
Spinal block
Topical only on mucosa
Ear drops
Tetracaine
Benzocaine
Motor > sensory blockade
Methemoglobinemia
Oxidizes heme iron
Results in hypoxemia
Symptomatic with metHb > 35%
Typically occurs in presence of
mutiple oxidative drugs (e.g.
sulfonamides, nitrates)
Reverse with methylene blue
(reduces metHb)
Onset is slow since Benzocaine and
Prilocaine are only used topically
Lidocaine
Amide-linked agent
Suppress ventricular tachycardia
Adjunct to general anesthesia
Transdermal patch
Neurotoxicity with intrathecal blocks:
Cauda Equina Syndrome
Transient radicular irritaition
SC Block
PN Block
Beir Block
Intraoperative neuraxial block
SC Block
PN Block
Mepivacine
SC Block
PN Block
Continuous epidural block (chronic pain)
SC Block
PN Block
Continuous epidural block (chronic pain)
Topical in coformulation with lidocaine (EMLA)
Bupivacaine
Ropivacaine
Prilocaine
EMLA
Eutectic Mixture of Local
Anesthetics
Topical cream
Transdermal patch
2.5% Prilocaine + 2.5%
lidocaine
Lowered melting point → increased absorption
Severe cardiac toxicity
Results in terminal ventricular
arrhythmias
Methemoglobinemia
SEDATIVE and HYPNOTIC DRUGS
Lorazepam
Benzodiazepines
Diazepam
Bind to allosteric site on
GABA(A) receptors and
potentiate Cl- conductance
with GABA binding
Oxazepam
Alprazolam
Clonazepam
DO NOT prolong the open
state of the channel
This is the mechanism of
barbiturates
Require γ subunit in GABA
receptor for BZ binding
AND
α2 subunit for anxiolytic effect
DOC: Acute attacks with GAD
Panic disorders
Sedation prior to invasive procedures
Tx transient anxiety with initiation of antidepressant
therapy
May be used for insomnia
Adjuncts for Tx of epilepsy
IV diazepam for termination of status epilepticus
Tx alcohol withdrawal
Tapered dose regimine
Daytime sedation
Ataxia
Memory dysfunction
Paradoxical hostility and rage
Fatal interaction with EtOH
Teratogenicity (Risk D)
Tolerance
Develops to sedative effect
NOT developed to anxiolytic effect
Dependence
Withdrawal symptoms (anxiety,
anorexia, seizures)
Addiction
Immediate onset
Extensive binding to plasma
albumin
Metabolism: hepatic
conjugation and renal
elimination
De-alkylated metabolites
have longer half-lives IF
NOT HYDROXYLATED
DOE NOT require the α1
subunit
Flumezenil
Zolpidem
Zaleplon
Eszoplicopne
Ramelteon
GABA receptor antagonist
Non-benzodiazapine Receptor
Agonists
NBRAs
PHYSIOLOGIC EFFECTS
Sedation
Hypnosis
Amneisa
Anyiolytic activity
Muscle relaxation
Anticonvulsant
Reverse effects of Bz
Overdose
Post-interventional
Hypnosis
May be used to treat chronic insomnia
Bind to distinct site on GABA
receptor from Bz
Require the α1 subunit
Require γ subunit for binding
Melatonin receptor agonist
This is RARE, and is highly
associated with history of
substance abuse (in particular,
EtOH).
May result in panic attacks and
convulsion if pt is dependent
Interactions with EtOH: motor
impairment, respiratory depression
Hepatic metabolism and
renal elimination
Tolerance and Dependence
Less than with Bz
No active metabolites!
