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Pharmacokinetics and pharmacodynamics

Pharmacokinetics Pharmacodynamics
How the drug moves through the body How the drug affects the body

Four steps of pharmacokinetics: Classification of a drug based on its effect:

1. Administration and absorption ● Agonist: mimics effects of an endogenous agonist
2. Distribution ○ Full: produces 100% of its effect
3. Metabolism ○ Partial: produces <100% of its effect
4. Clearance ● Antagonist: inhibits normal function of an endogenous agonist
○ Competitive: binds to the same site as an agonist
Elimination kinetics ○ Non-competitive: binds to a different site than the agonist
● Zero-order elimination: a certain amount of drug is eliminated per unit time, regardless of ● Inverse agonist: inhibits the activity of a receptor
concentration

● First-order elimination: a constant fraction of the drug is eliminated from the body over
time
Therapeutic-response curves: dose vs. response of patient
● ED50: effective dose where 50% of the population responded effectively
● TD50: toxic dose where 50% of the population had toxic side effects
● LD50: lethal dose where 50% of the population died

Half-life
The amount of time required to clear half of a drug’s active substance from the body
● In a zero-order reaction, the half-life depends on the initial concentration and rate constant
● In a first-order reaction, the half-life depends on the rate constant
○ Ex. drug has a half-life of 4 hours. Percent elimination follows this graph:

Effect of drug combinations

● Additive: combined effect of drugs will equal the sum of their individual effects
● Antagonistic: combined effect of drugs will diminish their individual effects
● Synergistic: combined effect of drugs will enhance their individual effects
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Local Anesthetics

Bind to voltage-gated sodium channels in nerve plasma membranes to inhibit nerve transmission

● Epinephrine in ASA 1 patient: 0.2 mg

Maximum dosages ● Epinephrine in cardiac patient: 0.04 mg
● Lidocaine with vasoconstrictor: 7 mg/kg
● Lidocaine without vasoconstrictor: 4.4 mg/kg

Drug Key facts

● Antihistamine
Diphenhydramine ● Can be used as local anesthetic

Amides

Metabolized in the liver

● Safest in children
Lidocaine ● Preferred anesthetic for inferior alveolar nerve blocks
● Adult dosing: 7 mg/kg
● Child dosing: 4.4 mg/kg

● Not safe for children

Bupivacaine ● Most cardiotoxic
● Longest duration of action
● Can be used at the end of an appointment to prolong anesthesia and pain control

Mepivacaine ● Typically does not contain epinephrine

● Short duration of action
● Typically used for infiltrations in pediatric patients to prevent lip biting

Articaine ● Additionally has one ester chain (can be metabolized in both the liver and plasma)
● Preferred anesthetic for local infiltrations

Prilocaine ● Risk for methemoglobinemia

Esters

Metabolized in the plasma*

*More allergenic due to PABA metabolites

● Vasoconstrictor
Cocaine ● Binds with high affinity to dopamine receptors in the central nervous system
● Enhances sympathetic effects: tachycardia, hypertension, and bronchodilation

Benzocaine ● Risk for methemoglobinemia

● Used as topical anesthetic
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Pharmacokinetics and pharmacodynamics of local anesthetics

● Lower tissue pH = ionized form of anesthetic (cannot enter cell membrane)

● Higher tissue pH = unionized form of anesthetic (can enter cell membrane)

Physiological change Resulting anesthetic property

Increased blood flow Shorter duration of action

Increased lipid solubility/hydrophobicity Increased potency

Longer duration of action

Increased protein binding Longer duration of action

Decreased tissue pH Relatively more ionized forms

Decreased efficacy

Decreased pKa Faster onset of action

Local anesthetic injections and techniques

Injection Key facts Area of numbness

● Highest failure rate

Inferior alveolar nerve (IAN) block ● Syringe positioned from
contralateral premolars

Buccal nerve block ● Usually completed in tandem

with IAN block

Mental nerve block

Incisive nerve block

● High risk of hematoma

Posterior superior alveolar nerve (PSA) block ● 25% chance of numbing MB
cusp of first molar

Anterior superior alveolar nerve (ASA) block

Middle superior alveolar nerve (MSA) block

Infraorbital block ● Combines ASA and MSA blocks

Greater palatine nerve block

Nasopalatine block ● Most painful injection

Local infiltration
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Bisphosphonates

