Routes of Drug Administration
Topical (Percutaneous)
Rectal or Vaginal
Pulmonal
Parenteral
Types of Orally Administered Drugs / Pills (single dose)
Tablets
Coated Tablets (shell)
Matrix Tablets (carrier meshwork)
Capsules (gelatin shell)
Troches/Lozenges
Solutions
Percutaneous Drug Administration / Ointment + Lipophilic cream
Paste
Lotion
Gels
Can be single or multilayer, or contained in a reservoir
Other Topicals / Eye Drops
Nose Drops
Pulmonary Formulations
Suppositories
Parenteral Drug Administration / Ampules
Vials
Cartridge Ampules
Infusions
Advantage: 100% Absorption, enters circulation without hepatic elim, better bioavailability of hydrophilic drugs
Types of Barriers for Drug Distribution/Absorption / External Absorption Barriers: (epithelial layer on skin, lung, intestine—Lipophilic barrier)
Internal Blood-Tissue Barriers: Cardiac muscle, endocrine glands, gut, liver, CNS
Drug Distribution / Passive Diffusion
Active Transport
Receptor-mediated Endocytosis
[DRUG] IS A FUNCTION OF ABSORBTION AND ELIMINATION!
Bioavailability / The AUC of the administered drug divided by the AUC of the intraveneously administered drug
IV>TD>IM=SC>Rectal>Oral=Inhal
Volume of Distribution
Rate of Elimination / Vd=Amt of drug in the mody/[drug]
R of E: Via kidney (filtration) or liver (metabolism)
Usually first order kinetics
3 drugs have zero-order kinetics
Clearance / Rate of Elim/[Drug]
Rate of Elim= k*Cp*Vd
K= ln2/T ½
CL= K*Vd
Phase I Reactions / Convert parent compound into more polar metabolite
Add/unmask functional group:
OH, SH, NH2, COOH, etc
Oxidation, Reduction, hydrolytic cleavage, Alkylation, Dealkylation, etc…
Phase II Reactions / Conjugation with endogenous substrate (increase aq solubility)
Conjugation with gucoronide, sulfate, acetate, amino acid
MFO
Mixed Function Oxidases / Require reducing agent and molecular oxygen
Two enzymes: 1) Flavoprotein, NADPH-cytochrome c reductase
2) Cytochrome P450 (electron acceptor); CYP
P450 Enzymes / PPAR ligands, CYP1, CYP2E, CYP2B
Polymorphisms cause changes in drug metab: CYP2C19, CYP2B, CYP2D6
Induction of P450 enzymes=metabolize drug
Conjugation Reactions / Glucoronidation
Sulfation
Acetylation
Amino acid Conj
Glutathione Conj
Fatty acid Conj
Condensation Reaction
Monoamine Oxidases (MAO) / Catalyze oxidative deamination of endogenous catecholamines (epinephrine)
Lacated in never terminals and peripheral tissues
Many drug/food interactions! (cheese, wine)
Inhib by MAO inhib
Therapeutic Index / Maximum non-toxic dose/Min effective dose
Doesn’t take into account variability btw indivs
LD50/ED50
Agonist / Can be drugs or endogenous ligands for the receptor
Increasing [agonist] will produce increase in biological response
Full:evokes 100% max possible effect
Partial: not 100%
Antagonist / Block or reverse effect of agonist
No effect on their own
Competitive, Non-competitive, inverse agonist (triggers neg response)
Four major drug targets / Receptor
Enzyme
Ion Channel
Transporter
Ca++ as a Second Messenger / Regulates many cellular and phys. Responses
Gradient btw extracellular and intracellular (high:low) creates many opportunities for regulation
Stored in ER and other
Ca Channels / Voltage mediated: L, N, T
Ligand gated
Store operated
Sesnsors: Annexins, EF-hand proteins, Calmodulin, ProponinC
Target of many drugs!