Tx: Onset insomnia
Buspirone
Partial agonist of serotonin (5HT 1A) receptors
GAD
SSRIs (general)
Inhibit serotonin reuptake by
presynaptic neuron
DOC for GAD and other anxiety disorders
Not a ‘controlled substance’
No sedation
No anticonvulsant or relaxant activity
No EtOH interaction
No dependence or addition
Serotonin Syndrome
Initial provocation of anxiety
GI: ND
SSRI withdrawal syndrome: flu-like
symptoms
Occurs with abrupt discontinuation
Serotonin Syndrome
Altered mental status,
hypertonicity, autonomic
Slow onset (2 – 4 wrks)
Slow onset (2 – 6 wrks)
dysfunction
Occur with SSRI is combined with
MAO inhibitor (inhibits metabolism)
ANTIEPILEPTIC DRUGS
General Features
CLINICAL USES
Primary Tonic-Clonic: phenytoin, valproate, carbamezapine
Partial with Secondary Generalization: phenytoin, Lamotrigine, Oxcarbazepine (metabolite of carbamazepine)
Absence: ethosuximide, valproate
Atypical absence, Atonic: valproate
Status Epilepticus: Lorezepam + Fosphenytoin
GENERAL TOXICITIES
CNS: sedation, dizziness, ataxia, blurred vision, some cognitive dysfunction
Teratogenicity: associated mainly with the first-generation drugs
Phenytoin
First-Generation Agents
Primary tonic-clonic
Partial with secondary generalization
Maintenance after termination of status epilepticus
Gingival hypertrophy
Hirsutism
Hypersensitivty
Osteomalacia + hypocalcemia
Inhibits VitD absorption
Folate deficiency
VitK deficiency
Valproic Acid
Prolong Na+ Inactivation
Phenytoin, carbamezapine,
valporate
Absence seizure
Myoclonus, atonic seizure, atypical absence
Teratogenicity
Blood dyscrasias: aplastic anemia,
neutropenia, thrombocytopenia
Weight gain
GI distress
Tremor
Decrease T-type Ca2+
conductance
Ethosuximide, valproate
Spina Bifida
Partial with secondary generalization
Blood dyscrasias: aplastic anemia,
neutropenia, thrombocytopenia
Phenobarbital
Maintenance after termination of status epilepticus
Teratogenicity
Teratogenicity
Ethosuxamide
Absence seizure
Involves abnormalities in T-type Ca2+ conductance
Carbamezapine
Potentiate GABA inhibition
Clonazepam, diazepam,
lorezepam, Phenobarbital
Termination of status epileptics
Must be followed by maintenance therapy
(Fosphenytoin)
Clonazepam
Diazepam
Lorazepam
GABApentin
Pregabelin
Second-Generation Agents
Typically used as second-line drugs for Tx of seizures
Prolong Na+ Inactivation
Lamotrigine, topiramate
Pregabelin: fibromyalgia, neuropathic pain, GAD
GABApentin: GAD
Decrease Glutamate Release
GABApentin, pregabelin
Lamotrigine
Topiramate
Lamotrigine is a DOC for Partial and Secondarily
Generalized seizures
Bind to presynaptic α2δ
domain of voltage-dependent
Ca2+ channel → decreased
secretion of excitatory
transmitters
Drug interactions via
occupation of CYP450
Decreases plasma halflife of other drugs
(including itself)
Teratogenicity
Tolerance
Dependence
Do not undergo
metabolism
Withdrawal syndrome
Circulate unbound to
plasma proteins
Renal elimination
Rash
Toxic Epidermal Necrolysis
ANTIDEPRESSANTS
General Features
ALL increase synaptic concentrations of monoamines (5-HT, NE)
Requires 2 – 6 wks of therapy for onset of effects
Proposed Mechansim
Increased synaptic NT → increased cAMP → activation of cAMP Response Element Binding Protein → upregulation of p11 → increased 5-HT1B expression and transport
METABOLISM
Converted to active metabolites by CYP450
→ conjugated with glucuronate
→ demethylated to metabolite with longer half-life