Usage Drug Key facts

Etidronate ● Potency of 1x
● Used to treat Paget’s disease, osteoporosis,
hypercalcemia of malignancy Pamidronate ● Potency of 100x
● MOA: inhibit osteoclasts, trigger apoptosis of
osteoclasts and inhibit angiogenesis Alendronate ● Potency of 100-1,000x, oral administration
● Causes disruption of resorption process
Risedronate ● Potency of 1,000-10,000x

Zoledronate ● Potency of >10,000x, IV administration

Cardiovascular

Class Drug Key facts

Furosemide ● Loop diuretic

● Inhibits Na/K/Cl channels
● Side effects: hypokalemia, hearing loss, and interstitial nephritis
Diuretics
Anti-hypertensive Hydrochlorothiazide ● Thiazide diuretic
MOA: reduce blood volume and blood pressure by inhibiting ● Inhibits Na/Cl channels
reuptake of sodium and water ● Side effects: hypokalemia, headaches, dizziness, xerostomia, and arrhythmias

Spironolactone ● Potassium sparing diuretic

● Antagonizes aldosterone receptors
● Decreases renal reabsorption of sodium, leading to reduced blood pressure
● Side effect: hyperkalemia

Vasodilators Hydralazine ● Causes direct vasodilation of blood vessels

Anti-hypertensive

Verapamil ● Blocks calcium influx

● Causes vasodilation, decreases cardiac workload, and lowers blood pressure
Diltiazem ● Nifedipine is an L-type calcium channel blocker
Calcium channel blockers ● Side effect: gingival hyperplasia
Anti-hypertensive
Amlodipine

Nifedipine

Lisinopril ● Blocks angiotensin converting enzyme which converts angiotensin I into

angiotensin II
ACE inhibitors ● Causes vasodilation
Anti-hypertensive Captopril ● Contraindicated if the patient is long-term user of NSAIDs
-prils ● Side effects: dry cough, orthostatic hypotension, rash, angioedema
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Cardiovascular continued

Class Drug Key facts

Angiotensin receptor blockers (ARBs) Losartan ● Blocks the angiotensin receptor, which when active causes vasoconstriction
Anti-hypertensive ● If patient has side effects on ACE inhibitors, they are often prescribed an ARB
-sartans Valsartan instead

Nitroglycerin ● Used if patient is experiencing chest pain (angina)

Anti-anginal ● Releases nitric oxide and causes smooth muscle vasodilation in coronary arteries
to increase oxygen supply to the heart

Anti-congestive heart failure Digoxin ● Blocks Na/K ATPase

● Increases calcium influx and force of heart contraction

Metoprolol ● Selective beta-1 receptor antagonist

● Decreases heart rate and contraction strength
Beta-blockers
Used to treat angina, heart failure, arrhythmias, and to control blood pressure Propranolol ● Beta-1 and beta-2 receptor antagonist
● Decreases heart rate, contraction strength, inhibits RAAS, and causes
peripheral vasoconstriction
● Avoid in combination with epinephrine due to activation of alpha receptors,
leading to high blood pressure

Atorvastatin ● Reduces the liver’s production of cholesterol

● Inhibits HMG-CoA reductase
Statins Rosuvastatin ● Side effect: muscle pain, dark urine
Cholesterol-lowering drugs
-statin Fluvastatin

Pravastatin

Clopidogrel ● Metabolite binds to ADP receptors on platelets

Anti-platelet
Affect platelet function Aspirin ● Irreversibly inhibits COX-1
● Decreases synthesis of thromboxane (TxA2) on platelets

Warfarin ● Vitamin K antagonist

○ Decreases vitamin-K dependent factors II, VII, IX, and X
● INR (international normalized ratio) measures the effectiveness of warfarin
○ Higher INR = thinner blood; lower INR = thicker blood
○ Values of 2.0-3.0 are usually considered the effective therapeutic range
Anticoagulants ○ If combined with acetaminophen, INR may become elevated

Heparin ● Activates antithrombin to inactivate Xa and IIa

Dabigatran ● Reversibly inhibits thrombin (factor IIa)

Apixaban ● Reversibly inhibits factor Xa

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Rivaroxaban

Diabetes

Drug Key facts

Metformin ● Used to improve insulin sensitivity

● Increases glycolysis, increases peripheral glucose uptake, and inhibits glucagon
● Episodes of hypoglycemia present with hypotension, nausea, tachycardia, and possible loss of consciousness
● Side effects: vitamin B12 deficiency, gastrointestinal upset, and metallic taste