G-Protein-coupled Receptors / GPCR: transmembrane
Bind GTP and GDP
GAPS, GEFS, RGSs important in this regulation
Main Targets: Phospholipase C, Adenylate cyclase
G-Proteins / G-Proteins: Guanine nucleotide binding proteins
2 groups:
Small GTP binding
Heterotrimeric G proteins
PKA / Target of cAMP
Four subunits (2 reg, 2 catalytic)
Phosphorylates transcription factors ex: CREB
Regulation of Receptors / Heterologous desensitization (Incoming signal from different receptor)
Homologous desensitization (only occurs on receptor which has already been stimulated)
Nuclear Receptors
GC, Mineralcorticoids, Retinoids PPARs / Lipid soluble ligands that penetrate cell membrane, Receptors contain DNA-binding domains (transcriptional activators/suppressors)
Takes longer to act—requires penetration and protein synth first
Phospholipids
Phospholipases / Common fatty acid chain+glycerol backbone+phosphor-residue
PLA2 (reg through Ca++ and phos), PLC (Beta: Reg through GPCR, Gamma: EGFR or TCR, activated through tyrosine phosphorylation
Phospholipases… / DAG: membrane bound, acts as a substrate for PLA2
IP3: Ca++ regulated
Arachidonic Acid Metabolism / Eicosanoids: derivative of arachadonice acid
Rapidly metab by COX into PG and LTs
1st reaction: cyclic ring structure (COX), 2nd reaction: oxidation (Peroxidase)
Function of PGs / Vascular tone (relaxation, constriction)
Platelet agg (Inc and Dec)
Uterus tone (Inc)
Bronchial Muscle (Contriction, relaxation)
Gastric secretion (Inib), temp/pain
Leukotrienes / LTC4, D4 and E4 mediate allergic rxn (SRS-A)
Mediate anaphylactic shock, 10,000 more postent than histamine
Constricts bronchi, dilates bv
LTB4 strong chemattractant for macrophage
Nervous System / Divided into CNS and PNS
PNS div into Somatic and Autonomous
Auto: Sypmathetic and Parasympathetic
Cholinergic Receptors / Muscarinic Receptors: Heterotrimeric G protein coupled, CNS, gastric mucosa M1
Cardiac=M2, Glandular=M3
Nicotinic Receptors: Ion channel coupled Muscle type, Ganglion type, CNS type
Cholinomimetics=
Parasympathomimetics / Direct Parasympathomimetics: Affinity for M or N receptors (mimic Ach)
Inderect Parasympathometics: Inhibit activity of Achesterase (Ach increased)
To affect Paraympathetic…
To Treat associated diseases…. / 1. Mimic Input
2. Block Input
3. Promote Parasymp
4. Block Symp
Pilocarpine
Muscarine / Muscarinic Parasymp, does not activate N rec, treates glaucoma (local! Eyedrops)
Muscarine has no therapeutic application!
Carbamate
Quaternary Alcohols / Achestease Inhibitors, raise Ach
Physiostigmine (topical only)
Neostigmine
Edrophonium (diagnose Myasthenia Gravis)
Horny Goat Weed / AcCh-ase inhib
Acts as AcCh-ase inhib but active ingredient unkown
Indirect stimulation of M3 receptor (vascular), triggers NO production=vasodilation
Action similar to Viagra (dangerous)
Ogranophosphates
Nerve Gasses / AcCh-ase inhibitors (irreversible)
No medical application
Atropine
Hyoscine / Muscarinic Parasympathomimetic
Atropine (antagonist of cholinergic system): CNS stimulant, before anesth. Prevent hypersecretion of bronchial mucus, treats bradycardy..
Hyoscine=CNS depressant, antiemetic,
Nicotinic Parasympatholytics / Competitive Antagonists: Compete with AcCh for N rec, prevent depolarization, reversible
Agonists: Depolarizing blockers, AcCh mimetics not hydrolyzed by AcCh-ase, trigger a sustained depolarization, irreversible
Succinocholine/Suxamethonium / Dimeric AcCh, Acts as agonist like AcCh, not hydrolyzed by AcCh-ase (only plasma esterase)
Depolarization triggers muscle twitching initially,
Used for brief procedures
Transmitters in the Autonomic Nervous System / AcCh: Preganglionic, parasyathetic post ganglionic neurons
Norepinephrine: Most symp. Post ganglionic neurons (except sweat glands and renal arteries)
Epinephrine (adrenalin): Adrenal medulla--symp impulses (no gang)
Termination of (Nor)epinephrine action / Reuptake into presynaptic nerve ending
Catechol-O-methyltransferase
MAO
Presynaptic alpha 2 receptors
Adrenergic Receptors / Alpha1 (vasc smooth muscle)
Alpha 2 (presynaptic)
Beta 1 (Heart)
Beta 2 (repiratory, uterine SM cells)
Beta 3 (Adipocytes)
Tranylcypromine
Moclobemide / MAO-Inhibitors
Indirect Sympathicomimetics
Inhib of MAO causes increase in free Nor-Ep, in CNS NAO metab dopamine and serotonin (inhib=increase in happy hormones)
Ephedrine / Indirect Sympathicomimetics
Displace nor-E in storage vesicles=forced release of NorE
Dietary Supplements
Amphetamines
Methylphenidate
Fenfluramine
Metamphetamine / Indirect Sympathomimetics
Displace norE in storage vesicles, forced release, inhib NorE re-uptake and deg by MAO (TRIPPLE ACTION), Meth=ADD, Fen=Appetite suppressant, Meta=more lipophilic, depletes NorE
Epinephrine
Norepinephrine / Non-selective Agonists
Sympathomimetics
Ep: Activates alpha and beta rec
Blood pressure increase, dilates bronchii, vasopressor, Treat anaphylactic shock
NorE: alph receptors, increase BP, potent vasopressor
Methoxamine
Phenylephrine
Naphazoline
Oxymetazoline
Xylometazoline / Alpha1 selective agonist
Sympathomimetics
Methoxamine: treatment of hypotensive state
Phen: Local vasoconstrictor, nasal decongestant
Zoline=alpha 1
Clonidine
Guanfacine / Alpha 2 selective agonist
Produce sympatholytic effect, but sympathomimetics! Actviate presynaptic a-2 rec in cardiovascular control in the CNS
BP decrease
Dobutamine / B1-selective agonist, stimulate heart
Strgon inotropic effect, little chronotropic effect, short term treatment of impaired cardiac function
Metaproterenol
Albuterol
Formoterol / B2 selective agonist
Treat asthma, non-selective sympathomimetics
Differ in speed and onset, duration of action
Non-selective Blockers
Phentolamine / Indicated for pheocromocytoma.