DOC for GAD: SSRIs + initial benzodiazapines + Buspirone
DOC for neuropathic pain: venlafaxine, duloxetine are used for diabetic polyneuropthy ; duloxetine, milnicipran for other chronic neurapthic pain
DOC for fibromyalgia: pregabelin, duloxetine, milnicipran
DOC for insomnia : atypical antidepressant (trazadone)
CI: Bipolar depressive episode (may actually provoke mania)
TOXICITIES
ALL: mania in BP II
SSRIs: initial anxiety, GI distress, weight gain, serotonin syndrome, SSRI discontinuation syndrome, teratogenicity
Tricyclics: overdose fatality, muscarinic block (urinary retention, confusion, loss of visual acuity, xerostomia), adrenergic block (arrhythmias), sedation
MAOIs: hypertensive crisis, interaction with SNRIs (hypertension) and SSRIs (serotonin syndrome)
Fluoxetine
Sertraline
Paroxetine
SSRI
Selectively inhibit the
reuptake of 5-HT into
presynaptic neuron terminals
DOC for treatment of GAD, MDD, PTSD, Panic
Disorder, Eating Disorders
Escitalopram
Initial anxiety
Insomnia
Tremor
GI distress
Weight gain
Serotonin Syndrome
Hypothermia, tetany, myoclonus,
mental status changes, autonomic
dysfunction
Citalopram
SSRI Discontinuation Syndrome
Least likely with fluoxetine due to
long half-life
Venlafaxine
Duloxetine
SNRI
Selectively inhibit the
reuptake of 5-HT and NE into
presynaptic neuron terminals
BUT no other receptor cross-
Second-line for treatment of MDD
Fibromyalgia: duloxetine, milnicipran (also
pregabelin)
Diabetic Polyneuropathy: venlafaxine, duloxetine
Teratogenicity
GI distress
Insomnia
Agitation
Nausea
Sedation
reactivity
Xerostomia, Constipation
Desvenlafaxine
Milnacipran
Phenelzine
Tranylcypromine
MAO Inhibitors
Inhibit oxidation of
monoamines
Selegiline
Headache
Xerostomia
Postural Hypotension
Malignant Hypertensive Crisis
Occurs with intake of tyramine
(converted to tyrosine and shunted
into the monamine synthesis
pathway)
Can only initiated > 2 wks
after discontinuation of SSRIs
May result in serotonin
syndrome
(> 5 wks for fluoxetine
due to long half-life)
Serotonin Syndrome
With concurrent or recent SSRI
therapy
Bupropion
Atypical Antidepressants
Inhibit the reuptake of 5-HT
and NE into presynaptic
neuron terminals
BUT Non-tricyclic structure
Tricyclic Antidepressants
Inhibit the reuptake of 5-HT
and NE into presynaptic
neuron terminals
Trazodone: Insomnia
Dizziness
Xerostomia
Sweating, tremor
Aggrevated psychosis
High-dose: seizures
Mirtazapine
Nefazodone
Trazodone
Amitriptyline
Desipramine
Impramine
Nortriptyline
Blockade of diverse receptors
H1, α1, muscarinic
Overdose Toxicity
Shock, respiratory depression,
agitation, delirium, hyperpyrexia,
conduction block, arrhythmias
Muscarinic Blockade
Xerostomia, cycloplegia, urinary
retention, confusion
Amitritptyline → Nortriptyline
Imapramine → Desipramine
Adrenergic Blockade
Orthostatic hypotension, QT
prolongation, cardiac arrhythmias
Histaminergic Agonism
Sedation
Amphetamines
Hypericin
DOC if MDD is refractory to standard therapy
No FDA approval
No demonstrated efficacy
Increases CYP3A4 activity
Thus, may result in
significant drug interactions
MOOD STABILIZERS : TREATMENT of BIPOLAR DISORDER
General Features
ACUTE MANIA
Initiate with atypical antipsychotic
Elaborate therapy with moos stabilizer (lithium, antiepileptic) when oral compliance is assured
Lithium
+ Valproate + Atypical Antipsychotic (aripiprazole, olanzapine)
BIPOLAR DEPRESSION
Any antidepressant. SSRIs preferred.