Glipizide ● Type of sulfonylurea

● Stimulates beta cells in pancreas to secrete insulin

Autonomic nervous system

Regulates the function of involuntary muscle (smooth & cardiac) and glands
Sympathetic: fight or flight
Parasympathetic: rest and digest
Most organs receive input from both sympathetic and parasympathetic systems

Class Drug Key facts

Pilocarpine ● Cholinergic muscarinic agonist, increases acetylcholine

● Stimulates salivary secretions
● Used to treat Sjogren’s syndrome
Parasympathetic agonists
Physostigmine ● Reversibly inhibits acetylcholinesterase, increases acetylcholine
● Stimulates salivary secretions
● Used to treat atropine overdose

Atropine ● Cholinergic muscarinic antagonist, decreases acetylcholine

● Decreases salivary secretions
Parasympathetic antagonists ● Used in emergencies to increase heart rate and to treat insecticide overdose

Pralidoxime ● Reactivates acetylcholinesterase

● Used to treat organophosphate insecticide poisoning

Epinephrine ● Adrenergic agonist

● Activates the sympathetic nervous system through all α and β receptors
● Avoid use in patients with uncontrolled hyperthyroidism to prevent hypertensive
crisis
Sympathetic agonists
Norepinephrine ● Adrenergic agonist
● Activates all α receptors and β-1 receptors

Albuterol ● Adrenergic agonist, resulting in bronchodilation

● Activates β-2 receptors
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● Used to treat asthma

Autonomic nervous system continued

Class Drug Key facts

Phentolamine ● Adrenergic antagonist

● Reverses soft tissue anesthesia
Sympathetic antagonists
Phenoxybenzamine ● α blocker
● Reverses the effects of epinephrine

Central nervous system and sedation

Drug Key facts

● Medicinally used to decrease nausea and vomiting, alleviate chronic pain, and decrease muscle spasms
Marijuana ● Delta-9-tetrahydrocannabinol (THC) is the main psychoactive chemical
● Associated with tachycardia, paranoia, and xerostomia

Methylphenidate ● Used to control symptoms of attention deficit hyperactivity disorder (ADHD)

● Methylphenidate (Ritalin®) is shorter acting than amphetamine/dextroamphetamine (Adderall®)
Amphetamine/dextroamphetamine ● Side effects: tachycardia, nervousness, weight loss, xerostomia, and sweating

Propofol ● Sedative
● Used for general anesthesia and IV sedation

● Blocks DOPA decarboxylase

Carbidopa ● Allows L-DOPA to cross the blood brain barrier
● Used to manage Parkinson’s disease

Class Drug Key facts

Haloperidol ● D2R antagonist

● Used to treat schizophrenia
Phenothiazine ● Side effect: tardive dyskinesia

Antipsychotics Risperidone ● Selective D2/5-HT2A receptor antagonist

● Used to treat bipolar disorder
● Side effect: tardive dyskinesia

Clozapine ● Selective dopamine and serotonin receptor antagonist, leading to less side effects
● Used to treat schizophrenia

Sertraline ● Selectively inhibit the reuptake of serotonin

● Increases risk of bleeding due to the need for serotonin for platelet function
Fluoxetine ● Anticholinergic side effects: xerostomia, dry eyes, blurry vision, and constipation

Antidepressants SSRIs Citalopram

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Trazodone

Central nervous system and sedation continued

Class Drug Key facts

Tricyclic SNRIs Amitriptyline ● Serotonin and norepinephrine reuptake inhibitor, allows for increased availability of
monoamines
Imipramine ● Anticholinergic side effects: xerostomia and dry eyes

Antidepressants (cont.) MAOIs Phenelzine ● Inhibit monoamine neurotransmitter degradation

Atypical ● Norepinephrine and dopamine reuptake inhibitor

Bupropion ● Used for smoking cessation
● May cause depression symptoms to worse
● Contraindicated for patients with epilepsy

Alprazolam ● GABA receptor agonists

● Increases chloride ion influx to slow down CNS
Midazolam ● Short-acting: alprazolam, midazolam, triazolam
Benzodiazepines ● Intermediate acting: lorazepam
Triazolam ● Long acting: diazepam
● Midazolam can be used to achieve conscious IV sedation
Lorazepam ● Diazepam produces active metabolites