Blocking α1 causes vasodilation; reducing BP
Blocking α2 removes inhibition, increasing NE action on β receptors à increasing HR and cardiac output
Prazosin, Terazosin, etc / Selective α1 Blocker
Indicated for hypertension and urinary retention.
Side effects: Reflex tachycardia and postural hypotension
Yohimibine / Selective α2 Blocker (sympathomimetic!)
Increases sympathetic outpout. Used for male sexual dysfunction and as a weight loss drug
Propranolol / Noncardioselective β blockers
1st gen. drug, cross reaction w/ β2 causes bronchoconstriction
Labetalol also blocks α1 receptors (strong antihypertensive drug)
same indications as cardioselective blockers
Metoprolol, Atenolol… / Cardioselective β blockers
Newer drugs are more β1 selective.
Indicated for angina pectoris, hypertension, cardiac dysrhythmias, myocardial infarction, heart failure, and stage fright (anxiolytic).
Potential targets of Antihypertensive drugs / CNS/ANS (decrease symp. tone)
Heart: decrease cardiac output
Veins: Dilate, decrease preload
Arterioles: dilate, decrease afterload
Kidneys: increase diuresis
Dihydropyridines:
Nifedipine, Nicardipine, Nimodipine… / Calcium channel blockers (antagonist)
Inhibit Ca entry into cells of arteries
Targets specifically L-type channels on VSMC, no cardiac effect
Can cause peripheral edema
Minoxidil / Potassium Channel Agonists
Increases membrane permeability to K+, K+ efflux causes membrane hyperpolarization, inhibiting voltage gated Ca2+ channels à relaxation of smooth muscles à vasodilation à reduces BP
Side effect: hair growth (Rogaine)
Nitroprusside / Vasodilator
Delivered thru iv only and is metabolized into NO which directly activates cGMP production à vasodilation, Rapid action!
(Caffeine & Viagra)
Hypertensive Emergencies!
Captopril
Enalapril
Benazepril
Lisinopril / ACE-Inhibitors, angiotensin I not converted into the active peptide (ATII), no aldosterone & ADH release à no fluid retention
-no sympathomimetic effects
-no vasoconstriction
Side effect – causes coughing
Losartan
Candesartan
etc… / Angiotensin II (ATII) Receptor Blocker
Inhibits the effect of AT II by blocking the receptor
usually used if patient cannot tolerate the cough caused by ACE inhibitors
Stable Angina
Unstable Angina
Variant Angina / Predictable episodes; usually during/after physical exertion or stress. Treatment: Nitrates & β-Blockers (Propranolol, etc.)
Chest pain unexpected and usually occurs at rest
Treatment: Nitrates
Chest pain almost always occurs at rest. Due to coronary artery spasm. Treatment: Calcium channel blockers (Nifedipine, etc…)
Nitroglycerine / Treats angina pectoris. Reduces cardiac workload (and its oxygen demand) by reducing venous return. Causes vasodilation primarily in veins. Oral, sublingual, IV, Buccal and Transdermal ROA
Do not combine w/ other vasodilators (Viagra)
Isosorbide-dinitrate
(ISDN)
Nitroprusside / More stable than nitroglycerine
Tolerance can occur, give lowest dose
Do NOT combine w/ other vasodilators
Promotes peripheral vasodilation.
IV only; rapid onset and short duration – allows for titration
Arrythmia Treatment
Class I / Sodium Channel Blockers
Slows depolarization phase of AP.