MAINTENANCE
Lithium + Anti-Epileptic (valproate)
DO NOT use antidepressant monotherapy
TOXICITY
Lithium: hypothyroidism, neurogenic myopathy, fine fremor, GI distress, nephrogenic DI, weight gain, arrhythmias, hypotension
Acute intoxication, sever neurologic toxicity, drug interactions, teratogenicity
Atypical Antipsychotics: DM II, weight gain, hyperprolactinemia, prolonged QT (adrenergic block), dyslipemia
DOC: Bipolar Disorder (I and II)
No psychotropic effects in NML
Lithium
Decreases expression of ANK3
subjects
and CACNA1C
Suppresses acute manic episodes
ANK3: regulates formation
Use in maintenance
Thyromegaly
and insertion of neuronal
Use with advent antidepressant or antipsychotic for
(indicates dysfunctional synthesis
Na+ channels
acute MDE
of thyroxine)
Acute Mania: 0.8 – 1.2 mEq/L
Maintenance: 0.6 – 0.8 mEq/L
Onset within 2 wks
Not metabolized
CACNA1C: subunit of
neuronal calcium channel
(Hypothyroidism)
Some insulin-like effects
Neurologic: muscle fatigue,
lethargy, fine tremor
WITH SEVERE NEUROTOXICITY
Confusion, hyperreflexia, gross
tremor, dysarthria, seizures,
focal signs, CN deficits
Increases monoamine
metabolism (deamination)
Suppresses DA receptor
transduction
Increases BCL-2 levels within
neurons
This is neuroprotective (aniapoptotic)
GI: anorexia, NV
Renal: Nephrogenic DI, RTA,
albuminuria
CV: cardiac arrhythmias,
hypotension
Drug Interactions:
Thiazides, loop diuretics, NSAIDs,
ARBs, ACE inhibitors
Acute intoxication: vomiting,
diarrhea, coarse tremor, ataxia,
convulsions, coma
Acute minor toxicity: GI distress,
sedation, fine tremor
Teratogenic: congenital cardiac
defects
Aripiprazole
Olanzapine
Quetiapine
Atypical antipsychotic agents
DOC as adjunct to Lithium in acute mania (with oral
compliance)
Renal elimination with 80%
reabsorbed in the PCT
Carbamezapine
Lamotrigine
Valproate
DEMENTIA
General Features
Treatment recommendation: AchE inhibitor + VitE
Only approved for patients with limited and moderate dementia
These drugs delay progression of cognitive decline
Improve QoL, cognitive function, agitation
ELEMENTS in the PATHOGENESIS of AD
Hippocampal →cortical degeneration of neurons
ACh depletion
Aβ: perivascular deposition and within neurotic plaques
May be generated by mutations in APP (Ala692Gly and Val717X) → results in abnormal proteolysis and formation of Aβ42
Neurofibrillary tangles
Abnormal tau and microtubule filaments
ApoE4 → decreased plaque solubility
ERAB
Elevated plasma homocysteine
May be reduced by B12, B6, and folate supplementation
Glutamate
Basis of therapy with memantidine
AChE
Donepezil
AchE inhibitors
Rivastigmine is a semiirreversible inhibitor
(carboymylates the active site
of AchE)
DOC for cognitive sparing in AD
Peripheral ARs due to excess
cholinergic signaling:
Nausea, diarrhea
Bradycardia
CI: GI bleeding
Selective for CNS isoform of
AChE
Second-line in treatment of AD
Rivastigmine
Donepezil and Galantamine
are reversible inhibitors
CNS: dizziness, headache, sedation,
tremor
Prominent PNS cholinergic effects:
NVD, abdominal pain, anorexia
Weight loss
Exacerbate peptic ulcer disease
Bradycardia
Urinary obstruction
Bronchoconstriction
Intake with meals (increases
absorption)
However, peak plasma
concentrations are
decreased
CI: GI bleeding
Second-line in treatment of AD
Galantamine
NVD, anorexia
Weight loss
Bronchoconstriction
CI: GI bleeding, hepatic or renal
impairment
Memantine
NMDA receptor antagonist
May actually result in symptom improvement
Decreases glutamate
neurotransmission →
protection of neurons from
cytotoxic influx of Ca2+
CI: renal failure
Allows appropriate influx with
high synaptic concentrations
of glutamate
Thus, blocks the tonic
pathological glutamate
release
ANTIPSYCHOTICS
General Features
PHARMACOLOGY
Ramped dosing
All drugs are highly lipid-soluble with large Vd
Thus, plasma levels do not correlate with therapeutic effect or toxicity
Parenteral depot forms: fluphenazine, haloperidol, resperidone
Rapid IM form: ziprasidone
METABOLISM
Extensive transformation and slow elimination (may have slow reemergence of symptoms)
Renal elimination of glucuronidated metabolite
CLINICAL EFFECT
Typical: reduce positive psychotic symptoms (delusions, hallucinations). No effect on negative symptoms.