Diazepam

GABA receptor antagonist ● Used as a benzodiazepine reversal

Flumazenil ● Benzodiazepine overdose signs: shallow breathing, rapid heart rate, and slurred
speech

● GABA receptor agonist

● Increases chloride ion influx to slow down CNS
Barbiturates ● Fast onset, short duration of action
● Overdose causes respiratory depression
Thiopental ● Contraindications: acute intermittent porphyria

Phenytoin ● Binds to voltage-gated sodium channels to prevent release of neurotransmitters

● Used to treat epilepsy
● Side effect: gingival hyperplasia

Anticonvulsants Gabapentin ● Binds to voltage-gated calcium channels to prevent release of neurotransmitters

● Used to treat epilepsy and trigeminal neuralgia
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Carbamazepine ● Binds to voltage-gated sodium channels to prevent release of neurotransmitters
● Used to treat epilepsy and trigeminal neuralgia

Stimulant Methamphetamine ● Activates the sympathetic nervous system

● Can cause dilation of pupils (i.e., mydriasis), hypertension, hyperventilation, dry
mouth

Antifungals

Drug Key facts

Azoles ● Inhibit cytochrome P450 to prevent synthesis or ergosterols

Fluconazole ● Inhibit cell membrane synthesis
Ketoconazole ● May increase INR if taken with warfarin
Clotrimazole ● Used to treat candadiasis

Nystatin ● Binds to ergosterol on cell membrane leading to pore formation and cell death
● Used to treat candadiasis

Amphotericin B ● Binds to ergosterol on cell membrane leading to pore formation and cell death
● Reserved for invasive, systemic fungal infections
● Side effects: edema, shortness of breath, hypotension, and hypokalemia

Antivirals

Drug Key facts

Acyclovir ● Inhibits viral DNA polymerase

● Acts as a nucleoside analog (guanosine)
● Used to treat herpes infections

Monoclonal antibody

Drug Key facts

Denosumab ● Acts as a RANK-L inhibitor, preventing osteoclast differentiation and survival

● Used to treat osteoporosis and bone cancers
● Can contribute to medication-related osteonecrosis of the jaw (MRONJ)
○ Antiresorptive effects diminish 6 months after discontinuation

Adalimumab ● TNF-alpha inhibitor, inhibiting inflammatory cytokines

● Used to treat rheumatoid arthritis

Miscellaneous drugs

Type Drug Key facts

Prednisone ● Corticosteroid used to treat inflammatory conditions

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● Common side effects: weight gain, hyperglycemia, hypertension, altered mood, and
sleep disturbances

Dexamethasone ● Corticosteroid used to treat inflammatory conditions

Immune
Methotrexate ● Interferes with DNA synthesis for chemotherapy and immunosuppression
● Used to treat Crohn’s disease, cancer, rheumatoid arthritis, and psoriasis
● May impair kidney function, necessitating creatinine clearance test
● Side effects: fever, vomiting, diarrhea, thrombocytopenia, anemia, gastrointestinal
disturbance, hepatotoxicity, and oral ulcerations

Cyclosporin ● Calcineurin inhibitor, causing immunosuppression

● Prevents organ rejection in transplant patients
● Side effect: gingival hyperplasia

Miscellaneous drugs

Type Drug Key facts

Levothyroxine ● Used to treat hypothyroidism

● Synthetic form of thyroxine (T4)
Thyroid ● Side effects: heat intolerance, sweating, anxiety, mood swings, and irritability

Methimazole ● Used to treat hyperthyroidism

● Inhibits thyroid peroxidase (TPO) to prevent synthesis of T3 and T4

Omeprazole ● Pro-drug
Gastrointestinal ● Proton pump inhibitor (PPI) that decreases gastric acid secretions
● Irreversibly inactivates H+/K+/ATPase
● Used in peptic ulcer disease and gastroesophageal reflux disease (GERD)
● Discontinuing treatment can lead to rebound acid hypersecretion and cause
esophageal ulcers

Herbal St. John’s Wort ● Used to treat depression

● Increases the availability of serotonin
● In combination with other drugs that increase levels of serotonin, patients are at risk
for serotonin syndrome
○ Other drugs include tramadol, SSRIs, MOIs, and opioids

Xanthine oxidase inhibitor Allopurinol ● Used to treat gout

● Decreases xanthine oxidase enzyme to decrease production of uric acid

Smoking cessation aid Varenicline ● Used to aid in smoking cessation

● Prevents withdrawal symptoms