Procainamide – used for atrial & ventricular arrhythmias
Lidocaine – used for acute ventricular arrhythmias
Flecainide – used for chronic treatment of ventricular arrhythmias
Arrythmia Treatment
Class II / β-Blockers
Propranolol
used for tachycardia
Arrythmia Treatment
Class III: / Potassium Channel Blockers
Prolongs repolarization by blocking potassium efflux.
Bretylium & Amiodarone
used for intractable ventricular arrhythmias
Class IV:
Calcium Channel Blockers / Prolongs repolarization by blocking calcium influx
Verapamil – blocks both L & T Type calcium channels!
Blocking T Type channels à slows conduction
(Blocking L Type channels à coronary + arterial vasodilation)
Other Cardiac Arrythmia Drugs / Adenosine – for paroxysmal supraventricular tachycardia
Digoxin – atrial fibrillation
Epinephrine - bradycardia
Congestive Heart Failure / Inadequate contractility; ventricles unable to expel blood à rise in venous blood pressure. Caused by blocked coronary arteries, viral infections, hypertension, leaky heart vavles, myocardial infarction
Right sided failure – lower limb edema, Left sided failure – pulmonary edema & respiratory distress
Cardiac Glycosides
(Digoxin) / Slows heart rate and increases contractility.
Inhibits Na/K ATPase, leading to an increase intracellular Na+, Increased Na+ slows Na/Ca exchanger, leading to an increase intracellular Ca++. Low therapeutic index.
Potassium competes with digoxin in binding to Na/K ATPase
ACE inhibitors &
ATII antagonists
Captopril & Losartan / Reduces cardiac workload, inhibits vasoconstriction, inhibits sodium/fluid retention, inhibits NE release
Vasodilators / Nitrates: Nitroglycerine, etc. (review Nitrates notes)
Carbonic Anhydrase Inhibitors
Azetazolamide
Dorzolamide / Inhibits conversion of CO2 à (H+) + (HCO3-), blocking reabsorption of Na+
-Usually indicated for Glaucoma
Causes metabolic acidosis (lower HCO3-)
Loop Diuretics (high ceiling)
Furosemide
Torasemide / Inhibits Na+/K+/2Cl- symporter at ascending limb in the Loop of Henle; blocking Na, K, Cl reabsorption
most potent diuretic
for severe/moderate hypertension & edema
Causes hypokalemia
Thiazide Diuretics
Hydrochlorothiazide
Benzthiazide / Inhibits Na+/Cl- symporter at distal convoluted tube
Used for moderate hypertension & heart failure (edema)
Causes hypokalemia
Potassium-Sparring Diuretics
Spironolactone
Amiloride / Acts as distal portion of distal tube; enhances Na excretion & reduces K excretion
Spironolactone – aldosterone receptor antagonist (slow)
Amiloride – directly blocks Na/K channel (fast)
Used in combo w/ other diurectics
Osmotic Diuretics
Mannitol / Non-reabsorbable molecules that inhibit passive reabsorption of water (promoting water excretion w/ little Na excretion), does not cross blood-brain barrier, so water goes from brain to blood, Used to reduce intracranial pressure, IV only
Uricosuric Agents
Probenecid / Indicated for kidney stones and gouts.
Therapeutic dose: promotes excretion and inhibits reabsorption of uric acid
Sub-therapeutic dose: inhibits both excretion and reabsorption
Strongly inhibits penicillin excretion which is good if need long lasting penicillin performance
Weak Bases:
Aluminum Hydroxide
Magnesium Hydroxide
PeptoBismol, Tums / Neutralizes stomach acid.
Magnesium Hydroxide – causes diarrhea
Aluminum hydroxide – causes constipation
Often combined to reduce side effects of each
H2 Receptor Blockers:
Cimetidine
Ranitidine / Competitively inhibits binding of histamine to H2 receptors on parietal cells; reduces histamine stimulated gastric acid production
Proton Pump Inhibitors:
Omeprazole
Lansoprazole
Esomeprazole
Rabeprazole / Irreversible inhibition of H+/K+ ATPase in parietal cells
Only active at low pH (activity restricted to stomach)
Inhibits acid production for 1-2days
Does not neutralize acid in stomach, only prevents production
Mucosal Protective Agents:
Misoprostol
Sucralfate / Misoprostol: PGE analog; stimulates mucus and HCO3 production
Combined w/ NSAIDS
Sucralfate: stabilizes mucus to inhibit H+ diffusion, not absorbed
Antiemetic Drugs:
Potential Treatment Options / H1 Antagonists
Muscarinic receptor antagonists
Benzodiazepines
D2 antagonists
Cannabinoids
H1 Antagonists
Muscarinic Receptor Antagonists
Benzodiazepines / Diphenhydramine, Meclizine, etc
Blocks H1 (histamine) receptors competitively
Scopolamine (anticholernergic)
Lorazempam; potentiates effects of GABA in CNS