Atypical: recue positive and negative symptoms. May be used in Bipolar manic and depressive episodes.
ADVERSE EFFECTS
Typicals: higher incidence of EPS, hyperprolactinemia
Atypical: weight gain, dyslipidemia, DMII
Shared: autonomic effects
Aripiprazole: partial agonist activity at D2 (thus, must be used at sufficiency high doses for antagonism)
Clozapine, Olanzapine: avid anti-muscarinic activity, also most extreme weight gain
Ziprasidone, Aripiprazole: least weight gain
Chlorpromazine
Typical Antipsychotics
(‘Neuroleptics’)
Fluphenazine
Perphenazine
Thiothixene
Trifluoperazine
Blockade of D2 > 5-HT2
receptors
Therapeutic effect derived
from DA antagonism in the
mesocorticolimbic pathway!
Haloperidol
Clozapine
Atypical Antipsychotics
Olanzapine
Blockade of 5-HT2 > D2
receptors
(There is still significant
Risperidone
DOC for active and residual
schizophrenia
DOC for bipolar mania
Adjuvant in bipolar MDE
ARs mainly ASSOCIATED WITH TYPICALS
High affinity for 5-HT2A
Nigostriatal Blockade
EPS: Parkinsonism, Acute Dystonia, Akatheisia,
Neuroleptic Malignant Syndrome, Perioral
Tremor, Tardive Duskinesia
IM depot formulation:
fluphenzine decanoate
Tubuloinfundibular Blockade
Hyperprolactinemia
Females: Amenorrhea,
galactoerhea, infertility
Males: decreased libido,
impotence, infertility
This is seen with ALL typical drugs
Also seen with atypical Respiridone
IM depot formulation:
haloperidol decanoate
Must track CBCs weekly
IM depot formulation
Quetiapine
Ziprazidone
activity at D2)
May be used in elderly patients with
dementia and psychosis
BUT increased mortality
Aripiprazole
Palperidone
Prochlorperazine
Tardive Dyskinesia
(This is actually an EPS)
Presents as oral and facial dyskinesia
Dysphagia, chocking, dysarthria, dyspnea
May also involve generalized dystonia or
choreoathetosis
Occurs with long-term therapy with typical
antipsychotics
Due to upregulated D2 receptors: increased
sensitivity
Thus, discontinuation of therapy may
exacerbate symptoms
Antiemetic only
Jaundice and blood dyscrasias
Toxic and Allergic Dermatitis
ARs mainly ASSOCIATED with BOTH CLASSES
Adrenergic Blockade
Orthostatic hypotension, urinary
retention, sexual dysfunction
Muscarinic Blockade
CNS: confusion, delirium
Seen with clozapine, olanzapine
H1 Blockade
Results In sedation
Seizures
Agonist at 5-HT1A
Rapid IM formulation
Agonist at 5-HT1A
Partial agonist at D2
Primary metabolite of
resperidone
This is a controlled release
system
Typicals: chlorpromazine
Atypicals: clozepine
Neuroleptic Malignant Syndrome
Hyperthermia, hypertonia, stupor, fluctuating BP
Distinguish from malignant hyperthermia
No responsive to dantrolene
Cardiac Toxicity
Increased risk of ventricular arrhythmia due to
prolonged QT interval
Agranulocytosis: clozapine
ARs ASSOCIATED WITH ATYPICALS
Weight Gain
Seen with olanzapine and clozapine
Glucose Intolerance and Insulin Resistance
Highest incidence with clozapine
Hyperlipidemia
Probably due to weight gain
Increased mortality in elderly with psychotic
dementia
STIMULANTS
General Features
Only approved for TX of ADHD and narcolepsy
These are distinct from antidepressants: cause generalized excitation due to effects on DA and NE
Related to atypical (heterocyclic) antidepressants (e..g Bupropion)
BUT not used to TX MDD
Atomoxetine: NRI; nonstimulant
Modafinil: non-amphetamine stimulant
Actually inhibits neurons in the VLPO ; some action at DAT and NET
Methyphenydate: equivalent to amphetamine
Amphetamine stimulant
TX: ADHD, narcolepsy
Amphetamine
Many ARs due to sympathetic
stimulation
S:R isomers in 3:1 formulation
Inhibits NE, DA, and 5-HT
reuptake
AND
Stimulates release of all
monoamines
Elevated mood
Increase wakefulness
Increase concentration
Decreased fatigue
Anorectic effect
Potentiates analgesic effect of opioids
CNS: insomnia, agitation,
effusiveness, psychosis
CV: arrhythmias, angina (increased
myocardial contractility), HTN
Metabolism via MAO and CYP
Urinary elimination is
sensitive to pH
Weight loss
Overdose Toxicity: confusion,
psychosis, HTN, palpitations,
convuslions
Mortality due to cerebral
Hemorrhage
TX: phentolamine (adrenergic
blocker; reduces BP), diazepam
(control seizures), acidification of
urine
Withdrawal: avolution, abulia,
depression
CI: anxiety, anorexia nervosa,
psychosis, CAD, HTN,
arteriosclerosis, MAOIs,
hyperthyroidism, glaucoma
Atomoxetine
Non-stimulant
TX: ADHD only
Selective NE reuptake
inhibitor (NRI)
No potential for abuse
Typically no ARs at low doses
May have increased risk of SI
Cocaine
Methamphetamine
Topical formulation for local anesthesia
Slow onset (1 – 3 wks)
Modafinil
Methylphenidate
Non-amphetamine stimulant
Used to increase wakefulness
Acts on circadian structures of
the hypothalamus
Inhibits the VLPO (via
blockade of NE reuptake)
TX: narcolepsy, shift-work sleep disorder, and OSA
Off-label: ADHD, depression, fatigue (occupational,
chemotherapy), AD
Binds to DA and NE reuptake
transporters
BUT action is not antagonized
by haloperidol
Stimulant
Equivalent to amphetamine
Headache
Nausea
Diarrhea
Anxiety
CI: peds, MAOIs, hepatic failure
TX: ADHD, narcolepsy
This is the most commonly used medication in
pediatric ADHD
Available in three different
formulations with varying
kinetics
HALLUCINOGENS
Lysergic Acid
Diethylamide (LSD)
Partial agonist at 5-HT
Produces the psychedelic experience
Activity at other monoamine
receptors
Physiologic effects: mydriasis, HTN,
tachycardia, flushing, hyperreflexia
(Requires ≤ 50 µg for effects)
Tachyphylaxis: rapid tolerance
Cross-tolerance with LSD,
psilocybin, and mescaline
NO physical dependence
Psychosis
Psilocybin
Partial agonist at 5-HT2A
Mescaline
receptors
Found in peyote
Partial agonist at 5-HT2A
receptors
High potency
Produces the psychedelic experience
Virtually equivalent to LSD, but less potent
Weak hallucinogen
Used to normalize and quantitate psychedelic
activity of other drugs
Used in NAC and two native groups in Mexico
NV
Tolerance develops with
repeated use
MDMA
This is actually a derivative of
mescaline
Entactogen
‘Ecstacy’
N-methyl derivative of MDA
Produces a unique psychological state:
Empathy, openness, acceptance
Previously used in psychotherapy
Neurotoxicity
With repeated dosing: depletion of
CNS serotonin
Causes degeneration of
serotonergic axon terminals
May be prevented by pretreatment
with SSRIs
Blocks reuptake of 5-HT, DA,
and NE
Increases release of 5-HT, DA,
NE
Requires monoamine
transporters to enter the
neuron
Direct agonism at 5-HT2A
Marijuana
Exogenous cannabanoid
Bind to CNS CB1 and CB2
receptors
Subjective effects: euphoria, sedation, visual and
auditory hypersensitivity, tactile enhancement,
increased appetite
Impairment of STM
Depersonalization
Hallucinations, paranoia, anxiety
TX: pain, antiemetic in pts undergoing chemotherapy
CV: tachycardia, vasodilation
(conjunctival eythema, orthostatic
hypotension)
Glaucoma (lowers IOP)
Muscle spasms
Insomnia
Antipyretic
May slow progression of AD: inhibits amyloid plaque
formation
Respiratory: bronchodilation
(acute) and bronchoconstriction
(chronic), lung carcinoma
No physical dependence seen with
moderate use

T s e n

Transcription

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